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(Radiology. 2001;219:785-792.)
© RSNA, 2001

Breast Imaging

Fine-Needle Aspiration Biopsy of Nonpalpable Breast Lesions in a Multicenter Clinical Trial: Results from the Radiologic Diagnostic Oncology Group V1

Etta D. Pisano, MD, Laurie L. Fajardo, MD, Daryl J. Caudry, MS, Nour Sneige, MD, William J. Frable, MD, Wendie A. Berg, MD, PhD, Irena Tocino, MD, Stuart J. Schnitt, MD, James L. Connolly, MD, Constantine A. Gatsonis, PhD, Barbara J. McNeil, MD, PhD and For the Radiologist Investigators of the Radiologic Diagnostic Oncology Group V.

1 From the Dept of Radiology, Univ of North Carolina, 101 Manning Dr, 515 Old Infirmary, Chapel Hill, NC 27599-7510 (E.D.P.); Dept of Radiology, Johns Hopkins Univ, Baltimore, Md (L.L.F.); Dept of Pathology, M.D. Anderson Comprehensive Cancer Ctr, Houston, Tex (N.S.); Dept of Pathology, Medical College of Virginia of Virginia Commonwealth Univ, Richmond (W.J.F.); Ctr for Statistical Sciences, Brown Univ, Providence, RI (C.A.G.); Dept of Radiology, Univ of Maryland, Baltimore (W.A.B.); Dept of Radiology, Yale Univ, New Haven, Conn (I.T.); Depts of Pathology (S.J.S., J.L.C.) and Health Care Policy (D.J.C., B.J.M.), Harvard Medical School, Boston, Mass; and Dept of Radiology, Brigham and Women’s Hosp and Harvard Medical School, Boston, Mass (B.J.M.). The radiologist investigators of the Radiologic Diagnostic Oncology Group V (RDOGV) and their affiliations are listed at the end of this article. From the 1999 RSNA scientific assembly. Received Aug 15, 2000; revision requested Sep 26; revision received Nov 8; accepted Dec 12. Supported by NIH grants UO1 CA62476, UO1 CA62514, UO1 CA62462. Address correspondence to E.D.P. (e-mail: etpisano@med.unc.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To determine the diagnostic accuracy of ultrasonographically (US) and stereotactically guided fine-needle aspiration biopsy (FNAB) in the diagnosis of nonpalpable breast lesions.

MATERIALS AND METHODS: At 18 institutions, 442 women who underwent 22–25-gauge imaging-guided FNAB were enrolled. Definitive surgical, core-needle biopsy, and/or follow-up information was available for 423 (95.7%) of these women. The reference standard was established from additional clinical and imaging information for an additional six (1.4%) women who did not undergo further histopathologic evaluation. The FNAB protocol was standardized at all institutions, and all specimens were reread by one of two expert cytopathologists.

RESULTS: When insufficient samples were included in the analysis and classified as positive, the sensitivity and specificity of FNAB were 85%–88% and 55.6%–90.5%, respectively; accuracy ranged from 62.2% to 89.2%. The diagnostic accuracy of FNAB was significantly better for detection of masses than for detection of calcifications (67.3% vs 53.8%, P = .006) and with US guidance than with stereotactic guidance (77.2% vs 58.9%; P = .002).

CONCLUSION: FNAB of nonpalpable breast lesions has limited value given the high insufficient sample rate and greater diagnostic accuracy of other interventions, including core-needle biopsy and needle-localized open surgical biopsy.

Index terms: Breast, biopsy, 00.126 • Breast neoplasms, 00.31. 00.32 • Breast neoplasms, US, 00.12985 • Stereotaxis, 00.1267


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Widespread screening with mammography and physical breast examination have been shown to reduce breast cancer mortality (1,2). However, many studies are false-positive, with positive predictive values (PPVs) for nonpalpable and palpable lesions ranging from 15% to 38% (3–6). Before the advent of percutaneous biopsy methods, many women underwent open surgical biopsy. With the introduction of stereotactic and ultrasonographically (US) guided methods for percutaneous sampling of nonpalpable lesions, fine-needle aspiration biopsy (FNAB) and core-needle biopsy have been used more widely in the evaluation of nonpalpable breast lesions (7–12).

