- Email: [email protected]
The evaluation of false negative mammography from malignant and benign breast lesions
Journal of Clinical Imaging 24 (2000) 96 ± 103
The evaluation of false negative mammography from malignant and benign breast lesions Jane Wanga, Tiffany Ting-Fang Shiha,b,*, Jane Chien-Yao Hsua,b, Yiu-Wah Lia,b a
Department of Medical Imaging, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan b Department of Radiology, College of Medicine, National Taiwan University, Taiwan Received 30 January 2000; accepted 30 May 2000
Abstract Preoperative mammograms from 395 breast cancers and 132 benign breast lesions were enrolled for this study. The false-negative (FN) rate for breast cancers from preoperative reading was 9.6% with 38 breast cancers missed on mammograms. The statistically significant differences occurred between true-positive (TP) and FN cancers for younger age (P < .025), smaller lesion size (P < .001), denser breast (P < .05), deep retroglandular location (P < .001). None of the FN cancers exhibited calcifications. The FN rate for mammography for benign breast lesions from preoperative reading was 18.9% with 25 lesions misdiagnosed. The statistically significant difference between benign TP and FN lesions occurred for central and subareolar location (P < .025). Exploration of possible factors and imaging features in FN mammograms can help reduce the FN rate for mammography. D 2000 Elsevier Science Inc. All rights reserved. Keywords: Mammography; False-negative; True-positive; Breast; Abnormalities
1. Introduction Mammography continues to be regarded as a useful diagnostic tool for detection and diagnosis of breast lesions. Although there have been many studies of false-negative (FN) mammograms for breast cancers [1 ± 10], mammograms for the benign equivalents have been studied very seldom. Some workers note common imaging characteristics for breast lesions and offer possible causes for FN mammograms [1,3,7]. False-negative (FN) rates for mammographic detection for breast cancers range from 4.3% to 34.2%, varying according to the sampled population and the definition of FN mammograms used [1,3,6 ± 8,10]. Bird et al. [1] found that missed cancers on mammograms tended to occur in denser breasts, were often present as developing densities, and were frequently located in the retroglandular region. Huynh et al. [2] noted that FN interpretation errors for mammograms may be caused by suboptimal viewing conditions, outside distractions, lack of a systematic approach,
* Corresponding author.
overlooking a subtle interpretation because of a more obvious finding, lack of knowledge of clinical findings, imprecise correlation with other studies, and simple disbelief. In addition, other authors have demonstrated that the missed cancers were statistically significantly lower in density, and more often visible on only one of two views, smaller in size [2,3]. Most early breast cancers present as microcalcifications, which can be reliably detected on mammograms [11,12]. Some lesions, however, present as palpable, noncalcified tumors and can be missed mammographically [6,7], thus the information provided by a clinical examination is important in conjunction with the assessment of mammograms for symptomatic patients [2,7]. The goal of this study is to discover the probable reasons for, and characteristics of, FN mammograms for breast cancers and benign breast lesions, particularly for Oriental women, whose breasts are usually smaller and denser than those of their Western counterparts. Acknowledgment of salient features and determining factors for FN mammograms, especially for breast cancers, can improve the lesiondetection rate by mammography, and thus reduce diagnostic delays and ultimately improve survival rates for breast cancer patients.
