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Original Research |
1 Department of Diagnostic Radiology, Research Institute of Radiological
Science, Yonsei University College of Medicine, Seodaemun-ku, Shinchon-dong
134, Seoul 120-752, South Korea.
2 Department of Diagnostic Radiology, Bundang CHA General Hospital, Pochon CHA
University, Sungnam, South Korea.
Received December 28, 2006;
accepted after revision July 15, 2007.
Address correspondence to E. K. Kim
(ekkim{at}yuhs.ac.kr).
Abstract
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MATERIALS AND METHODS. In this retrospective study, we included a total of 2,420 lesions from 2,198 women who had undergone sonographically guided 14-gauge core needle biopsy. For evaluating the diagnostic accuracy of this procedure, the pathologic results were reviewed and correlated with rebiopsy or long-term imaging follow-up. Agreement rate, high-risk underestimate rate, ductal carcinoma in situ (DCIS) underestimate rate, and false-negative rate were assessed. The false-negative diagnoses of core needle biopsy were reviewed in detail.
RESULTS. The pathologic results for the core needle biopsies were malignant in 52%, high-risk in 4%, and benign in 44%. The agreement rate was 96% (2,328 of 2,420). The underestimate rate was 29% (36 of 126) for DCIS and 27% (25 of 93) for high-risk (52% for 27 atypical ductal hyperplasia (ADH), 17% for 66 non-ADH). Of 1,071 benign lesions, malignancy was found at rebiopsy in 31 lesions (25 immediate and six delayed false-negative diagnoses), and the false-negative rate was 2.4% (31 of 1,312). The frequency of malignancy in lesions that had rebiopsy because of suspicious imaging findings (19.1%, 26 of 136) was significantly higher than that because of suspicious physical findings or request by patient or physician (0.9%, five of 584).
CONCLUSION. Sonographically guided 14-gauge core needle biopsy is an accurate method for evaluating breast masses. Imaging-pathologic correlation and follow-up of benign biopsy are essential for a successful breast biopsy program.
Keywords: breast biopsy • breast cancer • core needle biopsy • oncologic imaging • sonographically guided breast biopsy • women's imaging
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Since Parker et al. [4] first reported the use of sonographically guided core needle biopsy with a 14-gauge automated core biopsy needle for the breast, investigators have shown that this procedure is fast, safe, accurate, and cost-saving [3, 5-11]. However, there have been only a few large studies describing this procedure [3, 6, 8, 10]. For the evaluation of any biopsy technique, an appropriate follow-up for a benign biopsy is invaluable to accurately determine the false-negative rate [6]. The problem is that cancers may be missed during core needle sampling, leading to a false-negative diagnosis. In a study, unless all lesions are excised, a rigorous long-term follow-up is required to identify all false-negative diagnoses, and the actual true-negative and false-negative rates are determined by at least a 2-year follow-up of benign cases [12, 13]. However, most previous reports of sonographically guided core needle biopsy in the breast included benign biopsy results with a less-than-2-year follow-up; therefore, false-negative diagnoses could have been misinterpreted as true-negative diagnoses [3, 4, 6, 9]. For this study, we evaluated the results of 2,420 sonographically guided 14-gauge core needle biopsies at our institution with a follow-up of at least 2 years for benign biopsies.
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A total of 2,420 breast masses in 2,198 females (age range, 12-88 years; mean, 45.3 years; median, 45 years) were included in this study. Of the 2,198 patients, 167 had biopsies of two separate lesions, 23 had biopsies of three separate lesions, one had biopsies of five separate lesions, and one had biopsies of six separate lesions. The lesions ranged in size from 2 to 180 mm (mean, 18.7 mm; median, 15 mm) as measured by sonography. There were associated symptoms in 1,166 cases (48%): palpable masses in 1,141, localized pain in four, and bloody nipple discharge in 21. This study was conducted with institutional review board approval and a waiver of patient informed consent because this study was retrospective.
Biopsy Procedure
Sonographically guided core needle biopsies were performed using a
free-hand technique and a high-resolution sonography unit with 7.5- or 12-MHz
linear array transducers (HDI 5000 or 3000, Philips-Advanced Technology
Laboratories; or Logic 9, GE Healthcare). Each procedure was performed in an
outpatient setting with the patient under local anesthesia and in the supine
position. An automated gun (Pro-Mag 2.2, Manan Medical Products) and a
14-gauge Tru-Cut needle with a 22-mm throw (SACN Biopsy Needle, Medical Device
Technologies) were used. All biopsies were performed by one of nine
radiologists with fellowship training (n = 7) or extensive clinical
experience (n = 2) in breast imaging and biopsy. According to our
standard protocol, five core samples per lesion were routinely obtained (mean,
5.4; range, 3-8). Although fewer samples were occasionally taken, at least
three cores were obtained, and the appearance and behavior of the
formalin-fixed core samples were examined during the procedure to confirm that
the targeted lesion was sampled adequately
[14].
