The role of ultrasound in detecting early ovarian carcinoma:the National Ovarian Cancer Early Detection Program

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1 The role of ultrasound in detecting early ovarian carcinoma:the National Ovarian Cancer Early Detection Program D.A. Fishman 1,2,3 L. Cohen 1,3, K. Bozorgi 1,2,3 R.Tamura 1,3 and J.R. Lurain 1,3 Ovarian cancer is the leading cause of death from gynecologic malignancies. 1 Department of Obstetrics and Gynecology 2 Section of Gynecologic Oncology 3 National Ovarian Cancer Early Detection Program, Northwestern University Medical School, Chicago IL, U.S.A. In industrialized countries, ovarian cancer is the leading cause of death from gynecologic malignancies and is the fifth most common female malignancy. The incidence of ovarian cancer has been steadily increasing over the past ten years, now with an overall lifetime risk of 1.8%. The annual incidence for women over 45 years is 40/ , increasing to 50/ at age [1]. This year, in the United States alone, approximately women will be newly diagnosed with ovarian cancer and approximately will die from this disease. Due to our inability to detect cancer when it is confined to the ovary (Stage I disease), the majority of women (75%) are diagnosed when there is already widespread metastatic dissemination throughout the abdominal cavity (Stage III/IV). Epidemiologic factors associated with ovarian cancer include nulliparity, a personal history of breast cancer, the number of affected first degree relative(s) with ovarian or breast cancer, a family history of a BRCA mutation, or membership within a recognized inherited malignancy syndrome. Approximately 5% of all epithelial ovarian carcinomas are attributable to the inheritance of highly penetrant mutations in the breast/ovarian cancer susceptibility genes BRCA-1 and -2. Together, these women at increased risk form a cohort who might benefit from a combination of non-invasive and minimally invasive tests to detect early stage ovarian cancer [2]. PHYSICAL EXAMINATION A comprehensive gynecologic examination includes the bimanual and rectovaginal palpation of the female internal reproductive organs, and distal colon, for any evidence of structural abnormalities. Physical examination of the ovaries can be quite limited, due to patient discomfort and obesity, as well as their anatomic location deep within the pelvis surrounded by the small and large intestine. Extensive spread of ovarian carcinoma is frequently associated with symptoms such as bloating, early satiety, abdominal discomfort, or changes in bowel or bladder habits. When ovarian cancer is confined to the ovaries the symptoms, if present, are usually non-specific, so that they are often dismissed by the patient and/or healthcare provider. An even greater cause for concern is that many women with late stage disease may have minimal symptoms, which are usually attributed to gastrointestinal rather than gynecologic etiology. It is our current inability to accurately detect early stage ovarian cancer that results in women receiving more extensive surgical intervention and chemotherapy, and enduring increased morbidity and mortality. Overall 5-year survival rates for women with Stage I epithelial ovarian cancer (EOC) approach 90%, compared to 12% for advancedstage disease (III/IV). Thus, the challenge is to identify and develop highly sensitive and specific methods that can be applied to population-based screening for the detection of early-stage ovarian cancer. ULTRASOUND EXAMINATION Ultrasound has demonstrated utility in detecting ovarian cancer in asymptomatic women, but its value for the detection of early stage disease is uncertain. Bell et al. in a literature review of prospective ovarian cancer screening programs found that among high-risk women (women with a family history of ovarian cancer or a personal history of breast cancer) the sensitivity for detection of Stage I disease was 25% ( 95% CI 3-65%) while the sensitivity for low-risk women was 67 % (95% CI 22-96) [3]. This less-than-ideal sensitivity is not unexpected, because in many Stage I ovarian cancers, the ovaries are neither enlarged nor morphologically abnormal. In addition, the use of color or Power Doppler imaging has not been shown to add significantly to the diagnosis of early-stage disease. The low annual prevalence of ovarian cancer within the general population, the large number of women who must therefore be screened to identify 42 MEDICA MUNDI 45/2 July 2001

a single ovarian cancer, and the poor sensitivity of the test for Stage I disease make routine use of ultrasound for detection of ovarian cancer impractical. Van Nagell et al.

Women under 50 years of age who were deemed high risk and those over age 50 who were both low-risk and high-risk were candidates for inclusion.

