Edward J. Pavlik

Risk of malignancy in unilocular ovarian cystic tumors less than 10 centimeters in diameter

OBJECTIVE To determine the natural history and to estimate the risk of malignancy of unilocular ovarian cystic tumors less than 10 cm in diameter followed conservatively by transvaginal ultrasound. METHODS From 1987 to 2002, 15,106 asymptomatic women at least 50 years old entered the University of Kentuckys Ovarian Cancer Screening Program and underwent initial transvaginal ultrasonography. If the screen revealed nothing abnormal, women were asked to repeat transvaginal ultrasonography yearly. If the screen revealed abnormalities, transvaginal ultrasonography was repeated in 4 to 6 weeks, along with Doppler flow ultrasonography and CA 125 testing. RESULTS Of the 15,106 women at least 50 years old, 2763 women (18%) were diagnosed with 3259 unilocular ovarian cysts. A total of 2261 (69.4%) of these cysts resolved spontaneously, 537 (16.5%) developed a septum, 189 (5.8%) developed a solid area, and 220 (6.8%) persisted as a unilocular lesion. During this time, 27 women received a diagnosis of ovarian cancer, and ten had been previously diagnosed with simple ovarian cysts. All ten of these women, however, developed another morphologic abnormality, experienced resolution of the cyst before developing cancer, or developed cancer in the contralateral ovary. No woman with an isolated unilocular cystic ovarian tumor has developed ovarian cancer in this population. CONCLUSION The risk of malignancy in unilocular ovarian cystic tumors less than 10 cm in diameter in women 50 years old or older is extremely low. The majority will resolve spontaneously and can be followed conservatively with serial transvaginal ultrasonography.

Transvaginal sonography as a screening method for ovarian cancer a report of the first 1000 cases screened

From November 1987 to April 1989, 1000 women 40 years or older underwent screening vaginal sonography at the University of Kentucky Medical Center (Lexington, KY). Patients included in this investigation were all asymptomatic and had no known pelvic abnormalities. Each ovary was measured in three planes and ovarian volume was calculated using the prolate ellipsoid formula. The upper limit of normal for ovarian volume was 18 cm3 in premenopausal women and 8 cm3 in postmenopausal women. In patients with normal scans, mean ovarian volumes decreased from 6.8 cm3 to 3.0 cm3 with menopause. Thirtyone patients (3.1%) had abnormal vaginal sonograms and 24 underwent exploratory laparotomy. All patients undergoing surgery had ovarian or fallopian tube tumors with dimensions identical to those predicted by ultrasound. Histologic diagnoses of these tumors included the following: adenocarcinoma, one; serous cystadenoma, eight; endometrioma, six; and cystic teratomas, two. Vaginal sonography was performed easily and without complications, and was well accepted by patients. All patients with normal sonograms have been rescreened annually and none have subsequently developed ovarian cancer. Further clinical trials to determine the efficacy of vaginal sonography as a screening method for ovarian cancer are indicated.

Hydroxylapatite “batch” assay for estrogen receptors: Increased sensitivity over present receptor assays

Abstract A “batch” hydroxylapatite procedure for the adsorption of the uterine estradiol 17β-receptor complex is described. Characterization with respect to washing efficiency, binding specificity, competition, adsorption time, sensitivity and stability against increasing KC1 ionic strength were included. Equilibrium parameters obtained by Scatchard analysis were compared to the range of values found in the literature. K ta and receptor site concentration per uterus obtained by this “batch” technique were found to be well within the range described by these reported values. This technique is particularly advantageous due to its wide range of operational sensitivity (capable of detecting specific estradiol-17β binding to a cytosol fraction containing from 5 to 500 μg protein per 225 μl). The assay is run entirely at low temperature (0–2°C). In addition this technique depends on a homogeneous insoluble chemical, hydroxylapatite, which can be obtained in analytical grade quantities of uniform particle size, shows little affinity for free steroid, can be readily packed or resuspended, and appears independent of changes in concentrations of KC1 up to 2500 mM. Additional considerations include the effect of temperature during assay, the importance of empirical correction for non-specific binding, the contributions of binding information on the calculation of equilibrium parameters and statistical evaluation of random error and assay repeatability.

