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Commentary |
1 Department of Radiology and Greenebaum Cancer Center, 419 W. Redwood St., Ste. 110, Baltimore, MD 21201.
Received November 27, 2002;
accepted after revision November 27, 2002.
This article is a commentary on question and answer by Gerson.
Despite the proven benefits of mammography, results have been less promising when the tissue is dense. Dense tissue is common, especially in younger women. In the series of Stomper et al. [5], approximately 62% of women in their 30s, 56% of women in their 40s, 37% of women in their 50s, and 27% of women in their 60s had at least 50% parenchymal densities evident on mammography. Kerlikowske et al. [6] reported results of 27,281 screening mammograms and found the sensitivity to cancer was 98.4% in women 50 years old or older with fatty breasts and 83.7% in women with dense breasts (p = 0.01). In women less than 50 years old, the sensitivity was 81.8% in fatty breasts and 85.4% in dense breasts (p = not significant), although the number of cancers was small [6]. In women less than 50 years old with a family history of breast cancer, mammographic sensitivity decreased to 68.8% [6]. Thus, in women with dense breasts, and particularly those at increased risk because of a family or personal history of breast cancer or atypia, methods to supplement mammography are sought.
Although breast self-examination intuitively seems worthwhile, randomized controlled trials have not shown a reduction in mortality rates. The effect may have been too small to measure within the power and conditions of the trials. The Shanghai trial of 133,000 women randomized to receive instruction in breast self-examination or control groups found no difference in mortality rates; women in the breast self-examination group were 84% more likely to undergo an unnecessary breast biopsy with benign results [7].
No randomized controlled trials have been conducted to evaluate the impact of screening sonography on breast cancer mortality rates. However, in several single-center studies, whole-breast bilateral sonography has been shown to depict small nonpalpable invasive breast cancers not seen on mammography, particularly in dense breasts [8, 9, 10, 11, 12]. The survival of patients diagnosed with invasive breast cancer is a direct, but imperfect, function of tumor size [13], and although we presume that this early detection is of benefit, this benefit has not been proven. Until such ‘surrogate’ end points are further validated to reliably predict mortality rates, the efficacy of any new screening test can only be shown if it reduces breast cancer deaths in the setting of a randomized controlled trial. Any population based screening test to be recommended must be held to a high standard of proof of value because otherwise healthy women will undergo additional testing and possibly treatment for conditions that may never have come to clinical significance.
MR imaging has been proposed to screen women at high risk of breast cancer [14]. Several single-center studies have shown a 2–6% yield of cancers found only on MR imaging after normal results on clinical breast examination and mammography in high-risk women [15, 16, 17]. One study of 196 high-risk women found two invasive cancers on MR imaging that were occult to a combination of mammography, clinical breast examination, and sonography [18]. MR imaging requires injection of IV contrast material to depict cancers and is approximately 10 times as costly as sonography. Few centers offer breast MR imaging, and in those that do, time on the MR scanner is often limited. Breast sonography is widely available. Localization and biopsy of lesions seen only on MR imaging are challenging, and there is no equivalent to specimen radiography. Some patients are claustrophobic, have a pacemaker or aneurysm clips, or are otherwise unable to undergo MR imaging of the breasts. Sonography is attractive as a supplement to mammography because it is widely available, relatively inexpensive, and well tolerated by patients; futhermore, aspiration or biopsy of lesions seen only on sonography is readily performed [19, 20, 21].
Studies to date have examined the supplemental benefit of screening sonography after mammography, when radiologists have knowledge of the mammographic results. Although this is the logical clinical sequence for breast sonography, the knowledge of mammography results creates bias favoring sonography. Sonography may be unknowingly targeted to vague areas of asymmetry or architectural change. Second, if only mammographically negative cases are evaluated, sonography can only look better: false-negative findings of sonography will not generally be recognized. In the absence of a blinded trial, the independent accuracy of breast sonography cannot be verified, and the performance characteristics of sonography will be artificially inflated. Nevertheless, the results of single-center studies using screening sonography to supplement mammography have been encouraging, and further evaluation is warranted.
The prevalence of cancer seen on the initial screening mammogram is approximately five to seven cancers per 1000, decreasing to two to three cancers per 1000 in a population under going regular screening [22, 23, 24]. Rates of cancer detected on screening mammography increase from one to two per 1000 in women aged 40–49 years up to nine to 10 per 1000 on the prevalent (first) screen of women 70 years or older [23]. In one practice, overall cancer detection rates on screening mammography were six per 1000 women when breast imaging specialists performed the interpretation and only 3.4 per 1000 when generalists performed the interpretation [25].
In four series totaling 37,085 examinations, 127 additional cancers (0.34%) were identified only on sonography in 103 women [8, 10, 11, 12] (Table 1). In all except one of these studies [12], only a single screening sonogram was obtained that would detect prevalent cancers seen only on sonography; we do not have an estimate of the rate of incident cancers seen only on subsequent annual screening sonograms. Of the 127 cancers seen only on sonography [8, 10, 11, 12], 120 (94.5%) were invasive, and seven (5.5%), DCIS (Table 1). Of the 120 invasive cancers, 82 (68%) were less than 1 cm. When staging was detailed [11, 12], 30 (91%) of 33 cancers seen only on sonography were stage 0 or 1. None of the series included women with fatty breasts. Of the 103 women with sonographically detected cancers, 96 (93%) had either heterogeneously dense or dense parenchyma [8, 10, 11, 12].