Four women were diagnosed with ovarian cancer within one year of a negative ultrasound exam, yielding a sensitivity of 81% (17/21).

Of the Stage I tumors, 3 were abnormally enlarged as appreciated on clinical examination (2 borderline, 1 EOC).

2 a single ovarian cancer, and the poor sensitivity of the test for Stage I disease make routine use of ultrasound for detection of ovarian cancer impractical. Van Nagell et al. reviewed scans performed among women during a twelve-year period. Women under 50 years of age who were deemed high risk and those over age 50 who were both low-risk and high-risk were candidates for inclusion. Ultrasound examinations were performed transvaginally on an annual basis [4]. Ultrasound detected ovarian cancer in 17 women: 11 EOC, 3 granulosa cell tumors, and 3 borderline ovarian tumors. Four women were diagnosed with ovarian cancer within one year of a negative ultrasound exam, yielding a sensitivity of 81% (17/21). A total of 11 Stage I tumors were identified: 5 EOC, 3 granulosa cell tumors, and 3 borderline tumors yielding a sensitivity of 52% (11/21) for Stage I disease. Of the Stage I tumors, 3 were abnormally enlarged as appreciated on clinical examination (2 borderline, 1 EOC). It is noteworthy that only 1 of 15 malignancies (excluding borderline tumors and palpable tumors) developed within the entire study population under age 50. If one excludes granulosa cell and borderline tumors that are usually detected when confined to the ovary (Stage I), the sensitivity for EOC was approximately 31% [5]. It is a clinical reality that a negative ultrasound examination may be falsely reassuring, since women infrequently develop advanced stage ovarian cancer within 6-12 months of a normal scan. A major limitation of transvaginal architectural screening is that ovarian cancers can arise from normal-sized ovaries, of apparently normal structure, observed using advanced diagnostic imaging technology. Color and Power Doppler Imaging Bourne et al. evaluated high-risk women with a family history of ovarian cancer, and suggested that color Doppler analysis had value as a secondary test to decrease unnecessary operative interventions [6,7]. An initial report by Kurjak et al. found that a color Doppler resistive index (RI) of < 0.4 had a sensitivity and specificity of 100% and 99%, respectively, in predicting ovarian cancer [8]. Tekay and Jouipilla found that vessels with low impedance, RI < 0.4, could be identified in 43% of benign premenopausal tumors [9]. The National Institute of Health (NIH) reviewed the scientific data in 1995, and concluded that color Doppler may improve the specificity of ultrasound for predicting ovarian cancer, although its use should be considered investigational [10]. The limitations of spectral Doppler impedance measurements in accurately Figure 1. A simple 2.5 cm cyst in a premenopausal woman. Power Doppler reveals flow around the periphery of the cyst. Cystic interfaces >2.5 cm are a very common finding in pre-menopausal women (up to 25 %). These cysts will usually resolve spontaneously within six to eight weeks Figure 2.Typical appearance of peritoneal adhesive disease in a premenopausal woman with a previous history of multiple uterine myomectomies Figure 3. A 3.2 x 2.2 cm hemorrhagic corpus luteum cyst, typified by echogenic material within the cyst. Power Doppler reveals flow around the periphery of the cyst Figure 4. A 5 x 5 cm resolving hemorrhagic corpus luteum cyst. Color Doppler imaging reveals no evidence of flow within the central areas of the cyst. The appearance of resolving hemorrhagic corpus luteum cysts can be extremely complex in echo pattern. Failure to recognize a hemorrhagic corpus luteum can result in unnecessary operative interventions. MEDICA MUNDI 45/2 July

energy in the investigation of adnexal masses, and identified vascular flow within 100% of malignant and borderline tumors, and 80% of benign tumors [13].

Sensitivities were 93% and 87%, and specificities were 60% and 63%, for color Doppler and Power Doppler, respectively.

