Screening for Women at Increased Risk of Ovarian Cancer

In document Benson - Ultrasonography in Obstetrics and Gynecology - A Practical Approach to Clinical Problems, 2nd Ed. (Page 86-99)

The decision to implement a screening program is based on estimates of prevalence of the disease, cost per case discovered, altered clinical outcomes, and availability of a practical, sensitive screening test, among other factors.

Despite its obvious morbidity and mortality, ovarian can-cer has a relatively low incidence and prevalence (as com-pared, for example, with breast cancer, whose prevalence and incidence unquestionably make mammographic screening worthwhile). Current recommendations, there-fore, are for screening only a small subset of the popula-tion considered at increased risk for the disease by virtue of a family history of ovarian cancer or the presence of one of the syndromes known to confer a substantially in-creased risk of ovarian malignancy. Screening of the general population is not advocated by any authorities at this time.

Certain caveats with respect to screening bear mention.

The detection of ovarian cancer by screening may still not be early enough in the evolution of the disease to affect ul-timate outcome despite prompt intervention. The duration of preclinical disease has not been established; if it is short, screening at sufficiently close intervals to affect out-come may not be practically possible. There is also no as-surance that tumors detected at an early stage by a screen-ing program will exhibit the same biological behavior as those that are clinically manifested at the same stage.8That said, there is still a perceived benefit to be derived from screening a selected population.

Screening the high-risk patient is considered appropri-ate and advisable despite the current lack of definitive data to confirm improved outcomes from early detection. Logic dictates, however, that, because there is such a vast gap in 5-year survivals between early and advanced stages of the disease (90% vs. 15%, respectively), discovering and treat-ing ovarian cancer in stage I will inevitably be of benefit.

The goal in a screening program would understandably be the highest possible positive predictive value (PPV) for the process [i.e., (true-positive results/true-positive + false-negative)  100]. Clinical investigators have suggested that a PPV of less than 10% (i.e., nine negative surgeries for the discovery of each ovarian cancer) would not be accept-able to either clinician or patient.14

Screening programs have used the combination of CA 125 and transvaginal ultrasound. CA 125 is a protein in the blood that is increased in the majority of women with ovarian cancer.15Screening using both CA 125 and trans-vaginal ultrasound has been studied in the general popula-tion16–20and in women with an increased risk for ovarian cancer due to family history.21–23 Preliminary results sug-gest benefit of screening in the high-risk population with an overall specificity of 99.9% and a PPV of 26.8% in one 14495OB_C07_pgs.qxd 8/16/07 1:49 PM Page 77

early-stage tumors.33–36Three parameters are considered in the sonographic assessment of the ovary: gray-scale mor-phology, spectral Doppler waveforms and quantification, and color Doppler imaging. These three have been studied for specificity, sensitivity, and predictive values in screen-ing for ovarian cancer; each will be discussed and its over-all contribution to effective screening outlined.

Gray-Scale Morphology

Essentially, all investigators attempting to define gray-scale characteristics of benign versus malignant ovarian neoplasms have established some form of morphological classification that assesses several parameters: size, wall thickness, number and thickness of septa, soft tissue ex-crescences (from walls or septa), and overall

echogenic-ity.29,37–47Several authors have devised morphological

clas-sification systems that take into account sonographic characteristics, including size, wall characteristics, number and thickness of internal septa, and presence of internal debris. They assign numerical values to each factor and de-rive a composite score that reflects the likelihood of malig-nancy. This allows for at least a semiquantitative assess-ment of the likelihood a mass is malignant, although, admittedly, there is some measure of subjectivity to the in-terpretation of the transvaginal ultrasound. Most of the classification systems have considerable common ground;

we have chosen that published by DePriest et al47by way of example (Fig. 7–1).

Size of Ovaries

Estimation of ovarian size is accomplished with the for-mula for the volume of a prolate ellipsoid (oval with flat-tened ends): volume = length  width  height  0.5233 (or, by approximation, one half the product of the three di-mensions). In premenopausal women, the normal ovary typically has a volume between 5 and 15 mL, decreasing in size with advancing age. In postmenopausal women, ovar-ian volume is usually less than 10 mL41(Fig. 7–2). Although larger ovaries, those greater than 5 cm in largest diameter, have a higher risk of malignancy than smaller ovaries, the parameter of overall ovarian size is not as useful for identi-fying ovarian cancer as is the sonographic evaluation of ovarian parenchyma.38The size of ovarian lesions does cor-relate somewhat with the risk of cancer because, in gen-eral, the larger the ovarian mass, the more likely it is to be malignant.37,40

Wall Features of Ovarian Mass

The thickness and contours of the walls of an ovarian mass are particularly important for predicting malignancy.42,43 Solid tissue excrescences from the inner walls of a cystic mass and focal or diffuse thickening of the walls exceeding

3 mm are most worrisome for malignancy.38,40,44–47Overall, the greater the wall thickness and the more the number of soft tissue projections present, the higher the risk of ma-lignancy (Fig. 7–3, Fig. 7–4, Fig. 7–5).