FNAB has some advantages over core-needle biopsy in that it involves use of a smaller needle and thus has a lower probability of causing hematoma and other rare complications, such as pneumothorax (13–15). However, the clinical use of FNAB has been questioned because of the variability in results reported (16). When insufficient samples and atypical or benign cytologic findings are considered to be negative, sensitivities range from 43.8% to 95.0%; specificities, from 89.8% to 100%; PPVs, from 76.2% to 100%; and negative predictive values (NPVs), from 46.3% to 98.8%. When insufficient samples are excluded from analysis, the sensitivities and specificities range from 58.3% to 100% and from 55.5% to 100%, respectively; NPVs are between 46.6% and 98.6% (11,12,14,15,17–30). Core-needle biopsy generally has been more reliable than FNAB: Insufficient samples have been rare, and specificities and PPVs have ranged from 99% to 100% and from 94% to 100%, respectively. The sensitivities and NPVs of core-needle biopsy vary: 94%–99% and 78%–99%, respectively (31–33).

At least part of the demonstrated variability in FNAB results probably has been due to the different methods used at different centers. Needle size has varied from 20 to 23 gauge (14,15,17–19,34); both coaxial and multiple puncture techniques have been used, and the number of passes has varied from two to four or more (10,12,14,17,26,34). Not all studies have involved comparison of FNAB findings with histopathologic results from core-needle biopsy or open surgical biopsy or included long-term clinical follow-up of all cases (14,27–29,33–35). In addition, the experience of the radiologists and cytopathologists, the types of lesions sampled, the different guidance systems used, and the methods of specimen preparation and aspiration (eg, suction vs nonsuction) probably affect the success of FNAB in various published studies (12,14,15,17,18,34–37).

The acceptance of FNAB for nonpalpable lesions has been reduced because of the high percentage of insufficient samples: 0%–34% (10,12,14–18,21–24,29,34,38,39). Even FNAB of excised breast specimens yielded 7% insufficient samples (40). Because of variability in the results of FNAB of nonpalpable lesions, the National Cancer Institute funded the Radiologic Diagnostic Oncology Group V (RDOGV) trial, a multicenter clinical investigation to evaluate the sensitivity and specificity of FNAB. The reference standards for this study were the results of imaging-guided core-needle biopsy followed by either open surgical biopsy or mammographic and clinical follow-up for at least 20 months. As reported earlier (39), although the initial plan involved the enrollment of more than 2,000 women for all arms of the trial, the FNAB arms of the trial were closed to accrual early because of the high rate of insufficient samples; 128 (34%) specimens from 377 enrolled patients were insufficient. Since that study, complete data have been obtained in an additional 52 patients. Thus, at the time of this writing, the insufficient sample rate for RDOGV was 152 (35.4%) of 429 enrolled patients.

The National Cancer Institute convened a conference to make recommendations for breast FNAB methodology (41). The recommendations made by that group accurately define the methods used in the RDOGV study. The purpose of this study was to determine the diagnostic accuracy of US- and stereotactically guided FNAB in the diagnosis of nonpalpable breast lesions.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients were enrolled at 18 participating institutions (Table 1). At arm A institutions, patients underwent stereotactically guided biopsy only. At arm B institutions, patients underwent either stereotactically or US-guided biopsy. Radiologists at all institutions were required to have performed at least 50 imaging-guided FNAB procedures before entering patients into this study, but there was no minimum requirement for prior experience in FNAB for each participating radiologist. The number of radiologists who performed FNAB at each institution was not limited. The institutional review boards at all participating centers approved the RDOGV protocol, and all enrolled patients gave informed consent prior to their participation.