0899-7071/00/$ ± see front matter D 2000 Elsevier Science Inc. All rights reserved. PII: S 0 8 9 9 - 7 0 7 1 ( 0 0 ) 0 0 1 8 4 - 4
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
2. Materials and methods
Table 2 The average ages and sizes of malignant and benign mammo-TP and -FN lesions
2.1. Study population The preoperative mammograms from female patients with pathology-proven, malignant and benign breast lesions were collected over the period from January 1995 to February 1999. The intervals from mammography to surgery ranged from zero to 124 days (mean = 8.1) for malignant cases and zero to 134 days (mean = 19.1) for benign cases. The follow-up period ranged from 9 to 61 months (mean = 26.8). All the mammographic examinations were performed using a GE DMR dedicated mammography unit (GE, Senographe DMR, Buc, Cedex, France) with 18 24 cm Min-R M screens in combination with Min-R M films (Eastman Kodak, Rochester, NY). The processing time was 90 s for each exposure. The first, preoperative mammographic results were obtained using the services of a single in-house radiologist and based exclusively on mammograms that conformed to specially designed mammography questionnaires. The retrospective reviews were performed by a second inhouse radiologist utilizing adequate clinical breast examination results and corresponding sonographic findings. The radiologists worked independently and blindly, and their results were not compared by each other. Comparisons of preoperative and retrospective diagnoses of mammograms were performed by two radiologists in our department (J.W. and T.T.-F.S.). As an initial step in the elaboration and exploration of the features and characteristics of breast abnormalities, the definitions for TP and FN lesions need to be established. TP malignant lesions were defined where the abnormalities were detected on mammograms at the first reading, that is, preoperatively, these lesions being determined as suspicious or definitely malignant in nature, and a diagnosis of breast cancer delivered without delay. TP benign lesions were defined where the
Table 1 Categorization of mammographic FN (mammo-FN) lesions Type
Malignant FN
Benign FN
Type I FN
Lesions cannot be identified either preoperatively or retrospectively due to poor film quality Lesions cannot be seen either preoperatively or retrospectively with acceptable film quality Lesions cannot be detected preoperatively but can be depicted retrospectively Lesions misinterpreted as benign in nature
Same as left
Type II FN
Type III FN Type IV FN
97
Same as left
Same as left
Malignant Malignant TP FN P* Agea 51.8 (year) Sizeb 2.94 (cm)
47.7 2.04
Benign Benign TP FN P**
.01 < P < .025 45.9 P < .001
2.00
43.4 1.65
.1 < P < .2 P > .1
* Student's t test, the P value for malignant lesions. ** The P value for benign lesions. a The average age of TP and FN patients. b The average size of TP and FN lesions, across the largest diameter.
lesions were distinguished preoperatively. Four types of malignant FN lesions were established: Type I FN lesions were those that could not be detected either preoperatively or postoperatively due to poor image quality related to positioning or exposure problems; Type II FN lesions were those that could not be recognized either preoperatively or retrospectively despite acceptable image quality; Type III FN lesions could not be distinguished preoperatively but were identified in retrospective mammogram review; Type IV FN lesions were recognized preoperatively but misdiagnosed as benign in nature (Table 1). Only three types of benign FN lesions were established, Types I, II and III, using the definitions above (Table 1). The classification of breast tissue patterns is taken from the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BIRADS): ACR 1, breast with predominant fat; ACR 2, breast with predominant fat and up to 25% visible fibroglandular tissue; ACR 3, heterogeneous dense breast with over 25% as visible fibroglandular tissue; ACR 4, extremely dense breast [13]. The TP and FN groups for breast cancers and benign breast lesions were compared according to the following factors: the age of the patients, size of lesions (across the largest diameter), breast tissue patterns, lesion locations, predominant mammographic features and pathology types. The TP and FN groups of malignant lesions and the TP and FN groups of benign breast lesions were analyzed separately. The relationship between age and lesion size was analyzed using Student's t test. The relationships between TP and FN classes were analyzed for breast tissue pattern, lesion location, mammographic features, and pathology type using the chi-square test (c2 test) to assess goodness of fit and binomial distribution of TP and FN lesions. The threshold value (a) below
98
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
Table 3 The breast tissue patterns of malignant and benign mammo-TP and -FN lesions ACR breast patterns
Malignant TP (%)
Malignant FN (%)
Benign TP (%)
Benign FN (%)
1 2 3 4 3+4 Number of lesions
121 27 179 30 209 357
6 2 22 8 30 38
18 6 75 8 83 107
2 1 17 5 22 25
(33.9) (7.6) (50.1) (8.4) (58.5)
(15.8) (5.3) (57.9) (21) (78.9)
(16.8) (5.6) (70.1) (7.5) (77.6)
(8) (4) (68) (20) (88)
Numbers in parentheses mean percentages. 3 + 4: sum of ACR 3 and ACR 4 lesions. Binomial distribution for malignant TP and FN lesions for 3 + 4: P < .05. c2 Test for malignant lesions: .01 < P < .025. c2 Test for benign lesions: P > .1.
