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Negative Predictive Value of Sonography with Mammography in Patients with Palpable Breast Lesions

¹ Department of Radiology, Duke University Medical Center, P.O. Box 3808, Rm. 24244B, Durham, NC 27710.
² Present address: East Valley Diagnostic Imaging, 1125 E. Southern Ave., Ste. 300, Mesa, AZ 85212.
³ Present address: 72 E. 7th St., Apt. 1C, New York, NY 10003.

Received January 24, 2001; accepted after revision May 8, 2001.

 
Address correspondence to M. S. Soo.

Abstract

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OBJECTIVE. This study was performed to determine the negative predictive value of sonography with mammography in evaluating palpable breast lesions.

MATERIALS AND METHODS. Four hundred twenty patients with 455 palpable breast lesions were retrospectively identified from our mammography database as having negative mammographic and sonographic results. For patients diagnosed with breast cancer, images and medical records were reviewed to determine whether the palpable lesion evaluated on sonography and mammography corresponded to the patient's breast cancer. On the basis of the number of breast cancers that correlated to the palpable areas imaged, the negative predictive value of sonography with mammography was determined.

RESULTS. Sixty-two of the 420 patients in the study group were already diagnosed with breast carcinoma, and eight new carcinomas were diagnosed during the study period. Only one of six ipsilateral cancers corresponded to a palpable lesion that had a negative imaging evaluation. This lesion was diagnosed as an invasive lobular cancer, hard and fixed at physical examination. Imaging and clinical follow-up of the remaining patients showed no abnormality at the sites of previously investigated palpable abnormalities. The mean imaging follow-up was 25 months. The negative predictive value of sonography and mammography in the setting of a palpable lesion was 99.8%.

CONCLUSION. The negative predictive value of sonography with mammography is high, and together these imaging modalities can be reassuring if follow-up is planned when the physical examination is not highly suspicious. However, if the physical examination is suspicious, biopsy should not be delayed.

Introduction

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The false-negative rate of mammography in the detection of breast cancer has been consistently reported to be approximately 10%, as determined by studies such as the Breast Cancer Detection Demonstration Project [1, 2]. These mammographically occult lesions are usually discovered at physical examination and often occur in women with mammographically dense breasts. Therefore, a negative mammographic result cannot exclude malignancy in women with a palpable mass; the lesion should be biopsied if clinically indicated. A large number of patients with palpable breast lesions are referred to diagnostic breast centers for mammography and sonography to guide the treatment of the palpable breast mass and to screen the rest of the breast. Although the primary role of sonography in this setting has previously been to exclude a simple cyst, it is now used to characterize solid masses, and the additional information obtained could improve the ability of imaging to exclude malignancy in the setting of a palpable mass [3].

In general, the outcome of a sonographic evaluation of a palpable breast mass falls into one of three categories. First, if the lesion is a simple cyst, no further workup is required, although aspiration can be performed if desired by the patient or physician. Second, if the palpable lesion is a solid mass or complex cyst, further intervention is often required, such as fine-needle aspiration, needle core biopsy, or excisional biopsy. However, discrete noncystic masses in this category are now also being evaluated with other treatment strategies [4] on the basis of the imaging characteristics of the solid mass, as described in ground-breaking work by Stavros et al. [3]. Third, if findings from the sonography are negative (no discrete cystic or solid lesion are seen to correlate with the palpable mass) and the findings from the mammography are negative, then the treatment of the palpable abnormality is based on the results of the physical examination. If the lesion is suspicious at physical examination (discrete mass, fixed lesion, or firm region of thickening), tissue sampling is warranted. If the lesion is benign at physical examination, suggesting prominent fibroglandular tissue, then many clinicians choose a close-interval follow-up. Certainly not all palpable breast lesions in patients presenting for imaging would be considered a dominant mass when evaluated by an experienced breast surgeon. In fact, a large number of these patients present for evaluation of self-detected palpable abnormalities, many of which would be considered equivocal or not suspicious. However, imaging with mammography and sonography is still considered a critical part of the evaluation to exclude a suspicious lesion.