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  		TABLE 1. Institution and Number of Patients Enrolled

 
Eligible women were those with nonpalpable lesions detected at mammography within the 3 months prior to their participation. The types of lesions to be entered in the study were defined as those that were likely to necessitate biopsy on the basis of their mammographic features, as described in Table 2. This study began before the widespread use of American College of Radiology Breast Imaging Reporting and Data System categories and descriptors, so these were not used. However, all cases would have been considered for biopsy at the participating institutions regardless of their inclusion in this trial; thus, they would be considered Breast Imaging Reporting and Data System category 4 or 5 cases. To code the degree of suspicion of the lesions recommended for biopsy, all cases were classified by the participating radiologists as probably benign, indeterminate, suspicious, or malignant.


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  		TABLE 2. Mammographic Criteria for Eligibility in RDOGV Study

 
All mammograms were reviewed by one of two breast imaging radiologists (E.D.P. or L.L.F.) to ensure patient eligibility. In patients with more than one lesion, only the most mammographically suspicious lesion was sampled as part of the study. Other exclusion criteria were lesions located in a prior lumpectomy or radiation therapy site, anticoagulant therapy, pregnancy, known bleeding disorders, psychiatric conditions, and neurologic conditions that precluded cooperation during biopsy or adequate informed consent.

Patients were randomly selected by the American College of Radiology Statistical Center, Philadelphia, Pa, by means of telephone or e-mail correspondence. Patients enrolled at arm A institutions were randomly selected for stereotactically guided FNAB and stereotactically guided core-needle biopsy or for stereotactically guided core-needle biopsy only. Patients enrolled at arm B institutions were randomly selected for either US-guided FNAB and US-guided core-needle biopsy or US-guided core-needle biopsy only or for stereotactically guided FNAB and stereotactically guided core-needle biopsy or stereotactically guided core-needle biopsy only. Crossover from the assigned guidance system was allowed when the radiologist performing the biopsy deemed the lesion to be inaccessible with the assigned method. This occurred when lesions could not be seen at US (eg, frequently clustered calcifications) or when the lesion was too close to the chest wall to be sampled with stereotactic guidance.

The RDOGV FNAB protocol required a minimum of five needle passes with imaging guidance. More passes could be made at the discretion of the radiologist performing the biopsy or the accompanying cytopathologist, if one was available. Needle size could vary from 22 to 25 gauge. Coaxial guidance was permitted if it was desired by the radiologist performing the biopsy. Aspiration and nonaspiration techniques were permitted. For masses, samples were obtained at the center of the mass and along radii extending toward the 3, 6, 9, and 12 o’clock positions. Specific calcifications were targeted. For stereotactic biopsy, stereotactic radiographs were obtained after placement of the first- and last-pass needles. For stereotactically guided FNAB, real-time confirmation of needle placement was performed with each pass.

For sites sampled by using the coaxial FNAB method, three passes in the central plane of the lesion were performed at different depths, with subsequent movement of the coaxial guiding needle to another portion of the lesion for two additional passes.

Two methods of specimen preparation were used at all centers. At some centers, the specimens were smeared immediately by the radiologist, cytopathologist, or an assistant. Both air-dried and wet-fixed slides were made from specimens collected at each pass. For the second specimen preparation method, the aspirate was placed directly into a 50% Ringer lactate plus 50% alcohol solution or a balanced salt solution. These specimens were then transported to the cytology laboratory for millipore filter or cytospin preparation and subsequent Papanicolaou staining. The same solutions were used to wash the residual material in the FNAB needles at the centers where immediate smearing of samples was performed.

The slides and fixative rinses were transported to the cytopathology laboratory as soon as possible after they were obtained. All alcohol or spray-fixed smears were placed in Carnoy solution (acetic acid 1:6 and 70% ethanol) for approximately 5 minutes before staining to lyse the red blood cells. Air-dried slides were stained with Diff-Quik (Dade, Division of Travenol Laboratories, Miami, Fla) or other Romanowsky methods. Wet-fixed slides were stained with Papanicolaou or hematoxylin and eosin stain. The local cytopathologists at each site interpreted the specimens according to their routine institutional clinical protocol.