which statistical significance will be declared is set at 0.05 in this study. 3. Results The preoperative mammograms for 512 female patients were collected for this study. Of these, 395 malignant breast lesions were taken from 392 patients and 132 benign breast lesions were taken from 120 patients. Of the malignant lesions, there were 357 TP breast cancers from 354 patients (aged 24 to 91 years, mean 51.8 years) and 38 FN cancers from 38 patients (aged 31 to 75 years, mean 47.7 years) with an FN rate of 9.6%. The average age of TP patients and FN patients was 51.8 and 47.7 years, respectively (P < .025) (Table 2). The average size of the 357 malignant TP lesions and FN cancers were 2.93 and 2.04 cm, respectively, across the largest diameter (P < .001) (Table 2). The breast tissue patterns for malignant TP and FN lesions showed significant differences (c2 test, P < .025),
Table 5 Types and numbers of malignant and benign FN lesions Types Type I FN Type II FN Type III FN Type IV FN Total
Numbers of malignant lesions (%)
Numbers of benign lesions (%)
3 21 12 2 38
1 (4) 19 (76) 5 (20) ± 25
(7.9) (55.3) (31.6) (5.2)
Numbers in parentheses mean percentages.
the TP cancers occurred more often in fatty breasts (ACR 1), and FN cancers occurred more often in denser breasts (ACR 3 and 4) (P < .05, Table 3). For malignant breast lesions, the probability was higher that FN lesions would be located in the deep retroglandular portion of the breast, compared with TP lesions (P < .001) (Table 4). There were no statistically significant differences for the other lesion locations between the TP and FN groups (Table 4). Of the 38 FN cancers, three were classified as Type I FN lesions because they could not be identified either preoperatively or retrospectively as a result of poor mammographic techniques (Table 5) (Fig. 1). Of the remaining 35 FN lesions, 21 were classified as Type II FN lesions as the cancers could not be depicted either preoperatively or retrospectively with acceptable film quality (Fig. 2); Twelve lesions could be recognized on review (Type III FN lesions), and exhibited the following imaging features: focal discrete ill-defined mass with spiculated margin (n = 7), increased
Table 4 The lesion locations of malignant and benign mammo-TP and -FN lesions Location
Malignant Malignant TP (%) FN (%) P*
Lateral 159 (44.5) 10 (26.3) > .2 Medial 77 (21.6) 2 (5.3) > .5 Central and 39 (10.9) 3 (7.9) > .8 subareolar Deep 20 (5.6) 12 (31.6) < .001 retroglandular Othersa 62 (17.4) 11 (28.9) ±
Benign TP (%)
Benign FN (%) P * *
53 (49.5) 11 (44) > .7 22 (20.6) 2 (8) > .6 15 (14.0) 7 (28) < .025 2 (1.9) 15 (14.0)
0 (0)
±
5 (20) ±
Numbers in parentheses mean percentages. c2 Test for malignant lesions: P < .01. c2 Test for benign lesions: P > .1. * P: evaluation of binomial distribution of malignant TP and FN lesions by P value. ** P: evaluation of binomial distribution of benign TP and FN lesions by P value. a Others mean the locations crossing two or three areas mentioned above.
Fig. 1. The mammography of the right breast in MLO view of a 59-year-old woman shows no definite focal lesions even in retrospect. An infiltrating ductal carcinoma, with a 2-cm diameter, in the deep upper retroglandular portion of the right breast was discovered during surgery. The lesion was missed on mammography possibly due to poor positioning.
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
Fig. 2. The mammography of the right CC view of a 50-year-old woman (the right-hand side of the figure indicates the lateral aspect of the right breast) shows extremely dense fibroglandular stromas with no definite focal lesions identified. An infiltrating ductal carcinoma, with a 4-cm largest diameter, in the right central subareolar portion, was discovered during surgery. The right nipple (arrows) was not projected tangentially.
focal density or focal asymmetry (n = 3) (Fig. 3), and focal architectural distortion (n = 2). Compared to the TP cancers, FN cancers tend to present as focal mass, increased focal density or focal asymmetry, and architectural distortion on mammograms, however, the sample size is too small (Table 6). Two lesions were classified as Type IV FN (Table 5) due to their smooth and circumscribed borders (Fig. 4), the pathology types of which were revealed as being papillary and mucinous carcinoma, respectively. The predominant mammographic features of TP and FN cancers are summarized in Table 6, but were not analyzed using the chi-square test as only 14 of the 38 FN cancers could have been identified retrospectively. None of the FN cancers showed mammographically distinguishable microcalcifications. Of 357 malignant TP lesions, however, 162 (45.4%) exhibited indications of malignant microcalcifications (Table 6).