Ovarian cancer screening in asymptomatic postmenopausal women by transvaginal sonography

From November 1987 to January 1991, 1300 postmenopausal women underwent screening with transvaginal sonography (TVS). Women eligible for screening were all asymptomatic with no known ovarian tumors. Ovarian volume was calculated using the prolate ellipsoid formula, and a value in excess of 8.0 cm3 was considered abnormal. Ovarian abnormalities were detected in 33 women (2.5%), and 27 underwent exploratory laparotomy. Ovarian tumors were noted in all 27 patients, including 2 primary carcinomas and 14 serous cystadenomas. The two women with ovarian carcinomas had normal results of pelvic examinations and normal serum CA‐125 levels. Both women had Stage I disease, and are alive and well after conventional therapy. TVS was time efficient, easy to perform, and well‐accepted by patients. Currently, there are more than 3000 patient years of follow‐up in the screened population, and there have been no deaths due to ovarian cancer. A multi‐institutional trial to determine the efficacy of TVS as a screening method for ovarian cancer is indicated.

The prognostic significance of lymph-vascular space invasion in stage I endometrial cancer.

Surgical specimens from 111 patients with Stage I endometrial cancer were reviewed for the presence of lymph‐vascular space invasion by tumor cells. Lymph‐vascular space invasion was noted in 16 cases, and occurred most frequently in poorly differentiated tumors with deep myometrial penetration. Tumor recurrence developed in 44% of patients whose tumors demonstrated lymph‐vascular space invasion as opposed to only 2% of patients without this finding (p < 0.001). Of seven patients with lymph‐vascular space invasion who experienced tumor recurrence, five developed extra‐pelvic metastases. Discriminant function analysis of these data revealed a statistically significant correlation between lymph‐vascular space invasion and tumor recurrence, independent of histologic differentiation of myometrial penetration. These findings suggest that lymph‐vascular space invasion by tumor cells is an important prognostic variable in Stage I endometrial cancer which should be considered in treatment planning.

Preoperative differentiation of malignant from benign ovarian tumors: the efficacy of morphology indexing and Doppler flow sonography

OBJECTIVE The goal of this study was to determine the efficacy of morphology indexing and Doppler flow sonography as methods to predict risk of malignancy in sonographically confirmed ovarian tumors. METHODS Risk of malignancy was assessed preoperatively in 442 ovarian tumors using a new morphology index (MI) based on tumor volume and wall structure. Each tumor was assigned a score of 0 to 10 based on increasing volume and morphologic complexity. Doppler flow studies were performed on 371 of these tumors. Following morphologic evaluation, all ovarian tumors were removed surgically. RESULTS Of 315 tumors with a MI < 5 there was only 1 malignancy (a stage IA granulosa cell tumor <2 cm in diameter) whereas there were 52 malignancies in 127 tumors with a MI > or = 5. Stage of disease was as follows: stage I, 33; stage II, 6; stage III, 14. Risk of malignancy was related directly to MI score, varying from 0.3% in tumors with a MI < 5 to 84% in tumors with a MI > or = 8. A MI value of > or = 5 as indicative of malignancy was associated with the following statistical parameters: sensitivity 0.981, specificity 0.808, PPV 0.409, NPV 0.997. A pulsatility index (PI) < 1.0 as indicative of malignancy was associated with: sensitivity 0.528, specificity 0.776, PPV 0.288, NPV 0.906. A resistive index (RI) < 0.4 as indicative of malignancy was associated with: sensitivity 0.222, specificity 0.867, PPV 0.222, and NPV 0.867. The addition of Doppler flow indices to MI did not improve the accuracy of predicting malignancy. Likewise, the absence or presence of ovarian tumor blood flow was not reliable as a means to differentiate benign from malignant ovarian tumors. CONCLUSIONS Morphology indexing is an accurate and inexpensive method of differentiating benign from malignant ovarian tumors, and can be a valuable adjunct in treatment planning. The addition of Doppler flow studies did not improve diagnostic accuracy of MI.

Small cell carcinoma of the uterine cervix

From 1962 to 1985, 2201 patients with invasive cervical cancer were staged, evaluated, and treated at the University of Kentucky Medical Center. After a thorough evaluation, 25 cases (1.1%) fulfilled the histologic criteria for small cell cancer defined by Reagan and coworkers. These patients were computermatched for age, disease stage, and lesion size to 25 patients with large cell nonkeratinizing cancer and 25 patients with keratinizing squamous cell cancer. Morphometric analyses of nuclear size and maximum nuclear diameter were performed on all cases without knowledge of cell type. Small cell cancers were characterized by a nuclear area of 160 μ2 or less and a maximum nuclear diameter of 16.2 μ, which was significantly lower than that for large cell tumors. Thirty‐three percent of the small cell carcinomas stained positively for the neuroendocrine markers (neuron‐specific enolase [NSE] and chromogranin [CGR]), whereas the remainder contained only epithelial markers such as cytokeratin (CYK) and epithelial membrane antigen (EMA). Small cell cancers were associated with a high frequency of lymph‐vascular space invasion and a diminished lymphoplasmacytic response. Patients with small cell cancer had a significantly higher recurrence rate, particularly to extrapelvic sites, than the matched patients with large cell cancers, and their survival was lower. Clinical trials to determine the efficacy of adjuvant chemotherapy in the treatment of small cell cervical cancer are needed.