All cytopathologic specimens and reports were reviewed by one of two RDOGV central cytopathologists (N.S. or W.J.F.) for both a diagnosis and compliance with the RDOGV FNAB protocol. The local report was coded by one of these two reviewers only after reviewing the specimen and rendering a separate interpretation. Specimens were considered insufficient if there were fewer than six epithelial groups on the slides available to the central reviewers. The following classifications were used for local and central interpretations: insufficient, benign, atypical, probably malignant, and malignant. If the local report could not be coded by the central cytopathologist, it was classified as undetermined. If the central reader disagreed with the local reader regarding the diagnosis, a reading by the second central reader was performed. The majority opinion of the three available readers was considered the FNAB diagnosis for purposes of analysis in this study.

The reference standard was based on the result of open surgical biopsy if it was available, unless core-needle biopsy results revealed malignancy when open biopsy did not. For these patients, it was assumed that the entire malignancy was removed at core-needle biopsy. For patients with atypical findings at core-needle biopsy—that is, lobular carcinoma in situ, atypical lobular hyperplasia, or atypical ductal hyperplasia—who did not undergo open surgical biopsy, the reference standard was considered to be undefined.

If a patient advanced into the follow-up arm of the study, the reference standard was based on the result of at least 20 months of follow-up imaging. Exceptions to the 20-month requirement were made for patients with (a) lesions that were no longer seen on follow-up images (no minimum follow-up time required) and (b) masses that appeared smaller on follow-up images (at least 12 months of follow-up required). For these cases, the reference standard was defined as benign. For patients at follow-up who underwent subsequent core-needle biopsy, open surgical biopsy, or definitive surgery, the reference standard was based on histopathologic findings.

For patients at follow-up who had an abnormal change on a follow-up mammogram and did not undergo further biopsy, the reference standard was statistically determined; there were six such patients. In assigning all such cases, a malignant reference standard was considered to be inappropriate, because the majority of patients who had abnormal follow-up findings and underwent subsequent core-needle biopsy or surgical intervention were found to have benign lesions.

To determine a reference standard for these patients, logistic regression analysis was performed by involving all patients who had a valid reference standard. Two models were used: one for masses and one for calcified lesions. Data were stratified by means of consortium. For both lesion types, truth about malignancy status was known. For masses, the predictor variables were mammographic: basis for eligibility (eg, circumscribed mass with a diameter <1 cm that had grown since a prior mammogram), degree of suspicion of malignancy, shape and density of lesion, and US features (ie, homogeneity, echogenicity, shape, and posterior features). For calcified lesions, the predictor variables were mammographic features—specifically, degree of suspicion of malignancy, number of calcifications, and morphologic features of the calcifications (ie, linear and/or branching).

Data on the predictor variables were collected from assessments of the initial mammograms and US scans obtained at the time of study entry. All patients had mammographic data, but not all patients underwent US. The described variables were found to be the best predictors of malignancy and correlated very highly with many other variables from the initial mammographic and US assessments. In addition, we took into account the nature of the abnormal interval change on the follow-up mammogram and the findings of other follow-up images obtained in these patients.

By using the coefficients from the regression analysis, a probability of malignancy was calculated for the patients with an abnormal change on a follow-up mammogram and no subsequent surgical intervention. Lesions with a probability of malignancy greater than 35% were assigned a malignant reference standard.

The result of FNAB was dichotomized in several ways, and the sensitivity, specificity, PPV, NPV, and accuracy were computed for the varying definitions of malignancy. A benign FNAB finding was always defined as negative, and a suspicious or malignant finding was always defined as positive. The insufficient FNAB samples were alternately included in the negative group, included in the positive group, or excluded from analysis. The FNAB atypical category was likewise included first in the benign category and then in the malignant category. The reference standard, based on the results of open biopsy, core-needle biopsy, or follow-up, was defined such that negative was defined as benign disease, atypical ductal hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in situ at histopathologic analysis, or 20 months of follow-up mammography with no abnormal changes. Positive was defined as ductal carcinoma in situ, invasive cancer, or other nonbenign disease at histopathologic analysis, or an abnormal mammogram within 20 months of FNAB.