99
Fig. 4. The mammography of the right CC view showed a hyperdense lobulated mass about 4 cm in diameter in the inner part of the right breast (arrow) and was misdiagnosed as a benign lesion at the first reading. However, it was proved by histopathology to be a mucinous carcinoma.
There was no significant statistical difference for pathology types between mammography-defined TP (mammo-TP) and mammography-defined FN (mammo-FN) groups for malignant lesions (c2 test, c2[df 9] = 9.92, P > .1). Of the 132 pathology-proven preoperative mammograms from benign breast lesions from 120 female patients, 107 were TP mammograms from benign lesions from 99 patients (aged 15 to 79 years, mean 45.9 years), and 25 were FN mammograms from benign lesions from 21 patients (aged 34 to 61 years, mean 43.4 years) (Table 2). Three patients revealed one TP and one FN lesion each. The FN rate for mammography for benign breast lesions was 18.9%. The average age of the benign TP and FN cases was 45.9 and 43.4 years, respectively. Although the average age of TP cases was higher than that of the FN cases, there was no statistically significant difference between these groups (Table 2). The average size of the benign TP and FN lesions was 2.00 cm and 1.65 cm, respectively, across the largest diameter. The average size of TP lesions was greater than that of their FN counterparts but without a definite statistical difference (P > .1) (Table 2). Table 6 The predominant mammographic features of malignant TP and FN lesions
Fig. 3. The mammography of bilateral MLO views of a 48-year-old woman shows a focal asymmetry with increased density in the lower part of the left breast (arrowheads). The lesion was detected retrospectively and it was an infiltrating ductal carcinoma with a 1-cm largest diameter.
Signs
TP (%)
FN (%)
Mass Microcalcifications Mass with microcalcifications Architectural distortion Skin or nipple change Increased focal density or focal asymmetry Axillary lymphadenopathy
144 (40.3) 80 (22.4) 82 (23)
9 (64.3) 0 (0) 0 (0)
12 (3.4)
2 (14.3)
4 (1.1) 34 (9.5) 1 (0.3)
Numbers in parentheses mean percentages.
0 (0) 3 (21.4) 0 (0)
100
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
Table 7 The predominant mammographic features of benign TP and FN lesions Mass Mass with microcalcifications Increased focal density or focal asymmetry Benign appearing microcalcifications Benign coarse calcifications
TP (%)
FN (%)a
73 (68.2) 16 (15.0)
2 (40) 1 (20)
7 (6.5)
2 (40)
8 (7.5)
0 (0)
3 (2.8)
0 (0)
Numbers in parentheses mean percentages. Only five FN lesions can be identified retrospectively.
a
There was no statistically significant difference for breast tissue patterns between benign TP and FN lesions (Table 3). Benign TP lesions, however, occurred most commonly in heterogeneous dense breasts (ACR 3), followed in frequency by predominantly fatty breasts (ACR 1). The benign FN lesions also occurred most frequently in heterogeneous
Fig. 5. The mammography of the bilateral MLO (A) and CC (B) views of a 61-year-old woman. A papilloma 0.9 cm in diameter was detected at the left central breast on sonograms and proved by surgery, but the lesion could not be distinguished on the mammograms even on review. The focal asymmetry in the upper-inner quadrant of the right breast seen on the mammograms (arrows in A, B) did not have definite clinical and sonographic significance, and was a normal stroma.