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Women at high risk of breast cancer were two-to threefold more likely to have cancers seen only sonographically, with 51 (50%) of 103 of these women at high risk because of a personal history of breast cancer or of having a first-degree relative with breast cancer or prior atypia [8, 10, 11, 12]. In the series of Kolb et al. [12], of 2914 examinations performed in women at high risk with heterogeneously dense or dense breasts, 14 women (0.48%) had cancer seen only sonographically, compared with 16 (0.16%) of 9959 examinations in women not at high risk.
For 21,517 examinations, the results of mammography are also reported [10, 12]. Another 50 cancers (0.23%) were seen only mammographically, with 37 (74%) of the 50 due to DCIS and 13 (26%) due to invasive cancer. In the series of 8970 women evaluated by Buchberger et al. [10], including 867 women with palpable or mammographic abnormalities, mammography depicted 78% (142/182) of all cancers in women with other than fatty breasts, and 162 (89%) of 182 cancers were seen on sonography. In the series of Kolb et al. [12], in women with heterogeneously dense or dense breasts, sonography alone was again more sensitive than mammography, with 60 (57%) of 105 cancers seen mammographically and 83 (79%) of 105 cancers seen sonographically. The combination of mammography and sonography depicted 101 (96%) of 105 cancers in this group [12]. In both series in which the results of mammography and sonography were reported [10, 12], mammography and sonography appear complementary in that DCIS was better depicted mammographically and small, less than 1 cm, invasive cancers were better seen sonographically in dense breasts.
In the series by Kolb et al. [12], screening sonography appeared to be especially beneficial in women less than 50 years old with dense breasts, whereas mammography depicted only 21 (50%) of 42 cancers and sonography, 33 (79%) of 42 cancers. Younger age was predictive of increased prevalence of cancers seen only on sonography, independent of breast density [12].
A woman contemplating obtaining a screening whole-breast bilateral sonogram should be informed of certain risks. Across the single-center series, there was a 2–6% risk of an unnecessary aspiration or biopsy as a result of screening sonography [8, 9, 10, 11, 12]. The likelihood of malignancy for lesions recommended for biopsy and seen only sonographically is low, with only from 5% to 16% of lesions proving malignant in these series [8, 9, 10, 11, 12]. Another 3–10% of patients were recommended for short-interval follow-up as a result of findings on sonography [8, 9, 10, 11, 12]. More important, although criteria have been proposed [26, 27], it has not been established that certain solid masses or complicated cysts can be reliably assessed as probably benign sonographically and followed up with a risk of malignancy of less than 2%.
If screening sonography is to be used, it should be considered a supplement to screening mammography at this time; a woman should not forgo mammography. Even when both mammography and sonography are performed, there is at least a 2–4% risk that a cancer, if present, will remain undetected [12, 28]. Currently, neither private nor public insurance programs reimburse facilities for screening sonography; it is advisable that the patient sign a waiver acknowledging that she will assume financial responsibility for the screening sonogram. It is not known whether the results of single-center studies are generalizable to the average radiology practice. Breast sonography is highly operator-dependent, requiring real-time adjustments of gain, focal zones, dynamic range, angle of insonation, pressure, patient positioning, and, most important, recognition of abnormalities. We do not know if two operators performing breast sonography on the same patient will identify the same lesions or whether they will reliably record lesion location and size. Most series detail results of physician-performed sonography, although Kaplan [11] reported success with specially trained technologists performing the examination.
With the support of the Avon Foundation and the National Institutes of Health, through the American College of Radiology Imaging Network, a multicenter protocol to assess the efficacy of screening breast sonography will soon begin enrollment (for more information, go to www.acrin.org). Initially, 14 centers will enroll high-risk asymptomatic women with dense breasts for three annual screening mammograms and sonograms. Radiologists specially trained in technique and interpretation criteria will perform the examinations. The primary aim is to determine whether whole-breast bilateral screening sonography can identify cancers occult on mammography and whether such results are generalizable across multiple centers. Issues of the accuracy of breast sonography, reliability of breast sonography, and risk of malignancy of solid masses classified as probably benign will be addressed, as will cost-effectiveness and quality of life measures. More import, mammographic and sonographic interpretations will be independent, to gain true measures of the performance of sonography. A second integration interpretation will be performed, and it is anticipated that mammography and sonography will complement each other.
Only practitioners experienced in breast sonography should contemplate offering screening sonography, with full awareness that it is not currently the standard of care. Facilities and practitioners offering screening sonography should meet the equipment, experience, and continuing education criteria for accreditation by the American College of Radiology or the American Institute of Ultrasound in Medicine for performance and interpretation of breast sonography and performance of sonographically guided aspiration and core biopsy. All sites in the trial will meet these requirements.
If this trial is successful, a broader randomized study of screening breast sonography in women with dense breasts may be appropriate, including mortality rates as an end point. In the interim, the patient and practitioner must weigh the potential risks and benefits. Ideally, any results of screening sonography will be collected as part of appropriately designed clinical trials so that we will have accurate answers for both patients and physicians on the true benefits and proper role of screening breast sonography.
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