Summary measures for the various FNAB definitions of malignancy were reported for (a) all lesions together, (b) masses, (c) calcifications, (d) lesions with a low mammographic degree of suspicion of malignancy (ie, probably benign or indeterminate), (e) lesions with a high mammographic degree of suspicion of malignancy (ie, suspicious or malignant), (f) lesions sampled with US-guided FNAB, and (g) lesions sampled with stereotactically guided FNAB. Computations for categories d–g were performed for all lesions together and for masses and calcifications separately.

The sensitivity, specificity, PPV, NPV, and accuracy of FNAB for detection of masses were compared with the summary measures for calcified lesions. A comparison of summary measures for FNAB was performed also for lesions with a low mammographic suspicion of malignancy, lesions with a high mammographic suspicion of malignancy, lesions evaluated with US guidance, and lesions evaluated with stereotactic guidance. All comparisons were performed by using the Fisher exact test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Population
Between April 1994 and November 1996, 2,403 patients were enrolled in the study, and 2,074 (86.3%) were ultimately confirmed to be eligible for entry. Of the eligible patients, 484 were assigned to undergo either US-guided or stereotactically guided FNAB. Of these, 418 (86.4%) women actually underwent FNAB, and 66 did not. FNAB was performed in an additional 30 women who were not assigned to undergo the procedure. Thus, a total of 448 women underwent FNAB. The results for six patients who underwent FNAB could not be evaluated because their slides were either lost (three patients) or not sent for central cytopathologic review (three patients).

The reasons that FNAB was not performed in the 66 women who were assigned to undergo the procedure but did not were radiologist preference in 21 (31.8%) patients, technical difficulty in 19 (28.8%), patient discomfort in five (7.6%), refusal in four (6.1%), medical contraindication in one (1.5%), and miscellaneous other reasons in 16 (24.2%). The 21 cases in which radiologists chose not to perform FNAB even though it was assigned and the 30 cases in which FNAB was performed when it was not assigned technically were protocol violations.

Of the remaining 442 patients, 423 (95.7%) had reference standard information available for analysis (404 with histopathologic data and 19 with follow-up imaging data), and six (1.4%) had a reference standard imputed from other available imaging and clinical information. The other 13 (2.9%) patients did not have available reference standard information.

In the six patients with imputed reference standards, one mass was imputed to be malignant and the other five (four masses and one cluster of calcifications) were imputed to be benign. For all these cases, the local radiologist interpreted the lesion as indeterminate. The only lesion that was considered to be suspicious by the central reader was impugned to be malignant. The other five lesions for which the reference standard was imputed were considered by the central readers to be probably benign or indeterminate. The sources of reference standard information are listed in Table 3.


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  		TABLE 3. Sources of Information on Reference Standard

 
Of the 429 patients, 149 (34.7%) were assigned to undergo US-guided biopsy and 280 (65.3%) were assigned to undergo stereotactically guided biopsy. Twenty-six (6.1%) of the 429 patients were assigned to undergo core-needle biopsy only, but they underwent FNAB also. There was extensive crossover from the assigned guidance system to the other guidance system. The crossover rate from US to stereotactic guidance was 65.8% (98 of 149 patients), and the crossover rate from stereotactic to US guidance was 10.0% (28 of 280 patients).

Of 429 patients, 138 were enrolled at arm A institutions that did not have US guidance capability and thus could not have their guidance system changed. Of 291 patients enrolled at arm B institutions, which had both stereotactic and US guidance capability, 142 were assigned to undergo stereotactic guidance, 28 (19.7%) of whom were crossed over to US guidance. Of 149 patients enrolled at arm B institutions and assigned to US guidance, 98 (65.8%) were crossed over to stereotactic guidance.