Septa within Ovarian Mass

Septa within an ovarian mass are evaluated with respect to number, thickness, and irregularity. Masses with many septa have a greater chance of malignancy than those with few. Those with thick septa, especially septa measuring more than 3 mm or septa with focal thickening, have an increased chance of malignancy. Although the number of septa does correlate somewhat with malignancy, it should be noted that mucinous ovarian tumors, whether benign or malignant, tend to have more septations than serous tumors. Thus, no specific number of septa nor any ratio of septations to tumor volume can be used to dis-criminate a benign ovarian cystic mass from a malignant one (Fig. 7–6, Fig. 7–7, Fig. 7–8).38,40,44,48

Figure 7–1 Morphology index for classifying ovarian tumors based on size, wall structure, and septa. (From Ueland FR, DePriest PD, Pavlik EJ, Kryscio RJ, van Nagell JR Jr. Preoperative differentiation of malignant from benign ovarian tumors: the efficacy of morphology indexing and Doppler flow sonography. Gynecol Oncol. 2003 Oct, 91: 47. Reprinted by permission.)

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Figure 7–2 Normal ovaries. Sonographic images of ovaries from two different premenopausal patients. Multiple small follicles are seen in both. (A) Normal ovary; note multiple small follicles. (B) Nor-mal ovary with radial arrangement of norNor-mal follicles. (C) Sonogram

of ovary (arrows) in postmenopausal woman. The ovary contains no small follicles and is smaller than the ovaries in premenopausal women. (D) Normal ovary (arrows) with flow seen within it (arrow-head).

C D

A B

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Figure 7–3 Simple cyst. Normal ovary (arrows) contains a simple cyst measuring ∼33 mm in maximum diameter. This represents a functional (corpus luteum) cyst and will regress spontaneously. Folli-cles typically range up to 24 mm.

Figure 7–4 Thickening of cyst wall. Complex ovarian lesion (calipers) with thickening of some parts of the wall (arrows).

Figure 7–5 Mural nodules. (A) This histologically malignant ovarian neoplasm has at least two solid mural nodules (arrows), increasing its change of malignancy based on morphological criteria.

(B) Another ovarian cystic neoplasm with solid tumor nodule (ar-rows) along one wall.

A B

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Figure 7–6 Serous cystadenoma. (A) This benign cystic mass con-tains a few thin septa (arrows) less than 3 mm thick, but is otherwise purely cystic. (B) Another benign serous cystadenoma, this cystic

mass contains more septations (arrows), but they are still quite thin.

b, urinary bladder with artifactual echoes (open arrowhead).

A B

Figure 7–7 Thin septations. (A) Complex hemorrhagic ovarian cyst with many fine septations crisscrossing the cyst. (B) Mucinous cystadenoma with multiple fine septation and echoes within the cystic portion of the neoplasm.

A B

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Echotexture of Ovarian Mass

The majority of primary neoplasms of the ovary are ep-ithelial in origin; they are, to a greater or lesser degree, cystic. There is considerable variation in the amount of solid tissue within an epithelial tumor of the ovary and in the echotexture of the material within the mass. Tumors with a higher proportion of solid tissue admixed with the

cystic components have a higher likelihood of malignancy than those with less solid tissue, as do those masses with substantial echogenic internal debris in the cystic nents, when compared with those whose cystic compo-nents have few internal echoes. In general, the cystic com-ponents of mucin-producing tumors often demonstrate low-level internal echoes, sometimes with fluid/debris levels, presumed to represent the mildly echogenic mucin itself. Quantification of the amount of solid tissue present in any given tumor is subjective at best; and classification systems that assign numerical values to this factor do so on the basis of the subjective assessment.38,44,49Diagrammatic representation of the spectrum of solid tissue proportions is provided by charts such as the one in Fig. 7–1 to serve as a reference guideline (Fig. 7–9, Fig. 7–10, Fig. 7–11).