Stage I serous papillary carcinoma of the endometrium.

From 1973 to 1987, 16 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I serous papillary endometrial carcinoma were evaluated and treated at the University of Kentucky Medical Center (Lexington, KY). All patients were 60 years of age or older, and all were postmenopausal. Patients were treated with total abdominal hysterectomy, bilateral salpingo‐oophorectomy, and paraaortic lymph node sampling, and 38% were noted to have more extensive disease than appreciated clinically. Nine patients were given adjuvant postoperative radiation. Seven patients (44%) developed recurrent cancer with liver, lung, and upper abdomen being the most common sites of spread. Prognosis was most directly related to the presence of lymph vascular space invasion and the depth of myometrial penetration. No patient with serous papillary carcinoma confined to the endometriunt developed recurrent cancer. In contrast, the recurrence rate of patients having myometrial invasion was 70% (P < 0.03). Hormonal therapy was of limited value in the treatment of recurrent disease. This data suggests the need for adjuvant systemic therapy in the treatment of patients with Stage I serous papillary carcinoma of the endometrium who have myometrial invasion.

Long-term Survival of Women With Epithelial Ovarian Cancer Detected by Ultrasonographic Screening

OBJECTIVE: To estimate the effect of ultrasonographic screening on stage at detection and long-term disease-specific survival of women with epithelial ovarian cancer. METHODS: Eligibility included all asymptomatic women aged 50 years and older and women aged 25 years and older with a documented family history of ovarian cancer. From 1987 to 2011, 37,293 women received annual ultrasonographic screening. Women with abnormal screens underwent tumor morphology indexing, serum biomarker analysis, and surgery. RESULTS: Forty-seven invasive epithelial ovarian cancers and 15 epithelial ovarian tumors of low malignant potential were detected. No women with low malignant potential tumors experienced recurrent disease. Stage distribution for invasive epithelial cancers was: stage I, 22 (47%); stage II, 11 (23%); stage III, 14 (30%), and stage IV, 0 (0%). Follow-up varied from 2 months to 20.1 years (mean, 5.8 years). The 5-year survival rate for invasive epithelial ovarian cancers detected by screening was: stage I, 95%±4.8%; stage II, 77.1%±14.5%; and stage III, 76.2%±12.1%. The 5-year survival rate for all women with invasive epithelial ovarian cancer detected by screening as well as interval cancers was 74.8%±6.6% compared with 53.7%±2.3% for unscreened women with ovarian cancer from the same institution treated by the same surgical and chemotherapeutic protocols (P<.001). CONCLUSION: Annual ultrasonographic screening of asymptomatic women achieved increased detection of early-stage ovarian cancer cases and an increase in 5-year disease-specific survival rate for women with ovarian cancer. LEVEL OF EVIDENCE: II

Predicting risk of malignancy in adnexal masses.

OBJECTIVE: To estimate the accuracy of preoperative ultrasonography, serum CA 125, and patient demographics as a means of predicting risk of malignancy in women with a ultrasonographically confirmed adnexal mass. METHODS: Tumor morphology derived from ultrasonographic images, tumor size, tumor bilaterality, serum CA 125, and patient demographics were evaluated preoperatively in 395 patients undergoing surgery from 2001 to 2008. Tumor morphology was classified as complex, solid, or cystic. Preoperative findings were compared with tumor histologic findings at the time of surgery. Multivariable classification and regression tree analysis were used to identify a group of patients at high risk of ovarian malignancy. RESULTS: One hundred eighteen patients had ovarian cancer, 13 patients had ovarian tumors of borderline malignancy, and 264 had benign ovarian tumors. Multivariable classification and regression tree analysis defined women at high risk of ovarian malignancy as those with an adnexal mass having complex or solid morphology and a serum CA 125 value greater than 35 units/mL. This definition had a positive predictive value of 84.7% and a negative predictive value of 92.4% and correctly identified 77.3% of patients with stage I and stage II ovarian cancer and 98.6% of patients with stage III and stage IV ovarian cancer. CONCLUSION: Patients with solid or complex ovarian tumors and an elevated serum CA 125 level (greater than 35 units/mL) are at high risk of ovarian malignancy. LEVEL OF EVIDENCE: II