Of the patients enrolled at arm B institutions, 185 had masses, 94 of whom were assigned to undergo stereotactic biopsy; 28 (30%) of the 94 patients crossed over to US guidance. Ninety-one of the 185 patients were assigned to undergo US-guided biopsy; 49 (53.8%) of them crossed over to stereotactic guidance. In addition, 106 patients with calcifications were enrolled at arm B institutions. Forty-eight of these patients were assigned to undergo stereotactic guidance, and none of these women crossed over to US guidance. However, 56 (97%) of the 58 patients with calcifications who were assigned to undergo US guidance crossed over to stereotactic guidance.

The mean age of the 429 patients was 54.3 years (age range, 27.1–82.8 years). Three hundred forty-four (80.2%) of these women were white; 63 (14.7%), African-American; 17 (4.0%), Hispanic; four (0.9%), Asian; and one (0.2%), another race. The histopathologic descriptions of the lesions in this study are listed in Table 4. As the data in Table 4 indicate, 94.2% (404 of 429) of the patients who underwent FNAB also underwent histopathologic evaluation of their nonpalpable breast lesions. Of the 404 patients with available histopathologic data, 86 (21.3%) had malignant lesions, 317 (78.5%) had benign lesions, and one (0.2%) had samples that were inadequate for evaluation.


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  		TABLE 4. Available Histopathologic Data in 403 Patients Who Underwent FNAB

 
As reported in Table 5, the distribution of FNAB results was 46.6% benign, 35.4% insufficient samples, 4.4% atypical, and 13.5% probably malignant or malignant. The data in Table 6 show how the sensitivity, specificity, accuracy, PPV, and NPV of FNAB varied when atypical samples were considered to be positive and insufficient samples were either considered to be positive or excluded from analysis. As the data in Table 6 show, sensitivity varied from 85% to 88%; specificity, from 55.6% to 90.5%; and accuracy, from 62.2% to 89.2%. The PPV varied from 33.6% to 74.0%; the NPV was 95.0%. The data in Table 7 are FNAB outcome measurements obtained when atypical samples were classified as negative.


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  		TABLE 5. Distribution of Patients according to FNAB and Reference Standard Results

 

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  		TABLE 6. Test Outcomes when Atypical Samples Are Classified as Positive and Insufficient Samples Are Classified as Positive or Excluded from Analysis

 

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  		TABLE 7. Test Outcomes when Atypical Samples Are Classified as Negative and Insufficient Samples Are Classified as Negative or Positive or Are Excluded

 
As indicated by the data in Table 8, for the 331 (77.2%) patients with lesions that were considered to be probably benign or indeterminate at mammography, when both insufficient and atypical samples were considered to be positive, the sensitivity, specificity, and accuracy were 87% (26 of 30 patients), 56.5% (170 of 301 patients), and 59.2% (196 of 331 patients), respectively; the PPV was 16.6% (26 of 157 patients), and the NPV was 97.7% (170 of 174 patients). For the 98 (22.8%) patients with lesions that were considered to be suspicious or malignant at mammography, when both insufficient and atypical samples were considered to be positive, the sensitivity, specificity, accuracy, PPV, and NPV were 90% (51 of 57 patients), 49% (20 of 41 patients), 72% (71 of 98 patients), 71% (51 of 72 patients), and 77% (20 of 26 patients), respectively.


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  		TABLE 8. Distribution of Patients according to FNAB Results, Mammographic Impression of Malignancy, and Reference Standard Results

 
Note that Tables 5–8 include data on 10 (12%) breast cancers—four masses and six calcifications—of 87 diagnosed cancers that would have been missed if a benign FNAB result had stopped the diagnostic work-up. These 10 cases include four cancers that had a probably benign or indeterminate appearance at mammography.

FNAB in Patients with Masses versus Calcifications and according to Guidance System
In Table 9, the FNAB results are compared with the results of the reference standard for detection of masses and clustered calcifications and classified according to guidance system. Overall, FNAB had a higher but not statistically significant different sensitivity for the detection of masses compared with that for the detection of calcifications, 93% (50 of 54 patients) versus 82% (27 of 33 patients) (P = .169). There was a statistically significant difference in specificity for masses versus calcifications, 60.9% (131 of 215 patients) versus 46.5% (59 of 127 patients) (P = .009), and a statistically significant difference in accuracy, 67.3% (181 of 269 patients) for the detection of masses and 53.8% (86 of 160 patients) for the detection of calcifications (P = .006). The PPV of FNAB was 37.3% (50 of 134 patients) for masses versus 28% (27 of 95 patients) for calcifications (P = .201). The NPV for FNAB was 97.0% (131 of 135) for masses versus 91% (59 of 65 patients) for calcifications (P = .081).