Ovarian benign teratomas or dermoid tumors consti-tute a significant exception to the correlation between in-ternal echogenicity of an ovarian mass and its risk of ma-lignancy. Ovarian teratomas are usually benign tumors, although there are no reliable sonographic criteria for dif-ferentiating the benign from the malignant. Teratomas commonly have substantial internal echogenicity in the form of highly echogenic mural nodules of tissue (the

“Rokitansky nodule” or “dermoid plug”) or considerable amounts of highly echogenic material, representing fat or hair, often within a cystic area with fluid/debris levels.50–53 It should be noted that the hair or fat found in a dermoid will be considerably more echogenic than the low-level re-flectivity of mucin in an epithelial malignant neoplasm.

Figure 7–8 Thick septations. (A) Cystic ovarian benign neoplasm with thick septation (arrow) crossing it. (B) Cystic ovarian malignant neoplasm with several thick septations (arrows). Blood flow is seen with color Doppler within one of the septations on this image.

A B

Figure 7–9 Ovarian cyst with internal echoes. Sonogram of right ovary containing a cyst (calipers) filled with homogeneous echoes.

This proved to be a benign endometrioma.

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echotexture. Morphologies that are typically benign, in-cluding anechoic simple cysts, cysts with smooth, thin sep-tations less than 3 mm, complex cysts with homogeneous internal echoes, and typical dermoid tumors, have high negative predictive value of 99%.48 Masses with sono-graphic findings worrisome for malignancy, including The finding of a highly echogenic focus producing

shadow-ing within a cystic mass strongly suggests calcification and reinforces the diagnosis of a dermoid tumor (Fig. 7–12).

The sonographic appearance of an ovarian mass can be used to predict whether it is benign versus malignant based on its composition (cystic versus solid) and internal

Figure 7–10 Mixed cystic and solid ovarian lesions. (A) Mucinous cystadenofibroma with solid component (arrows) and echoes in the cystic por-tion. (B) Mucinous cystadenoma with solid component (arrows) making up almost half the tumor.

A B

Figure 7–11 Ovarian cancer. (A) Large cystic ovarian carcinoma with irregular solid component (arrows) located centrally. (B) Another ovarian malignancy (calipers) with large solid component (arrows).

A B

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multiple septations, thick septations, solid components, and echogenic cystic areas, have a positive predictive value for malignancy of∼50%.

Most clinicians consider that a simple unilocular cyst less than 6 cm in a premenopausal woman has such a low chance of malignancy that it can be followed to resolution by ultrasound, rather than needing surgical removal. Like-wise, a simple unilocular cyst less than 5 cm in a post-menopausal woman is considered safe to monitor with pe-riodic ultrasound examinations.54

Several other neoplastic processes in the ovary (both primary and secondary) demonstrate high proportions

of solid tissue. Endometrioid carcinoma of the ovary, metastatic tumors from several different primary ma-lignancies (e.g., breast, lung, gastrointestinal tract) grouped under the broad heading of Krukenberg’s tu-mors, germ cell tutu-mors, and lymphoma all produce pre-dominantly solid enlargement of the ovary or solid ovar-ian masses55–60 (Fig. 7–13). It is uncommon for these processes to resemble epithelial carcinomas of the ovary sonographically.

Spectral Doppler Imaging

The neovascularity produced by malignant neoplasms typically lacks both vasomotor control and muscular walls. As a result, the vascularity in a malignant tumor is usually high flow with a low-resistance perfusion pattern that translates into large passive forward diastolic flow.

This effect is reflected in measurements of both the resis-tive index (RI) and the pulsatility index (PI). The RI [(peak systolic flow – end diastolic flow)/peak systolic flow] is calculated from the spectral Doppler waveform, as is the PI [(peak systolic flow – end diastolic flow)/mean Doppler shift]. Lower RI and PI values are associated with in-creased risk of malignancy, with acceptable cutoffs for RI of 0.40 and for PI of 1.0. Doppler waveforms yielding an RI or PI less than these values are indicative of increased di-astolic flow and thus are suggestive of malignancy. Benign neoplasms, on the other hand, generally display little passive diastolic flow because they have high-resistance vascular Figure 7–12 Dermoid. (A) Transverse image. (B) Left parasagittal

image. In many cases, the echotexture of an ovarian mass will strongly suggest dermoid. This highly echogenic mass (arrows and

calipers) containing mostly fat is seen to have an even more echogenic focus [wavy arrow in (B)] representing calcification. b, uri-nary bladder; u, uterus.