Postbiopsy Management
For each lesion that underwent a core needle biopsy, a radiologist reviewed
the final pathology report in conjunction with the images obtained before,
during, and after the biopsy procedure and, according to the review, made
specific recommendations for the patients and the referring physicians
[15]. Malignant lesions (e.g.,
invasive carcinoma, ductal carcinoma in situ [DCIS], lymphoma, metastases) at
14-gauge core needle biopsy were accepted as the final diagnosis, and
immediate definitive surgery or chemotherapy was recommended in those patients
as deemed clinically appropriate. High-risk lesions (e.g., atypical ductal
hyperplasia [ADH], lobular neoplasia, radial sclerosing lesion, papillary
lesions with atypical features, possible phyllodes tumors) and benign lesions
(i.e., neither malignant nor high-risk) with imaging-histologic discordance
resulted in recommendations for surgical excision
[16,
17].
Sonography follow-up at 6 months after biopsy and then annually for at least 2 years was recommended in patients with concordant benign lesions. For some concordant benign lesions, immediate rebiopsies were done because of a request by the patient or referring physician or because of suspicious physical findings (i.e., palpable mass or nipple discharge), and delayed rebiopsies were done because of lesion progression at sonography follow-up, suspicious physical findings, or a request by the patient or referring physician. Rebiopsies were done by surgical excision or by vacuum biopsy (i.e., sonographically guided 8- or 11-gauge vacuum-assisted core needle biopsy) with the intention of removing all sonographic evidence of lesions. Results of sonographically guided core needle biopsy, rebiopsy, and follow-up were obtained from review of the institution's radiology and pathology databases.
Data Analysis
The diagnostic accuracy of sonographically guided core needle biopsy was
assessed using a 4 x 4 table method introduced by Burbank and Parker
[18], with which we could make
pathologic comparisons between core needle biopsy and the gold standard. The
gold standard diagnosis was composed of the results of surgical excision,
vacuum biopsy, or long-term imaging follow-up. Unlike the 2 x 2 table
method, in which all abnormalities are summarized as either positive
(malignant) or negative (nonmalignant) lesions, leading to a major problem
with the categorization of high-risk lesions or DCIS, the pathologic
comparisons in the 4 x 4 table method were classified into the following
four categories: invasive cancer, DCIS, high-risk lesions, and benign lesions.
The 16 cells in the 4 x 4 table were simplified into only three
clinically distinct cells: agreement, underestimate, or miss
[18,
19]
(Fig. 1A). Burbank and Parker
[18] argue that overestimates
of core needle biopsy are actually clinically relevant agreements rather than
disagreements. The lower degree of pathology seen in an excisional biopsy
specimen can be explained by either complete removal of the lesion by the core
needle biopsy or inadequate excision
[13,
20]. For clinically relevant
purposes, a lesion with a benign diagnosis on core needle biopsy that was then
upgraded to high risk after excision was reclassified as being in agreement
because no clinical consequences would result
[20].
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Subsequently, we calculated the agreement rate, the high-risk underestimate rate, the DCIS underestimate rate, the false-negative rate, and the sensitivity rate of sonographically guided core needle biopsy [19, 20]. The high-risk underestimate rate was defined as the proportion of lesions diagnosed as high risk by core needle biopsy that were upgraded to DCIS or invasive cancer after surgical excision, which were measured for ADH lesions, non-ADH lesions, and all high-risk lesions (i.e., combined ADH and non-ADH). The DCIS underestimate rate was defined as the proportion of lesions diagnosed as DCIS by core needle biopsy that were upgraded to invasive cancer after surgical excision. The false-negative rate was defined as the proportion of all breast cancers (invasive cancer and DCIS) with a benign diagnosis on sonographically guided core needle biopsy. The sensitivity rate was defined as the proportion of malignancies that were identified by core needle biopsy. The agreement rate was defined as the proportion of lesions that were not classified as DCIS underestimate, high-risk underestimate, or false-negative diagnosis.
For the false-negative diagnoses of sonographically guided core needle
biopsy, the time interval between core needle biopsy and excision, the reasons
for rebiopsy (suspicious imaging findings [i.e., discordance or growth] vs
suspicious physical findings or request by the patient or physician), and the
characteristics of the lesions (i.e., palpable abnormality [palpable vs
nonpalpable] or lesions size [
5, 6-10, 11-15, and > 15 mm]) were
analyzed. Statistical analysis was performed with the chi-square test using a
computerized statistics program (MedCalc, version 6.0.0, MedCalc Software),
and a p value of less than 0.05 was considered statistically
significant.