Fig. 6. The mammograms of the bilateral CC views showed heterogeneous dense breasts and increased focal density in the right inner breast (arrow). The lesion was not identified preoperatively but was distinguished retrospectively and was a fibroadenoma with a diameter of 2 cm.
dense breasts with occurrence in extremely dense breasts (ACR 4) the next most frequent. Benign TP lesions, however, were more likely to occur in fatty breasts as compared with FN lesions, which occurred more frequently in extremely dense breasts. There were no statistically significant differences for lesion locations in lateral and medial portions of breast between benign TP and FN groups (Table 4). Both the benign TP and FN lesions are most frequently located in the lateral part of the breast, but the benign FN lesions are more often found in the central to subareolar portions of breasts in comparison with TP lesions (P < .025) (Table 4). The predominant mammographic features for benign TP and FN lesions are listed in Table 7. There are 27 (25.3%) benign TP lesions showing mammographically evident calcifications. None of the benign TP and FN lesions present with architectural distortions on mammograms (Table 7). Of the 25 benign FN lesions, one of them (4%) was Type I FN (Table 5). Nineteen FN lesions (76%) were Type II FN (Fig. 5). Five of the 25 FN lesions (20%) were classified as Type III (Table 5). Of the five Type III FN lesions, two of them (40%) exhibited as the major feature a distinct focal well-circumscribed mass on only one view, two lesions (40%) revealed focal asymmetry or increased focal density (Fig. 6), and one lesion (20%) exhibited a focal mass with very faint microcalcifications on a poorly exposed mammogram (Table 7). There was no benign FN lesion exhibiting features of microcalcifications without the associated mass (Table 7). No statistically significant difference exists for pathology types between mammographically benign TP and FN lesions in this study (c2[df 9] = 12.51, P > .1). 4. Discussion Mammography is a useful imaging modality for breast cancer screening, since it can detect microcalcifications with
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
high sensitivity, indications of which are frequently the hallmark of noninvasive breast carcinoma [11,12]. The FN rates for mammography for detection of breast cancers vary with different series. Bird et al. [1] define FN results as pathology-derived diagnoses of breast cancer within 1 year after negative mammographic results, or more than 1 year if the cancer could be distinguished from the mammogram on a retrospective review, the FN rate from this research in a screened population being 24%. Georgen et al. [3] define a missed cancer as a cancer misdiagnosed by one, or occasionally both, of the primary screening radiologists, an FN rate from this research from a screened population being 22%. Mann et al. [6] evaluate the FN mammograms from symptomatic patients with palpable cancers with the FN rate as high as 34.2%. From the work of Kalisher [8], the lowest FN rate documented was 4.3%. The causes of FN mammograms should be the subject of discussion and analysis in order to improve the accuracy of interpretation and thus reduce the possibility of delayed diagnosis, especially for malignancies. Reviewing the literature, it can be concluded that missed breast cancers tended to occur in denser breasts, were less likely in association with malignant calcifications, were more likely to exhibit developing opacity [1], were more often smallersized cancers and of relatively low density, and that cancers visible from only one of two views were more easily missed [2,3]. A lack of knowledge of results available from the clinical examination may be an important factor in the generation of FN results [2,7]. The inherent limitations of screen-film mammography, inadequacies in technique, subtle lesion characteristics, and interpretation error may be the four main factors for FN mammograms [2]. In this study, the FN rate for mammography in detecting breast cancers was 9.6%. There were several factors influencing the detection of FN cancers. These are tabulated and analyzed in Tables 2± 4. The average age for TP cancer patients was slightly higher than for FN cancer patients. The average size for TP cancers (2.94 cm across the largest diameter) was significantly greater than that for FN cancers (2.04 cm across the largest diameter), logically therefore, smaller cancers, mostly with the size less than 2 cm across the largest diameter were more easily missed on mammograms. The percentage of dense breasts (ACR pattern 3 and 4) for FN cancers was significantly greater than that for TP lesions, indicating that the FN cancers were more prone to occur in dense breasts. Since breast fibroglandular stromas become more fatty as age increases, it seems reasonable to suggest that the breast cancers are more frequently missed in younger, denser breasts [1,6]. The FN cancers tended to be located in the deep retroglandular portion of breasts in our series, the results were comparable with those obtained by Bird et al. [1], suggesting that the deeper lesions may readily escape detection on film due to their very peripheral location and the limitations of the mammography equipment. Sometimes, only
