Frank R. Reale

Profile of women 45 years of age and younger with endometrial cancer

Objective The clinical characteristics and outcomes of endometrial cancer patients 45 years of age and younger were compared with those of patients older than 45 years of age. Methods We performed a cross-sectional study of 301 consecutive endometrial cancer patients referred to our center from 1989 to 1994. Of the 289 patients eligible for study, 40 were 45 years of age or younger (group A) and 249 were older than 45 years of age (group B). Results The majority of patients in both groups presented with stage I disease. Of the women with stage I disease, patients in group A were more likely than those in group B to have low-grade disease localized to the endometrium (P < .001; relative prevalence 3.39; confidence interval [CI] 1.88,6.12). However, the distribution of stages I to IV overall was the same for the two groups (P = .269). Although univariate analysis revealed that 11% of the patients in group A and 2% in group B had synchronous ovarian malignancies (P = .007; relative prevalence 5.42; CI 1.39, 21.14), multivariate logistic regression found that nulliparity, not age, was an independent risk factor for synchronous ovarian malignancy (P = .017; relative prevalence 6.15; CI 1.52, 25.61). There were no statistically significant differences by age in the prevalence of high-risk endometrial histology (serous and clear cell carcinoma) or in survival. Conclusion The overall distribution of tumor stage and survival were the same for the younger and older women; this finding contradicts previous reports that suggest that young women with endometrial cancer are at lower risk. Additionally, nulliparity, which occurs with a higher prevalence in younger women who develop endometrial cancer, is associated statistically with the development of synchronous ovarian malignancies.

Accuracy of frozen-section (intraoperative consultation) diagnosis of ovarian tumors.

OBJECTIVE Frozen-section evaluation of ovarian tumors can be used to establish a histopathologic diagnosis and guide the surgeon to perform the appropriate surgical procedure. A retrospective study was conducted to determine the accuracy of frozen-section diagnosis of ovarian tumors. STUDY DESIGN Frozen- and permanent-section diagnoses were divided into three categories (benign, borderline, and malignant). The sensitivity, specificity and predictive values, and 95% percent confidence intervals of each frozen-section diagnosis were determined. RESULTS Three hundred eighty-three ovarian tumors that underwent frozen-section evaluation between June 1983 and June 1993 were studied. The final histopathologic diagnosis was 61.1% benign, 7.6% borderline, and 31.3% malignant. Frozen section was accurate in 92.7% of all cases and inaccurate in 7.3%. The sensitivity for malignant tumors was 92.5% tumors (95% confidence intervals 87.7% to 97.2%), the sensitivity for borderline tumors was 44.8% (95% confidence interval 26.4% to 63.2%). The specificity for benign tumors was 92.0% (95% confidence interval 88.6% to 95.4%) but increased to 97.9% (95% confidence interval 96.1% to 99.7%) if borderline tumors were excluded. The positive predictive value and 95% confidence intervals were 92.0% (88.6% to 95.4%) for benign tumors, 65% (43.6% to 86.5%) for borderline tumors, and 99.1% (97.3% to 100.0%) for malignant tumors. Thirteen of 16 (81%) ovarian lymphomas and tumors metastatic to the ovary were correctly identified by intraoperative frozen section. The sensitivity for borderline serous tumors was 64.3% and for borderline mucinous tumors 30.8% (p = 0.48). CONCLUSION With the exception of borderline tumors, the sensitivity and specificity of frozen-section diagnosis of ovarian tumors are high. Borderline tumors remain difficult to accurately diagnose at frozen section because of the extensive sampling required. Frozen-section diagnoses have important implications regarding the type and extent of surgery performed at the initial operation.

Radiation therapy for surgically proven para-aortic node metastasis in endometrial carcinoma

The impact of para-aortic field radiation therapy upon survival was studied among 26 patients with para-aortic nodal metastases from carcinoma of the endometrium. Seventeen of these 26 patients received postoperative radiation therapy to the para-aortic field as a part of their primary therapy. Sixteen of the 17 also received adjuvant hormonal therapy. Nine of 17 patients (53%) are alive without evidence of disease (18-55 months) with a median survival time of 27 months. Of the remaining eight patients, six (35%) died of endometrial cancer at 6-38 months, with a median survival time of 14.5 months. Five of these patients had distant disease. Two of the 17 patients (12%) died of intestinal obstruction felt to be secondary to radiation enteritis, one of whom was disease free. No difference in survival was detected in patients treated with radiation therapy with microscopic versus macroscopic nodal involvement. Of the nine patients who did not receive para-aortic radiation, eight were treated with hormonal therapy (n = 6) or chemotherapy (n = 2). Seven patients died of disease from 5-28 months, with a median survival time of 13 months. One patient is alive at 12 months. Survival in the 17 patients treated with para-aortic radiation was better than the eight patients not treated with para-aortic radiation (p = 0.004). This survival difference remained significant for patients with microscopic but not macroscopic nodal disease. Para-aortic field radiation appears to improve survival, but has a significant complication rate, and should be reserved for patients with histologic evidence of para-aortic metastases.