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Of the 1,071 benign lesions, immediate rebiopsy (n = 644) was done by surgical excision (n = 489) or by vacuum biopsy (n = 155) because of discordance (n = 110), request by the patient or referring physician (n =484), or suspicious physical findings (n = 50). Delayed rebiopsy (n = 76) was done by surgical excision (n = 36) or by vacuum biopsy (n = 40) because of progression at sonography follow-up (n = 26), request of the patient or referring physician (n = 40), or suspicious physical findings (n = 10). The number of vacuum biopsy samples ranged from five to 60 (mean number of samples: overall, 17; with 8-gauge needle, 18; with 11-gauge needle, 16). The other 351 benign lesions had stable sonography follow-up for at least 24 months (range, 24-61 months; mean, 35.8 months; median, 35 months) and are assumed to be benign.
Malignancy was found at immediate rebiopsy in 25 lesions (immediate false-negative diagnoses) that had rebiopsy because of discordance (n = 21), palpable mass (n =3), or nipple discharge (n = 1) and at delayed rebiopsy in six lesions (delayed false-negative diagnoses) that all had rebiopsy because of lesion progression at sonography follow-up (Table 2). All false-negative diagnoses were confirmed after surgical excision.
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Of the 1,312 lesions with a final diagnosis of malignancy, the initial core needle biopsy diagnoses were malignant (n = 1,256), high risk (n = 25), and benign (n = 31), giving a sensitivity of 96% (1,256 of 1,312) and a false-negative rate of 2.4% (31 of 1,312) of malignant lesions. The frequency of malignancy in lesions that had rebiopsy (n = 720) because of suspicious imaging findings (19.1%, 26 of 136) was significantly higher than because of suspicious physical findings or request by the patient or physician (0.9%, five of 584) (p < 0.0005). There was no significant difference in the false-negative rate according to lesion characteristics (Table 3).
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However, false-negative diagnoses are unavoidable and may delay the diagnosis and treatment of breast cancer. For reducing them, the imaging-histologic correlation is of critical importance in percutaneous imaging-guided breast biopsy to confirm that tissue was retrieved from the target lesion [23]. Most false-negative diagnoses were detected by imaging-histologic discordance [3, 7, 8, 10]. In this study, the frequency of malignancy in lesions that had rebiopsy due to suspicious imaging findings (discordance or increase in size) was significantly higher than that in lesions that had rebiopsy due to suspicious physical findings or request by the patient or physician. Of the false-negative diagnoses, 84% (21 of 25) underwent immediate surgical excision because of imaging-histologic discordance, which can avert a delayed diagnosis. Therefore, if a discordant benign lesion is promptly recognized, a rebiopsy is warranted, and a false-negative diagnosis can be identified prospectively, avoiding a delay in diagnosis. To identify imaging-histologic discordance, the radiologist performing the biopsy must be familiar with the imaging features of a vast array of pathologic breast lesions and be able to correlate imaging and pathology results [14].
In this study, six cancers had delayed diagnoses, of which four delayed false-negative findings were diagnosed more than 2 years after the initial core needle biopsy (Table 2). These lesions were found because of lesion progression at sonography and had not undergone any scheduled imaging follow-up before rebiopsy. In other studies with a minimum 2-year follow-up, delayed false-negative diagnoses were also reported. Crystal et al. [10] reported that three cases of 373 lesions had a delayed diagnosis of cancer because of interval growth on follow-up sonography 16, 23, and 27 months, respectively, after initial biopsy. Schoonjans and Brem [8] reported that one false-negative case was found at the 6-month imaging follow-up because of an increase in size.
For early detection of possible false-negative diagnoses, therefore, appropriate follow-up is essential after a concordant benign biopsy, but there is no standard follow-up guideline. For a follow-up interval, some recommend a close follow-up for 2 years with a clinical breast examination and diagnostic imaging studies biannually for the first year and annually for the second year [24, 25]. Others suggest a short-interval follow-up imaging at 6 months, unless a specific benign diagnosis (e.g., fibroadenoma, lymph node, cyst) with sufficient sonographically guided biopsy experience is yielded and long-term outcomes are carefully audited [26]. For a follow-up imaging technique, because changes in lesions may not be mammographically visible, especially in a mammographically dense breast, follow-up with sonography for 2 years and at least one standard mammography examination for patients older than 35 years is recommended [10, 25, 27]. In addition, patient compliance with the recommended follow-up schedule is essential if further delay in diagnosing missed malignant lesions is to be avoided. Goodman et al. [28] reported only 54% compliance with follow-up recommendations for imaging surveillance, and five patients with delayed false-negative diagnoses did not undergo imaging follow-up as recommended.