101
the anterior part of a deep lesion is detected on mammograms so these types of lesions may be overlooked. The detection rate for such cases may be improved through the use of various additional views, for example: axillary tail view for far-lateral superior lesions, cleavage view for deep-medial lesions, lumpogram for extreme-upper lesions, and caudocranial view for lowermost lesions. Combining the use of identification markers can also be helpful. None of the FN cancers on mammograms presented as microcalcifications (Table 6). Mammography is a highly sensitive tool for detecting calcifications, high-contrast images achievable with low kilovolt peak (kVp) setting permitting the differentiation of fine breast structures and densities, especially for the delineation of microcalcifications. Essentially, all the mammograms collected in this study were obtained with a modern, dedicated mammographic unit and high-contrast images were obtained in almost all of the films, with the exception of two of three Type I FN cancers and one benign Type I FN lesion. Subtle, very faint microcalcifications may exist in these lesions but they escaped identification due to poor contrast. Among the 12 Type III FN cancers, the most common mammographic feature detected in retrospect was ``focal mass'' with all the mass exhibiting spiculated, poorly defined margins. Other features in decreasing order of frequency are signs of increased density or focal asymmetry, and architectural distortion. This suggests that missed radiologist diagnoses are sometimes do occur though the indicator of mass is more easily recognized than other imaging features. The causes of missed diagnoses in such lesions may be due to disbelief or distraction while reading the films [2], or relatively low density of the mass [3]. From some workers, Type III FN cancers, (i.e., lesions distinguished in retrospect) were more common than other types of missed lesions [1,5,10]. This, however, is not the case in our study, where Type III FN cancers are less common than Type I and Type II lesions. The reasons for the difference remain unclear, however, it could be argued that most of the mammography-defined FN cancers in our series present as noncalcified masses in dense breasts, so there is no distinct ``contrast'' between the lesion and adjacent fibroglandular tissues to provide better delineation. The pathology types do not play a distinctive role in the differentiation of malignant TP and FN lesions, this conclusion compatible with some studies [1,3] but contradictory to other series [4,7]. Turning to benign mammograms for TP and FN lesions, the only statistically significant factor in the occurrence of TP and FN lesions was ``central and subareolar location,'' the percentage of centrally located FN lesions being significantly higher than that of TP lesions. This difference may be attributable to the fact that fibroglandular tissue in central subareolar portions of breast is denser than tissue in other locations for most patients. Ergo, a lesion is more easily missed if it is superimposed on, or hidden in the central and subareolar breast. There were no benign mam-
102
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
mo-FN lesions and only two benign TP lesions located in deep retroglandular tissue, the result in contrast to the situation for malignant lesions. This contrast may be explained by two factors, the relatively small sample size for benign lesions in this study, and, the fact that most benign lesions tend to manifest as a well-circumscribed mass that may be clearly delineated if located in the deep retroglandular part of the breast, some distance from adjacent fibroglandular tissue. The malignant lesions seated in deep retroglandular part can sometimes be missed as a result of a manipulation of film exposure aimed at producing adequate density for retroareolar glandular tissue [2,3]. this can result in the density of lesions in deep retroglandular parts appearing to be relatively lower, and the relatively spiculated margin of malignant lesions may be mistaken for normal fibroglandular stromas, with the result that the lesions are more liable to be overlooked. Whilst there was no statistically significant difference for average age, size and breast tissue pattern between benign mammographic TP and FN lesions using the chi-square test, although some clinical differences do exist. The average age for benign TP patients was greater than that for FN cases and the average size across the largest diameter for benign TP lesions was greater than that for benign FN lesions in this