Accuracy of frozen-section diagnosis at surgery in clinical stage I and II endometrial carcinoma.

OBJECTIVES: The purpose of our study was to determine if frozen section accurately identifies certain poor prognostic pathologic factors in endometrial carcinoma that are known to be associated with pelvic and paraaortic nodal metastasis, including deep myometrial invasion, poorly differentiated tumor, cervical invasion, adnexal involvement, and poor histologic type. STUDY DESIGN: The frozen-section pathologic results of 199 patients with clinical stage I and II endometrial cancer were retrospectively compared with permanent-section pathologic findings. RESULTS: The depth of myometrial invasion (superficial third vs deep two thirds) was accurately determined by frozen-section diagnosis at surgery in 181 of 199 cases (91.0%). The sensitivity of frozen-section diagnosis for deep myometrial invasion was 82.7%, and the specificity was 89.1%. The following tumor characteristics were accurately determined on frozen section at surgery: poorly differentiated tumor (95.0%), cervical invasion (94.0%), adnexal involvement (98.5%), and histologic type (94.0%). Frozen section underestimated deep myometrial invasion in 17.3% of patients with this characteristic and poorly differentiated tumor in 26.3% when compared with permanent-section diagnosis. In patients with unfavorable histologic types, papillary serous and adenosquamous carcinomas were the most commonly misdiagnosed histologic types by frozen section at surgery (70.6%). However, when the preoperative curettage pathologic findings were included, these inaccuracies in tumor grade and histologic type dropped to 15.8% and 35.3%, respectively. Only 13 of 199 patients (6.5%) were not correctly identified by frozen section at surgery as having poor prognostic pathologic features. CONCLUSION: Frozen section diagnosis at surgery is an important procedure that enables the surgeon to identify patients at high risk for pelvic and paraaortic nodal metastasis.

Primary radiation therapy for endometrial carcinoma: A case controlled study

PURPOSE Primary radiation therapy is generally considered inferior to a surgical approach for patients with endometrial carcinoma and is reserved for patients with a high operative risk. These patients are usually elderly, have multiple medical problems and frequently die of intercurrent disease. To evaluate the efficacy of primary radiation therapy a case controlled analysis comparing corrected survival of patients treated with primary radiation to patients treated with surgical therapy with or without radiation therapy was performed. METHODS AND MATERIALS Sixty-four patients treated with primary radiation therapy were retrospectively studied. A Kaplan-Meier product limit survival analysis was used to estimate survival among patients treated with primary radiation therapy. A case control study matched by clinical stage, tumor grade, and time of diagnosis was performed. The Mantel-Cox statistic was used to evaluated the equality of the survival curves. RESULTS Primary radiation therapy was used to treat 9.0% of the patients with endometrial carcinoma during the study period. Cardiovascular disease, diabetes, age greater than 80 and morbid obesity were the most common indications. Ninety percent of patients had either Stage I or II disease. Forty-eight of the 64 patients (75%) completed treatment which included both teletherapy and brachytherapy. Ten patients received brachytherapy only. Twelve complications, both acute and chronic, occurred in eleven patients (17%). Intercurrent disease accounted for 13 of the 36 (36%) of the deaths. Clinical stage of disease and histologic grade of the tumor were significant predictors of survival, p = 0.0001 and p = 0.013, respectively. The case controlled study of Stage I and II patients treated by primary radiation therapy matched to surgically treated controls showed no statistical difference in survival. Dilatation and curettage after the completion of radiation therapy was predictive of local control, p = 0.003. CONCLUSION Although surgery followed by tailored radiation therapy has become widely accepted therapy for Stage I and II endometrial carcinoma, even in patients who are a poor operative risk, the survival with primary radiation therapy is not statistically different.

Adenoid cystic carcinoma of the vulva: A radiosensitive tumor

A patient with adenoid cystic carcinoma of the vulva treated primarily with surgery developed multiple local and distant recurrences in which radiotherapy repeatedly achieved complete local control. The patient survived 11.5 years from original diagnosis and 9.5 years from primary recurrence before dying of pulmonary metastases. Adenoid cystic carcinoma of the vulva is a highly radiosensitive tumor. Adjuvant radiotherapy should be considered as a part of the primary therapy, to improve local control, on the basis of the much larger experience with adjuvant radiotherapy with this tumor in the head and neck. Also on the basis of head and neck tumors, it is unlikely that radiotherapy will affect survival.