3 energy in the investigation of adnexal masses, and identified vascular flow within 100% of malignant and borderline tumors, and 80% of benign tumors [13]. They found that the pulsatility indices and diagnostic accuracy in predicting ovarian malignancy were similar. Sensitivities were 93% and 87%, and specificities were 60% and 63%, for color Doppler and Power Doppler, respectively. The authors did not find that the use of Power Doppler was more advantageous than that of color Doppler. Figure 5. A 6 x 5 cm endometriotic cyst in a pre-menopausal woman.typically on transvaginal ultrasound, these cysts are filled with uniform low-level echoes. The cyst may be multiloculated and can display varying internal echogenecity, depending on how recently bleeding into the cyst has occurred.there can be ultrasonic overlap with the internal echogenecity of mucinous cysts or ovarian abscesses. Guerriero et al. used Power Doppler as a secondary test performed after assigning a grayscale impression based on probable histology [14]. The Power Doppler assessment was based simply on the presence or absence of central vascularity within solid elements or excrescences. Specificity improved from 83% to 92% with the addition of Power Doppler as a secondary test. Significantly, the authors observed that requiring an impedance Doppler RI value of < 0.4 resulted in a marked drop-off in sensitivity, from 100% to 58%. A negative ultrasound examination may be falsely reassuring. Solid elements with vascular flow are the most important sign of malignancy. Figure 6.Typical appearance of a densely echogenic cystic teratoma, measuring 5 x 2.5 cm, in a pre-menopausal woman. Posterior shadowing is observed. Color Doppler reveals no evidence of flow within the densely echogenic region of the mass.the ultrasound appearance of cystic teratomas can be highly variable in nature and may confused with frankly malignant tumors. Cystic teratomas are the most common benign tumor of the ovary in women from age 20 to 40. predicting ovarian cancer were reviewed by Tailor et al. [11]. They found that time-averaged velocity measurements (TAMV) were more accurate than impedance measurements (RI, PI). However, they recommended that Doppler be used as part of a combined score that included the patient s age and papillary projection score. Schelling et al., using multiple logistic regression, found that the presence of central solid elements with vascular flow was the most important criterion in distinguishing benign from malignant masses [12]. In a prospective study of 257 women, they reported a 92% sensitivity and 94% specificity. Power Doppler Energy Tailor et al. explored the use of Power Doppler Specificity of Grayscale Ultrasound One of the major limitations of ultrasound screening is the large number of false positive examinations. Coincident operative intervention has varied between 3 and 100 operations for each case of malignant disease identified [3]. The grayscale scoring systems of Sassone et al. and modification by Lerner et al. report specificities of 83% and 77%, respectively [15,16]. These scoring systems require grading for echogenicity, wall thickness, solid elements, and degrees of septation. Ferrazzi et al. found, in a prospective series of 330 patients, that the Sassone score and Lerner score were less specific, with values of 65% and 59%, respectively [17]. The suboptimal specificity of these and other grayscale scoring systems can result in many unnecessary operations when an asymptomatic population is screened for ovarian cancer 3-D Ultrasound 3-D volume acquisition and 3-D Power Doppler may help in the early identification of abnormal vascularity and architectural changes within the ovary [18,19] (Figures 1, 2). Excrescences not seen by 2-D technology may be observed. While 3-D Power Doppler provides a new tool for measuring the quality of ovarian vascularity, its clinical value for the early detection of ovarian carcinoma has yet to be determined. 44 MEDICA MUNDI 45/2 July 2001

The Northwestern approach Adnexal masses are initially described by size and then categorized as cystic, multiloculated, complex, or solid.

categorized as such (Figs 1-6). 3-D Power Doppler imaging is used to both evaluate internal excrescences and the vascular supply within the mass.

We have found that the addition of 3-D Power Doppler is particularly useful in differentiating adenofibromas and cystic teratomas from borderline and malignant tumors.

This translates into improved patient care by reducing the total number of operative procedures [20].