The negative predictive value of sonography with mammography for palpable abnormalities has been reported in a small series of patients, ranging from 96.5% to 100%; however, these studies were limited because of small patient populations [5,6,7]. A recent larger study describes a negative predictive value of 100% [4]. Knowledge of the negative predictive value of sonography with mammography for palpable lesions would be valuable to the clinician and radiologist to support the decision to biopsy versus follow up a palpable abnormality. The purpose of our study was to determine the negative predictive value of sonography in a large population of patients who presented with palpable breast lesions and had negative findings on mammography.

Materials and Methods

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From August 1994 through December 1998, 74,378 breast imaging examinations were performed at our institution, and the results were entered into a mammographic database. From data entries of 3563 patients presenting with one or more palpable lumps, we retrospectively selected those patients whose results of mammography and sonography of the palpable lesion were negative. This group of 420 patients with 445 palpable lesions constituted the study population.

Each palpable lesion was evaluated with dedicated mammography (Mammomat II, Mammomat III, Mammomat 3000; Siemens Medical, Iselin, NJ) using the film-screen technique. Before mammography, metallic markers were placed on the patient's skin overlying the region of the palpable abnormality; then standard mediolateral oblique and craniocaudal images were obtained. During the last year of the study, tangential magnification images of the palpable area were also obtained. Sonograms targeted to the palpable lesions were obtained in each patient by dedicated breast imaging radiologists. Before sonography, the patient would point out the palpable area to the radiologist, who subsequently would perform a physical examination of the abnormality. Sonograms were obtained using real-time technique with 7.5- to 10-MHz transducers (AI 3000 Acoustic Imaging, Phoenix, AZ; and Sonoline Elegra Siemens Medical, Issaquah, WA). For the last 8 months of the study, tissue harmonic imaging was used in addition to conventional sonography to evaluate lesions. Patient age and mammographic description of breast tissue composition (using the Breast Imaging Reporting and Data System [8], categories 1 through 4) were recorded.

The radiologist's physical examination of the palpable area at the time of sonography was recorded in the imaging report in 322 patients (77%). These findings were reviewed and categorized as no mass palpated, focal region of thickening, or discrete mass with defined borders. The name, date of birth, and medical record number of each patient were linked to the institution's tumor registry and to the state tumor registry to identify all patients in the group who had a diagnosis of breast cancer. Linkage to our institution's tumor registry was performed 3 months after completion of the study and then updated 12 months after completion of the study when all cancer listings from 1998 and earlier had been entered into the registry. Linkage to the state tumor registry was performed 8 months after completion of the study when all cancer listings from 1994 to 1997 and one third of 1998 cancer listings were entered. Of the patients who were diagnosed with breast cancer, medical records were reviewed to determine whether the palpable lesion evaluated on sonography and mammography during the study corresponded to the patient's breast cancer.

In addition to tumor registry linkage, the medical records of all 420 patients in the study were reviewed and categorized according to histology, imaging, and clinical follow-up. Sixty-four palpable lesions (14%) in 62 patients (15%) were sampled by either surgical excision (n = 15, 23%), needle core biopsy (n = 12, 19%), or fine-needle aspiration (n = 37, 58%). Forty-three of these patients (69%) also underwent imaging follow-up (mean, 33 months). An additional 219 lesions (49%) in 201 patients (48%) underwent imaging follow-up, documenting stability of the previously evaluated palpable area. The mean imaging follow-up time was 25 months (range, 6-70 months). Twenty-five lesions (6%) in 25 patients were decreased or resolved at a follow-up physical examination, with a mean follow-up of 15 months (range, 1-55 months). Fifty-seven patients (14%) with 61 lesions were seen at our institution for medical reasons unrelated to breast disease in the subsequent 1-69 months (mean, 24 months) without a record of subsequent breast problems or malignancy. Seventy-five patients (18%, 76 lesions) were not followed up or were lost to follow-up; 56 of these patients (75%) were less than 40 years old.

Results

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The mean patient age was 43 years (age range, 17-87 years). The breast composition based on mammographic tissue density was extremely dense in 214 patients (51%), heterogeneously dense in 145 patients (35%), scattered fibroglandular density in 35 patients (8%), and fatty in 26 patients (6%). Table 1 shows the breast tissue density distributed according to patient age. The physical examinations of the 322 lesions described in the imaging reports resulted in 112 discrete masses (35%), 62 thickenings (19%), and no discrete lesion in 148 (46%), according to the radiologists' physical examinations.