A B

Figure 7–13 Lymphoma. Coronal image of both ovaries. Both the right (RT) and left (LT) ovaries are enlarged and solid due to lym-phoma.

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Color Doppler Imaging

Logic dictates that the neovascularity generated by a neoplasm would produce a significant increase in the color flow Doppler pattern. This premise has led several investigators to evaluate the presence, distribution, and prevalence of color flow signals in ovarian masses in an attempt to distinguish between benign and malignant processes.48,61,71–73Unfortunately, as with spectral Doppler in ovarian masses, there is considerable overlap in the color Doppler findings in benign and malignant ovarian masses, beds and therefore, produce higher RI and PI

val-ues42,44,45,61–67(Fig. 7–14 and Fig. 7–15).

Unfortunately, there is considerable overlap in RI and PI values from spectral Doppler waveforms of benign and malignant ovarian neoplasms, making these parameters on their own of little clinical utility for distinguishing be-tween benign and malignant disease.40,46,48,49,68–71No cutoff value for RI or PI has acceptable sensitivity and specificity.

Spectral Doppler on its own is, therefore, not considered a diagnostic parameter to distinguish between benign and malignant ovarian processes.

Figure 7–14 High-resistance flow. (A) Doppler waveform from a vessel in the solid component of an ovarian neoplasm. The pulsatility index (PI) of 1.52 indicates high-resistance flow, more often seen in benign than in malignant tumors.

Figure 7–15 Doppler flow in ovarian cancer. (A) Doppler waveform from a vessel in the solid component of a malig-nant ovarian neoplasm. The resistive index (RI) of 0.50 is higher than the cutoff of 0.4 used to define low-resistance flow characteristic of malignancy.

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making this parameter of limited value for distinguishing benign from malignant. In general, the less flow in a mass, the less likely it is to be malignant.44,48Flow within a nodule in the wall of a cystic mass or within a thick septation is suggestive of malignancy (Fig. 7–16, Fig. 7–17).44The pres-ence of central flow is seen more often in malignant masses than in benign ones, and absence of central flow suggests a benign process74,75; however, complete absence of color flow still does not exclude malignancy.48,69 Further-more, these observations may not hold as color Doppler equipment improves and more sensitive equipment is able to detect scant and slower flow than could previously be detected.

In short, the basic premise that malignant tumors of the ovary will generally demonstrate more color flow,

lower-resistance spectral tracings with higher passive diastolic flow, and lower RI (< 0.4) and PI (< 1.0) values compared with benign masses, appears to be valid. However, at-tempts thus far to establish discriminatory parameters that result in adequate sensitivity, specificity, and PPV have not been successful. Studies are ongoing, including those assessing ultrasound contrast agents,76and there is reason to believe that practical, applicable criteria will be developed to improve the ability of ultrasound and Doppler to distinguish benign from malignant ovarian masses. At present, findings of increased vascularity of low resistance by either spectral or color flow techniques will at least serve to raise suspicion of a malignant process and prompt further workup. It should be remembered that several nonmalignant processes (e.g., pelvic inflammatory Figure 7–16 Color Doppler flow in an ovarian neoplasm. (A) Image of ovarian carcinoma with a central solid component in which blood flow is seen on color Doppler. (B) Extensive blood flow seen with color Doppler within the solid component (arrows) of another ovarian neoplasm.

A B

Figure 7–17 Color Doppler flow in a thick septation. (A) Flow identified with color Doppler within a thick septation (arrows) and (B) within two septations in two different ovarian neoplasms.

A B

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with advanced disease (stage III and IV). Several authors now advise prophylactic oophorectomy at age 35 or when childbearing is complete for women with two first-degree relatives with ovarian cancer or the inherited conditions discussed above.7,13

Both spectral and color flow Doppler are currently felt to be of adjunctive value in the assessment of ovarian masses; findings with these modalities influence levels of suspicion, but currently have insufficient discriminatory value to be used as stand-alone criteria to characterize a

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disease, ectopic pregnancy, corpus luteum of pregnancy) may also produce hypervascularity with relatively low-resistance flow patterns.

Summary

The role of ultrasound in screening for ovarian malignancy is still evolving with respect to technique, criteria, and ap-plication. Screening of the general population is not felt to

The role of ultrasound in screening for ovarian malignancy is still evolving with respect to technique, criteria, and ap-plication. Screening of the general population is not felt to

In document Benson - Ultrasonography in Obstetrics and Gynecology - A Practical Approach to Clinical Problems, 2nd Ed. (Page 86-99)