Histologic underestimation occurs when a percutaneous biopsy identifies the presence of a high-risk or malignant lesion but incompletely characterizes the pathology. In these lesions, the pathologic findings may be heterogeneous, and excision of the complete lesion may be necessary in a portion that was not sampled by the core needle biopsy. In the studies of 14-gauge core needle biopsy (mostly, stereotactic guidance), the ADH underestimate rate was 20-56% and the DCIS underestimate rate was 16-35% [29]. In the studies of sonographically guided core needle biopsy, the DCIS underestimate rate was 20-67%, and the ADH underestimate rate showed limited results (range, 0-100%; mean, 46%) because ADH cases were rare (1.1% of total biopsies; mean, 4.9 cases) [3, 5-8, 10, 30].
Our data for ADH and DCIS underestimate rates (52% [14 of 27] and 29% [36 of 126], respectively) are comparable with those mentioned. It is remarkable in our study that a sizable number of ADH and DCIS lesions were present as a mass because ADH and DCIS generally manifest as microcalcifications and therefore have constituted only a small number of lesions shown on sonography in previous studies [6, 8]. Even if the management of a non-ADH high-risk lesion is not well established and uncertainty remains, the underestimate rate (17%, 11 of 66) in this study supports the need to perform surgical excision. Further study with a large population is needed.
In this study, a large number of patients with palpable lesions (47%, 1,141 of 2,420) were included. For the diagnosis of palpable breast masses, palpation-guided fine-needle aspiration cytology can be performed as an initial sampling method. However, because of the limitations of fine-needle aspiration—that is, insufficient samples, false-negative results, and occasional false-positives [31]—sonographically guided 14-gauge core needle biopsy is initially performed at our facility to biopsy sonographically visible breast lesions regardless of the palpability of the lesion, which explains why the proportion of palpable lesions was high [32-34]. The pathologic results for sonographically guided core needle biopsy in this study were malignancy in 52% (1,256 of 2,420) of the cases, which is higher than the 20-30% reported for minimally invasive breast biopsy [4, 6, 22]. We choose to confirm an imaging or clinical finding that is highly suspicious for breast cancer by core needle biopsy rather than by surgical excision, which certainly has contributed to our higher malignancy rate [35]. The frequency of surgical excision after benign core needle biopsy was high in this study (67.2%, 720 of 1,071). Even though benign breast disease is not typically life-threatening and patients can often be reassured regarding the diagnosis of the benign nature of a mass, some women do not accept follow-up and insist on resolution by means of surgical excision. The underlying reasons for this decision are multiple: anxiety, fear, pregnancy, hormonal therapy, or moving out of the area, and so on [36, 37].
Our study has certain limitations. First, the cases included in this study were not consecutive. Benign biopsy results that were not proven by surgical or vacuum biopsy and did not have at least a 2-year follow-up were excluded. Therefore, a selection bias may exist, and it is possible that there were more false-negative diagnoses in the excluded cases. Second, in cases of false-negative diagnoses, the pathologic slides of core sample were not reviewed by a pathologist. We cannot conclude that there were no interpretative or clerical errors to account for cancers missed by the sonographically guided core biopsy. In other words, the possibility of false-negative diagnoses may not be caused by the biopsy procedure itself but rather by mistakes in the pathologic examination. Third, the use of sonographically guided vacuum biopsy with an 8- or 11-gauge needle as one of the gold standards is a new concept and has not been proven. Sonographically guided vacuum biopsy has been reported to be an accurate method for breast mass diagnosis [38-41]. Complete removal of all imaging evidence of a lesion using this instrument may reduce sampling error; however, it does not ensure complete excision of the pathologic abnormality, and underestimation and false-negative diagnoses have been reported in short-term follow-up studies [5, 29, 30, 36, 38, 40, 41]. Nevertheless, about its use in the resection of benign lesions, several studies have shown that this procedure could be an alternative to surgical excision [36, 39, 42, 43].
In conclusion, sonographically guided 14-gauge core needle biopsy is an accurate alternative for evaluating breast masses, but radiologists performing this procedure need to be aware of the possibility of a false-negative diagnosis. Careful imaging-histologic correlation allows the radiologist to identify discordant lesions prospectively and recommend prompt rebiopsy, avoiding diagnostic delay. In addition, the radiologist should emphasize to the patient or physician the importance of follow-up imaging after a benign concordant biopsy so that possible delayed cancers showing interval changes can be detected.
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