study. The percentage of ACR 4 (extremely dense) breast tissue patterns occurring for benign FN lesions was greater than that for benign TP lesions. There was a tendency for smaller-sized lesions in extremely dense breasts to be missed on mammograms. The pathology type is not significant in the relationship between TP and FN lesions for both benign and malignant lesions. In the review of the 25 benign FN lesions, only five (20%) can be distinguished retrospectively. When compared for mammographic feature of ``focal asymmetry or increased focal density,'' the benign FN lesions exhibited this feature more frequently than benign TP lesions. Compared for the feature of focal mass, the TP lesions tended to exhibit mass that are more discernible than those exhibit in FN lesions, since most of the TP masses show well-circumscribed borders. This may explain why an obvious benignappearing mass is rarely overlooked on a mammogram, and focal asymmetry or increased focal density are more subtle lesion characteristics than focal mass, since the focal asymmetry or increased density are mostly interpreted as normal on mammograms. Many studies stress the importance of independent double reading for mammography, because this can increase the cancer detection rate by up to 15% [14 ±18]. Only single readings were performed in our department preoperatively, and the second readings were performed retrospectively by another radiologist with the benefit of detailed clinical information. If the Type III and IV FN cancers are categorized as ``warranting second reading,'' there are 36.8% FN cancers that can be recognized at the ``second reading.'' If the Type III benign FN lesions are referred to as the results of ``the second reading,'' there are additional 20% benign
FN lesions that will be detected at the ``second reading.'' However, this is just a supposition. Knowledge of clinical findings may indeed improve the detection rate, and this is especially beneficial for malignant cases [2]. Knight et al. [19], however, demonstrated that while clinical findings had an influence on radiologists' patterns of referral, such findings did not influence the accuracy of cancer detection. In conclusion, mammographically FN cancers revealed the following characteristics: a tendency to occur at younger ages, in smaller sizes, denser breasts, and deeper locations with analysis of these factors revealing statistically significant differences when compared to mammographically TP cancers. The benign mammographically FN lesions tended to occur in central subareolar locations with a statistically significant difference. There were no significant differences for pathology types for malignant and benign TP and FN lesions. Calcified lesions are rarely missed on mammograms but noncalcified masses may sometimes be mammographically occult. The FN rate for mammography for breast cancers was less than that for the benign equivalent, perhaps because more breast cancers present as calcifications and thus more easily identified on mammograms. References [1] Bird RE, Wallace TW, Yankaskas BC. Analysis of cancers missed at screening mammography. Radiology 1992;184:613 ± 7. [2] Huynh PT, Jarolimek AM, Daye S. The false-negative mammogram. RadioGraphics 1998;18:1137 ± 54. [3] Goergen SK, Evans J, Cohen GPB, et al. Characteristics of breast carcinomas missed by screening radiologists. Radiology 1997;204: 131 ± 5. [4] Holland R, Hendriks JHCL, Marvunac M, et al. Mammographically occult breast cancer: a pathologic and radiologic study. Cancer 1983;52:1810 ± 9. [5] Martin JE, Moskowitz M, Milbrath JR. Breast cancer missed by mammography. Am J Roentgenol 1979;132:737 ± 9. [6] Mann BD, Giuliano AE, Bassett LW, et al. Delayed diagnosis of breast cancer as a result of normal mammograms. Arch Surg 1983; 118:23 ± 4. [7] Wallis MG, Walsh MT, Lee JR. A review of false negative mammography in a symptomatic population. Clin Radiol 1991;44:13 ± 5. [8] Kalisher L. Factors influencing false negative rates in xeromammography. Radiology 1979;133:297 ± 301. [9] Feig SA, Shaber GS, Patchefsky A, et al. Analysis of clinically occult and mammographically occult breast tumors. Am J Roentgenol 1977;128:403 ± 8. [10] Cahill CJ, Boulter PS, Gibbs NM, et al. Features of mammographically negative breast tumors. Br J Surg 1981;68:882 ± 4. [11] Bassett LW, Jahan R, Fu YS, et al. Diagnosis of Diseases of the Breast. 1st edn. PA: Saunders, 1997. pp. 447 ± 8. [12] Kopans DB. Breast Imaging. 2nd edn. PA: Lippincott-Raven, 1998. p. 388. [13] Kopans DB. Breast Imaging. 2nd edn. PA: Lippincott-Raven, 1998. p. 245. [14] Ciatto S, Turco MRD, Morrone D, et al. Independent double reading of screening mammograms. J Med Screening 1995;2:99 ± 101. [15] Linver MN, Paster SB, Rosenberg RD, et al. Improvement in mammography interpretation skills in a community radiology practice after dedicated teaching courses: 2-year medical audit of 38.633 cases. Radiology 1992;184:39 ± 43.