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  		TABLE 9. Comparison of FNAB Results to Reference Standard Results for Detection of Masses and Calcifications and according to Guidance System

 
The performance of FNAB according to guidance system was strongly affected by its performance according to lesion type: Only two (1.2%) of 160 patients with calcification clusters underwent sampling with US guidance. Stereotactic guidance had a lower sensitivity (88% [60 of 68 patients] vs 90% [17 of 19 patients], P = .999), specificity (51.8% [146 of 282 patients] vs 73% [44 of 60 patients], P = .003), and accuracy (58.9% [206 of 350 patients] vs 77% [61 of 79 patients], P = .002) than did US guidance. The PPVs and NPVs for stereotactic guidance were 30.6% (60 of 196) and 94.8% (146 of 154 patients), respectively, versus 52% (17 of 33 patients) and 96% (44 of 46 patients), respectively, for US guidance (P = .027 and P = .999, respectively).

There was a statistically significant reduction in the number of insufficient samples when a cytopathologist was present for FNAB: 23% (22 of 97 samples) with cytopathologist versus 38.8% (128 of 330 samples) without cytopathologist (P = .004). As indicated by the data in Table 10, this reduction was due primarily to the difference in the number of insufficient calcification samples, almost all of which were collected with stereotactic guidance. The data in Table 11 show that there was a statistically significant improvement in the specificity of FNAB when a cytopathologist was present for the procedure and insufficient samples were considered to be positive. When insufficient samples were considered to be negative, there was no statistically significant difference in the sensitivity, specificity, PPV, NPV, or accuracy of FNAB. In addition, there was large variability in the rate of insufficient samples across institutions: from one of 27 (3.7%) samples to four (100%) of four samples.


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  		TABLE 10. Effect of Cytopathologist Presence during FNAB Procedure on Number and Percentage of Insufficient Samples

 

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  		TABLE 11. Effect of Cytopathologist Presence during FNAB Procedure on Summary Measures

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
REFERENCES
 
Our study results strongly suggest that the large proportion of insufficient samples (35.4%) reduced the usefulness of FNAB for the evaluation of nonpalpable breast lesions. Because an insufficient sample can be obtained, even when the patient has cancer, treating the insufficient result as a negative outcome is a poor policy that has the potential to cause harm to patients and delay the diagnosis of breast cancer. Thus, additional testing—that is, histopathologic sampling of the mammographic finding—is always required for such patients. This is not cost-effective when core-needle biopsy provides accurate histopathologic information without additional testing (7–12).

In addition, even when FNAB provided a sample that could be interpreted by a cytopathologist, the results did not correlate with the reference standard results with acceptable sensitivity and specificity. Specifically, this study included 10 (12%) breast cancers of 87 breast malignancies that were diagnosed but would have been missed if a benign FNAB result had stopped the diagnostic work-up. These 10 cases included four cancers that had a probably benign or indeterminate appearance at mammography and presumably might have been managed by using follow-up in a practice where FNAB is performed to triage patients. In actual practice, the sensitivity in our patient population of 85.1%–88.5%, even with insufficient samples excluded, would not be acceptable to patients and the clinicians caring for them.

Some centers where FNAB is performed have reported better diagnostic accuracy and lower insufficient sample rates than those observed in the present study (29,42–44). This is owing to meticulous and careful attention to detail, as well as superior training in lesion aspiration, slide preparation, and specimen interpretation. This protocol requires a skilled staff that is dedicated to making this method work well for many women. Given the variability of results seen among the participating sites in this study, it would be advisable for radiologists who are considering using FNAB in place of more invasive diagnostic methods to prove the accuracy of their FNAB results by means of outcome analysis and comparison with the results of more invasive examinations.