Seventy of the 420 patients in the study group had a diagnosis of breast carcinoma. Sixty-two patients (89%) in this group had a breast cancer diagnosis before the study period, and eight (11%) were diagnosed during the study period. Of the eight newly detected cancers, two occurred in the contralateral breast, and six occurred in the ipsilateral breast, including six invasive ductal carcinomas and two invasive lobular carcinomas. Of the six tumors in the ipsilateral breasts, only one, which had negative findings on imaging evaluation, corresponded to the palpable lesion evaluated with sonography and mammography. The other five cancers were detected on mammography (n = 2) or at physical examination (n = 3) during a follow-up evaluation of a different quadrant of the breast. This finding was confirmed on rereview of all the available mammograms, sonograms, and imaging reports that showed new and unrelated lesions found in different quadrants of the breast from that of the initial palpable mass.

The one cancer resulting in false-negative findings on mammography and sonography was described as hard and fixed at physical examination and was diagnosed without delay at excisional biopsy as a 1.8-cm invasive lobular carcinoma. The mammogram showed dense fibroglandular tissue with no abnormality (Fig. 1A,1B). On sonography, no discrete lesion was identified prospectively. Retrospective review of static images, however, did show a questionable area of shadowing posteriorly in the breast (Fig. 1A,1B). The breast composition on sonography was heterogeneous, showing mixed echogenic fibroglandular and fatty regions. This lesion was the only one of 65 histologically sampled lesions that was positive for breast carcinoma; all others were negative for malignancy.

View larger version (110K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A. —64-year-old woman with invasive lobular carcinoma. Mediolateral oblique mammogram of right breast shows heterogeneously dense tissue with metallic marker indicating palpable abnormality located posteriorly in breast. No mammographic abnormality is seen.

View larger version (134K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B. —64-year-old woman with invasive lobular carcinoma. Sonogram with false-negative findings for palpable invasive lobular carcinoma that was prospectively interpreted as negative shows vague ill-defined hypoechoic region posteriorly (arrows). In retrospect, this finding may relate to carcinoma located posteriorly in breast. Color Doppler imaging showed no blood flow.

Imaging and clinical follow-up of all remaining patients showed that no suspicious abnormality had developed at the site of the previously investigated palpable abnormality. For the patients lost to follow-up, none appeared in either the institution's tumor registry or in the state tumor registry as having developed breast carcinoma during the subsequent 9-62 months. Overall, only one of 445 lesions that showed no abnormal findings on mammography or sonography during the initial evaluation was diagnosed as carcinoma. The negative predictive value of sonography and mammography in the setting of the palpable lesion was 99.8%.

Discussion

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Patients with palpable breast masses commonly present for imaging evaluation. Unfortunately, false-negative mammographic findings in the setting of a palpable breast mass have been estimated to be between 4% and 12% [1, 2, 9]. Therefore, malignancy cannot be excluded when mammographic findings of a palpable mass are negative. Treatment of a palpable mass in this setting is based on the results of a physical examination, with aspiration or biopsy performed on clinically suspicious lesions. Sonography is used as an adjunct to mammography to further evaluate palpable masses, especially in women with mammographically dense breasts. Sonography often detects cysts or solid lesions that are obscured on the mammogram by the surrounding fibroglandular tissue and can reduce the number of surgical biopsies required when cysts are identified [10, 11]. Although the role of sonography initially was to establish or exclude the cystic nature of a mass, it has expanded with improvements in equipment because sonographic findings can often confirm a cancer that is obscured mammographically by dense breast tissue.

Currently, if findings on mammography and sonography are both negative, showing no cyst or discrete solid mass, then the decision to biopsy a palpable lesion or follow it up with a physical examination is based on the degree of suspicion at physical examination. The decision rests with the referring physician, whose experience in breast physical examination may be extensive or limited. Patients and referring physicians appear to rely on the negative results of imaging studies, as evinced by the predominately young patients in our study population who did not undergo a follow-up physical examination of the lesion. Therefore, knowledge of the negative predictive value of sonography and mammography is crucial if a negative imaging result affects clinical treatment.