High-dose, short-duration cisplatin/doxorubicin combination chemotherapy for advanced ovarian epithelial cancer

Sixty‐one patients with epithelial ovarian cancer were treated with intensive high‐dose, short‐course chemotherapy that consisted of cisplatin (120 mg/m2) and doxorubicin (70 mg/m2) every 3 weeks for four cycles. Patients in complete clinical remission were offered second‐look laparotomy (SLL). Patients with minimal or no residual disease at SLL were randomized to either cyclophosphamide (1000 mg/m2 every 21 days for six cycles) or whole‐abdominal radiation therapy. All patients completed therapy with a median leukocyte nadir 1.3/μl and platelet nadir of 90/μl. Forty‐five patients (74%) had a complete clinical response. Results of twenty‐two of 36 second‐look procedures (64%) showed no evidence of disease (NED). After SLL, 19 patients received six courses of cyclophosphamide and 16 patients received whole‐abdominal radiation. Nine patient who refused SLL and one patient with negative SLL findings refused additional treatment. The median survival time for all patients was 51.3 months. High‐dose intensive chemotherapy regimens have high response rates, but survival needs to be compared with traditional low‐dose regimens. Although high‐dose cisplatin and doxorubicin were myelosuppressive, the resulting complications were manageable. There was no significant difference between the mean survival times of patients receiving Cytoxan, abdominal radiation, or no treatment as second‐line therapy.

Preoperative CA-125 levels predict poor prognostic pathologic features in early stage, FIGO grade 1 and 2 endometrial adenocarcinoma.

Preoperative CA-125 levels were studied in patients with favorable histology and early clinical stage endometrial adenocarcinoma to determine its ability to predict the presence of poor pathologic prognostic features on final pathology. One hundred and one patients with clinical stage I (N = 65) or II (N = 19) or diagnosed by endometrial curettage (EMC) only (N-17) with grade 1 or 2 endometrial adenocarcinoma without gross cervical involvement underwent preoperative CA-125 levels. Final pathology was reviewed for five poor prognostic pathologic features: FIGO grade 3 histology, unfavorable histologic type (sarcoma, clear cell, or papillary serous), invasion into the outer third of the myometrium, extension to the cervix, and extra-uterine metastases. Fifteen patients (14.9%) had CA-125 levels greater than 30 IU ml−1. Of these 15 patients, 12 had one or more of the five poor prognostic pathologic features (positive predictive value 80.0%, specificity 95.8%, P < 0.0001). However, since 30 of the 101 patients were found to have one or more of these poor prognostic pathologic features the sensitivity was only 40.0%. When clinical stage I patients were analyzed separately three patients (4.6%) had CA-125 levels greater than 30 IU ml −1 (positive predictive value 100%, specificity of 100%, sensitivity of 21.4%, P = 0.008). For patients with clinical stage II carcinoma, CA-125 was not predictive of pathologic findings except as a negative predictor of disease in a subgroup of patients whose endocervical curettage (ECC) demonstrated carcinoma unattached to endocervical tissue. In patients diagnosed by EMC only, an elevated CA-125 level was associated with poor prognostic pathologic features (P = 0.001). An elevated preoperative CA-125 reliably predicts advanced disease even in patients with apparently favorable histology and clinical stage, however the sensitivity of this method remains low.

False-positive elevation of CA-125 in papillary serous carcinoma of the endometrium treated with postoperative whole abdominal radiation

Two patients with Stage I papillary serous carcinoma of the endometrium treated with postoperative whole abdominal radiation developed elevated CA-125 levels. In neither patient was evidence of recurrent disease identified. Hepatic veno-occlusive disease, a known complication of whole abdominal radiation and certain chemotherapy regimens, was confirmed by liver biopsy in both cases. CA-125 levels may not be reflective of disease status in this setting.

Accuracy of frozen section diagnosis at surgery in clinical stage I and II endometrial carcinoma

OBJECTIVES The purpose of our study was to determine if frozen section accurately identifies certain poor prognostic pathologic factors in endometrial carcinoma that are known to be associated with pelvic and paraaortic nodal metastasis, including deep myometrial invasion, poorly differentiated tumor, cervical invasion, adnexal involvement, and poor histologic type. STUDY DESIGN The frozen-section pathologic results of 199 patients with clinical stage I and II endometrial cancer were retrospectively compared with permanent-section pathologic findings. RESULTS The depth of myometrial invasion (superficial third vs deep two thirds) was accurately determined by frozen-section diagnosis at surgery in 181 of 199 cases (91.0%). The sensitivity of frozen-section diagnosis for deep myometrial invasion was 82.7%, and the specificity was 89.1%. The following tumor characteristics were accurately determined on frozen section at surgery: poorly differentiated tumor (95.0%), cervical invasion (94.0%), adnexal involvement (98.5%), and histologic type (94.0%). Frozen section underestimated deep myometrial invasion in 17.3% of patients with this characteristic and poorly differentiated tumor in 26.3% when compared with permanent-section diagnosis. In patients with unfavorable histologic types, papillary serous and adenosquamous carcinomas were the most commonly misdiagnosed histologic types by frozen section at surgery (70.6%). However, when the preoperative curettage pathologic findings were included, these inaccuracies in tumor grade and histologic type dropped to 15.8% and 35.3%, respectively. Only 13 of 199 patients (6.5%) were not correctly identified by frozen section at surgery as having poor prognostic pathologic features. CONCLUSION Frozen section diagnosis at surgery is an important procedure that enables the surgeon to identify patients at high risk for pelvic and paraaortic nodal metastasis.