The number of insufficient samples can be lowered and the specificity and accuracy of FNAB improved by having a cytopathologist present during the procedure (Table 10). Because this factor was not randomized in this study, it varied according to enrolling site, so its effect could not be distinguished from other institutional effects. The presence of an additional physician at breast FNAB with stereotactic guidance increases the costs of this triage examination to levels that are not competitive with the costs of other available technologies—namely, stereotactically guided core-needle biopsy, which requires the presence of only the physician obtaining the sample. Although US-guided FNAB, with or without a cytopathologist, is less expensive than US-guided core-needle biopsy in most centers, the high rate of insufficient samples with US-guided FNAB drives up the costs, because all patients with insufficient samples will require additional examinations.

In this study, there was a high rate of crossover from the assigned guidance system to the alternative system when both systems were available (ie, at arm B institutions); a greater percentage of patients crossed over from US to stereotactic biopsy (65.8% vs 19.7%). This is probably because patients were recruited on the basis of a positive mammogram, which ensured that all the lesions were visible mammographically but not necessarily visible ultrasonographically. The crossover was greatest for patients with calcifications: 96.6% of those assigned to US guidance were crossed over to stereotactic guidance. As has been well documented in the literature (45), some mammographically visible lesions are not accessible to stereotactic biopsy.

Some might say that our study was limited because we did not provide uniform training of the operators at each site. We believe that the results reported here more closely reflect the way that FNAB is practiced within communities at large in the United States. FNAB of nonpalpable breast lesions is very operator dependent. For nonpalpable breast lesions, both core-needle biopsy and needle-localized open surgical biopsy are more accurate and less operator dependent than FNAB.

Radiologist Investigators of the Radiologic Diagnostic Oncology Group V: Daniel Sullivan, MD, University of Pennsylvania, Philadelphia; Murray Rebner, MD, Henry Ford Hospital, Detroit, Mich; Gillian Newstead, MD, New York University Hospital and Belleview Hospital, New York, NY; Jana Rice, MD, Case Western Reserve University, Cleveland, Ohio; Melvin Clouse, MD, New England Deaconess Medical Center, Boston, Mass; Irena Tocino, MD, Yale University, New Haven, Conn; Denise Farleigh, MD, Providence Imaging, Anchorage, Alaska; Sakaran Babu, MD, Madigan Army Hospital, Tacoma, Wash; W. Phil Evans, MD, Baylor-Komen Breast Center, Dallas, Tex; John Milbrath, MD, Breast Diagnostic Clinic, Waukesha, Wis; Debra Monticciolo, MD, Emory University, Atlanta, Ga; Rachel Brem, MD, Johns Hopkins University, Baltimore, Md; Steve Parker, MD, Radiology Imaging Associates, Denver, Colo; Stephen Feig, MD, Thomas Jefferson University, Philadelphia, Pa; Wendie A. Berg, MD, PhD, University of Maryland, Baltimore; Etta D. Pisano, MD, University of North Carolina, Chapel Hill; Laurie L. Fajardo, MD, University of Virginia, Charlottesville.

Author contributions: Study concepts and design, E.D.P., L.L.F., C.A.G., B.J.M.; literature research, E.D.P.; clinical and experimental studies, E.D.P., L.L.F., W.A.B., I.T., RDOGV radiologist investigators; data acquisition, E.D.P., L.L.F., N.S., W.J.F., W.A.B., I.T., RDOGV radiologist investigators; data and statistical analyses, C.A.G., D.J.C.; manuscript preparation, E.D.P.; manuscript definition of intellectual content, editing, and revision/review, all authors; manuscript final version approval, E.D.P., D.J.C.


   FOOTNOTES
 
Abbreviations FNAB = fine-needle aspiration biopsy NPV = negative predictive value PPV = positive predictive value RDOGV = Radiologic Diagnostic Oncology Group V

Author contributions: Guarantor of integrity of entire study, E.D.P. The complete list of author contributions appears at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 

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