Our study showed a high negative predictive value (99.8%) for sonography and mammography in the setting of a palpable lump, which should assist the referring physician in decision-making and support clinical follow-up rather than biopsy for palpable lesions that are not clinically suspicious. Our high negative predictive value in this larger population parallels that of a recently reported large series and previously reported small series [4, 5, 7]. Moreover, the only palpable lesion that was false-negative for cancer in our study was diagnosed as an invasive lobular carcinoma, which was the same diagnosis that others have reported as causing a false-negative finding on mammography and sonography [5]. Paramagul et al. [12] reported the variable sonographic appearance of 19 invasive lobular carcinomas, including smooth or irregularly marginated masses with or without posterior acoustic shadowing, or no finding. However, in their study, which evaluated sonographic images that were taken before 1994, no invasive lobular carcinomas showed false-negative findings on both mammography and sonography [12].

Sonographic technology for breast imaging has dramatically improved in the past decade, as has an increased understanding of the findings associated with breast cancer. The invasive carcinoma that was not identified prospectively on mammography or sonography in our study was evaluated using a 7.5-MHz transducer with a sonography unit that is not currently considered the highest resolution equipment; and in retrospect, the static images suggested a subtle ill-defined hypoechoic region that may have been interpreted as an abnormal finding if obtained today prospectively. Higher frequency (13-MHz) transducers are now available, providing exquisite resolution of superficial structures and may prove optimal for imaging lesions in the breast. Tissue harmonic imaging is another technical development that can improve lesion conspicuity and possibly lead to better sonographic detection of lesions [13]. With further improvements in sonographic technology and careful prospective real-time evaluation of palpable breast lumps, perhaps the negative predictive value will one day approach 100%, ideally providing complete confidence for follow-up rather than recommending biopsy of these lesions.

Palpable abnormalities range from highly suspicious lesions that are almost certainly malignant to lesions that are equivocal or not identifiable by a physician skilled in clinical breast examination. In a study of 605 young patients less than 40 years old who presented with palpable breast masses, only 36% of lesions detected by the patient and 29% of lesions detected by primary care providers were considered a dominant mass by an experienced breast surgeon, resulting in a biopsy of the lesion. [14].

Lesions that are not considered dominant masses and, therefore, are less suspicious, are often initially identified by the patient as a change at breast self-examination. Usually, at the time of the imaging examination, the radiologist evaluating a palpable breast abnormality has not been informed of the degree of suspicion that the referring physician has regarding the palpable abnormality. Although the radiologist formulates his own opinion about the lesion, it would probably be useful to prospectively stratify lesions into categories on the basis of the referring physician's level of clinical suspicion. Stratifying the results of the physical examination into benign, indeterminate, or malignant categories has been used to refine the "triple test," which uses mammography, physical examination, and fine-needle aspiration to evaluate palpable breast lesions [9]. Morris et al. [9] reported that stratifying each component of the triple test into the three categories would reduce the number of surgical biopsies performed on benign lesions.

A similar system could be applied to patients undergoing mammography, sonography, and physical examination, as proposed by Weinstein and Conant [15]. The smaller number of patients with highly suspicious lesions and negative imaging would require tissue sampling immediately; the larger group of less suspicious lesions could be placed into a category of follow-up physical examinations. Patients with equivocal findings at physical examination and negative findings on imaging could be reassured, and in this subset, follow-up may not be necessary.

This proposed categorization and treatment of palpable lesions are probably practiced by referring clinicians to some degree, although, to our knowledge, it has not been formally investigated. Given the recent interest in this issue in the radiology community, a multiinstitutional trial could be performed to validate the method of treating palpable breast lesions on the basis of negative findings on mammography and sonography [4,5,6,7, 15,16,17]. In our practice, we still recommend that patients undergo follow-up as directed by their referring physicians, although we try to reassure anxious patients who have equivocal lesions or lesions that are not suspicious at physical examination that the lesion is probably benign.

In conclusion, the negative predictive value of sonography with mammography is high, and together these imaging modalities can be reassuring to the clinician if follow-up is planned when the physical examination is not highly suspicious. However, if the physical examination is suspicious, biopsy should not be delayed. The categorization of lesions based on clinical suspicion should be incorporated prospectively into the evaluation of palpable breast masses with negative imaging, and further study at a multiinstitutional level is warranted.

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