4 The Northwestern approach Adnexal masses are initially described by size and then categorized as cystic, multiloculated, complex, or solid. Masses containing echo features that are highly characteristic of hemorrhagic cysts, endometriomas, cystadenomas, cystic teratomas, paramesonephric cysts, or peritoneal adhesive disease are categorized as such (Figs 1-6). 3-D Power Doppler imaging is used to both evaluate internal excrescences and the vascular supply within the mass. Masses displaying solid elements or excrescences with vascularity are considered to be malignant (Figs 7-12). We have found that the addition of 3-D Power Doppler is particularly useful in differentiating adenofibromas and cystic teratomas from borderline and malignant tumors. In our experience the addition of 3-D Power Doppler significantly improves our ability to distinguish accurately between benign and malignant changes (specificity increased from 54% to 75%). This translates into improved patient care by reducing the total number of operative procedures [20]. It is also our practice to expectantly follow simple menopausal thin-walled cystic masses < 5 cm since they have a malignancy risk < 1%. To date, the efficiency of 3-D Power Doppler imaging in identifying Stage I ovarian cancer has yet to be determined. It is important to differentiate between published series that represent large general population screening protocols for ovarian cancer in low-risk asymptomatic women, those that evaluate symptomatic women with adnexal masses found on pelvic examination or imaging studies, and those that study a variable, often incorrect, group of women labeled as high risk. It is equally important to evaluate the specific histology of the identified ovarian malignancies, as the tumor biology and stage at presentation is quite distinct between epithelial, stromal/sex-cord, and germ cell malignancies. Figure 7.This 4 x 3 cm complex predominantly cystic mass with a small area of internal excrescences was identified in a postmenopausal woman. 3D-Power Doppler imaging revealed no evidence of vascularity within the cyst wall or the excrescence. Pathology revealed a benign cystadenofibroma. Figure 8.This 10 x 8 cm mass was identified in a post-menopausal woman.a few thin septations with vascular flow were identified. No central flow was otherwise observed. Pathology revealed a mucinous cyst adenoma Figure 9.This 4 x 3 cm multiloculated ovarian mass was identified in a post-menopausal woman.three Dimensional Power Doppler flow revealed no evidence of central flow.pathology revealed a benign serous-cyst adenoma of the ovary. Figure 10.A 4 x 2 cm biloculated cystic mass in a perimenopausal woman on Tamoxifen. Multicystic masses are not uncommon in preand perimenopausal women on Tamoxifen. National Ovarian Cancer Screening Program It is the goal of the National Ovarian Cancer Early Detection Program to use the scientific basis of ovarian carcinogenesis, invasion, and metastatic dissemination to establish new means for the accurate detection of early rather than advanced stage epithelial ovarian carcinoma. The optimal assessment of an adnexal mass requires familiarity not only with new ultrasound technology, but also with pertinent medical history, in addition to a comprehensive clinical examination. Improved ovarian visualization via diagnostic imaging technologies is critical for the early detection of MEDICA MUNDI 45/2 July

The mass reveals marked central vascularity with Power Doppler examination.

5 ACKNOWLEDGEMENT Improved ovarian visualization is critical for early detection of asymptomatic lesions. Figure 11.This highly complex 14 x 10 cm mass was identified in a post-menopausal woman who presented with complaints of abdominal bloating and shortness of breath. The mass reveals marked central vascularity with Power Doppler examination. Surgery showed a Stage III C poorly differentiated adenocarcinoma of the ovary The work described in this article was supported by NIH/ NCI Early Detection Research Network Grant UO1CA85133, Friends of Prentice Foundation, Northwestern Memorial Hospital, Stenn Fund for Ovarian Cancer Research, Joanne Silverman Cancer Foundation, Illinois Department of Public Health, and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. REFERENCES [1] Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer Statistics, CA-a Cancer J Clin 2000; 50: [2] Bell R, Petticrew M, Sheldon T. The Performance of Screening Tests for Ovarian Cancer: Results of a Systematic Review. British Journal of Obstetrics and Gynaecology 1998; 105: Figure 12. A solid echogenic 8 x 6 cm mass in a postmenopausal woman. Power Doppler reveals marked vascular activity centrally within the mass. Surgery showed a Stage IVA poorly differentiated adenocarcinoma of the ovary asymptomatic lesions of the ovary and should decrease the number of inappropriate operative interventions. The role of innovative diagnostic imaging technologies in identifying early stage ovarian cancer is currently under evaluation within the National Ovarian Cancer Early Detection Program. It is anticipated that newly validated biologically relevant serum/plasma markers in combination with improved ultrasound technologies will make possible the detection of early stage epithelial ovarian cancer. [3] Narod S A, Moslehi R, Chu W et al. BRCA1 and BRCA2 Mutation Analysis of 208 Ashkenazi Jewish Women with Ovarian Cancer. American Journal of Human Genetics 2000; 66: [4] Van Nagell, JR., Depriest PD, Reedy MB et al. The Efficacy of Transvaginal Sonographic Screening in Asymptomatic Women At Risk for Ovarian Cancer. Gynecol Oncol 2000; 77: [5] Fishman DA, Cohen LS. Is Transvaginal Ultrasound Effective for Screening Asymptomatic Women for the Detection of Early-Stage Epithelial Ovarian Carcinoma? Gynecol Oncology 2000; 77: [6] Bourne T, Campbell S, Reynolds K et al. Screening for Early Familial Ovarian Cancer with Transvaginal Ultrasonography and Color Blood Low Imaging. BMJ 1993; 306: [7] Bourne TH. Should Clinical Decisions be made about Ovarian Masses using Transvaginal Color Doppler? Ultrasound Obstet Gynecol 1994; 4: MEDICA MUNDI 45/2 July 2001

6 [8] Kurjak A, Zalud I, Alfirevic Z. Evaluation of Adnexal Masses with Transvaginal Color Ultrasound. J Ultrasound Med 1991; 10: [9] Tekay A, Jouppila P: Blood Flow in Benign Ovarian Tumors and Normal Ovaries during the Follicular Phase. Obstet Gynecol 1995; 86: [10] Consensus Development Panel on Ovarian Cancer. JAMa 1995; 273: [11] Tailor A, Jurkovic D, Bourne T. Sonographic Prediction of Malignancy in Adnexal Masses using Multivariate Logistic Regression Analysis. Ultrasound Obstet Gynecol 1997; 10: 41. [12] Schelling M, Braun M, Kuhn W et al. Combined Transvaginal B-Mode and Color Doppler Sonography for Differential Diagnosis of Ovarian Tumors: Results of a Multivariate Logistic Regression Analysis. Gynecol Oncol 2000; 77: [13] Tailor A, Juirkovic D, Bourne T, Natucci M, Collins WP, Campbell S. Comparison of Transvaginal Color Doppler Imaging and Color Doppler Energy for Assessment of Intraovarian Blood Flow. Obstet Gynecol 1998; 91: [14] Guerriero S, Ajossa S, Risalvato et al. Diagnosis of Adnexal Malignancies By Using Color Doppler Energy Imaging as a Secondary Test in Persistent Masses. Ultrasound Obstet Gynecol 1998; 11; [15] Sassone AM, Timor-Tritsch IE, Artner A, Westhoff C,Warren W. Transvaginal Sonographic Characterization of Ovarian Disease: Evaluation of a New Scoring System to Predict Malignancy. Obstet Gynecol 1991; 78: [16] Lerner JP, Timor-Tritsch IE, Federman A, Abramovich G. Transvaginal Ultrasonographic Characterization of Ovarian Masses with an Improved, Weighted Score. Am J Obstet Gynecol 1994; 170: [17] Ferazzi E, Zanetta G, Dordoni D, Berlanda N, Mezzophane R, Lissoni G.Transvaginal Ultrasonographic Characterization of Ovarian Masses: A Comparison of Five Scoring Systems In a Multicenter Trial. Ultrasound Obstet Gynecol 1997; 10: [18] Bonilla-Musoles F, Raga F, Osborne NG. Three-Dimensional Ultrasound Evaluation of Ovarian Masses. Gynecol Oncol 1995: [19] Kurjak A, Kupesic S, Breyer B. The Assessment of Ovarian Tumor Angiogenesis: What does Three-Dimensional Power Doppler add? Ultrasound Obstet Gynecol 1998; 12: [20] Cohen LS, Escobar P, Scharm C, Glimco B, Fishman DA. Three-Dimensional Ultrasound Improves the Diagnostic Accuracy for Ovarian Cancer Prediction. Gynecol Oncol 2001 (In Press) MEDICA MUNDI 45/2 July

Three-dimensional Power Doppler Ultrasonography for Discriminating Benign from Malignant Ovarian Tumors:

Three-dimensional Power Doppler Ultrasonography for Discriminating Benign from Malignant Ovarian Tumors: 3D Power Donald Doppler School Ultrasonography Journal of Ultrasound for Discriminating in Obstetrics Benign and from Gynecology, Malignant Ovarian April-June Tumors: 2008;2(2):17-26 Current Experience