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103 [16] Thurfjell EL, Lernevall KA, Taube AA. Benefit of independent double reading in a population-based mammography screening program. Radiology 1994;191:241 ± 4. [17] Hulka CA, Slanetz PJ, Halpern EF, et al. Patients' opinion of mammography screening services: immediate results versus delayed results due to interpretation by two observers. Am J Roentgenol 1997;168:1085 ± 9.
103
[18] Brown J, Bryan S, Warren R. Mammography screening: an incremental cost effectiveness analysis of double versus single reading of mammograms. Br Med J 1996;312:809 ± 12. [19] Knight JA, Libstug AR, Moravan V, et al. An assessment of the influence of clinical breast examination reports on the interpretation of mammograms in a breast screening program. Breast Cancer Res Treat 1998;48:65 ± 71.
The evaluation of false negative mammography from malignant and benign breast lesions Jane Wanga, Tiffany Ting-Fang Shiha,b,*, Jane Chien-Yao Hsua,b, Yiu-Wah Lia,b a
Department of Medical Imaging, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan b Department of Radiology, College of Medicine, National Taiwan University, Taiwan Received 30 January 2000; accepted 30 May 2000
Abstract Preoperative mammograms from 395 breast cancers and 132 benign breast lesions were enrolled for this study. The false-negative (FN) rate for breast cancers from preoperative reading was 9.6% with 38 breast cancers missed on mammograms. The statistically significant differences occurred between true-positive (TP) and FN cancers for younger age (P < .025), smaller lesion size (P < .001), denser breast (P < .05), deep retroglandular location (P < .001). None of the FN cancers exhibited calcifications. The FN rate for mammography for benign breast lesions from preoperative reading was 18.9% with 25 lesions misdiagnosed. The statistically significant difference between benign TP and FN lesions occurred for central and subareolar location (P < .025). Exploration of possible factors and imaging features in FN mammograms can help reduce the FN rate for mammography. D 2000 Elsevier Science Inc. All rights reserved. Keywords: Mammography; False-negative; True-positive; Breast; Abnormalities
1. Introduction Mammography continues to be regarded as a useful diagnostic tool for detection and diagnosis of breast lesions. Although there have been many studies of false-negative (FN) mammograms for breast cancers [1 ± 10], mammograms for the benign equivalents have been studied very seldom. Some workers note common imaging characteristics for breast lesions and offer possible causes for FN mammograms [1,3,7]. False-negative (FN) rates for mammographic detection for breast cancers range from 4.3% to 34.2%, varying according to the sampled population and the definition of FN mammograms used [1,3,6 ± 8,10]. Bird et al. [1] found that missed cancers on mammograms tended to occur in denser breasts, were often present as developing densities, and were frequently located in the retroglandular region. Huynh et al. [2] noted that FN interpretation errors for mammograms may be caused by suboptimal viewing conditions, outside distractions, lack of a systematic approach,
* Corresponding author.
overlooking a subtle interpretation because of a more obvious finding, lack of knowledge of clinical findings, imprecise correlation with other studies, and simple disbelief. In addition, other authors have demonstrated that the missed cancers were statistically significantly lower in density, and more often visible on only one of two views, smaller in size [2,3]. Most early breast cancers present as microcalcifications, which can be reliably detected on mammograms [11,12]. Some lesions, however, present as palpable, noncalcified tumors and can be missed mammographically [6,7], thus the information provided by a clinical examination is important in conjunction with the assessment of mammograms for symptomatic patients [2,7]. The goal of this study is to discover the probable reasons for, and characteristics of, FN mammograms for breast cancers and benign breast lesions, particularly for Oriental women, whose breasts are usually smaller and denser than those of their Western counterparts. Acknowledgment of salient features and determining factors for FN mammograms, especially for breast cancers, can improve the lesiondetection rate by mammography, and thus reduce diagnostic delays and ultimately improve survival rates for breast cancer patients.
0899-7071/00/$ ± see front matter D 2000 Elsevier Science Inc. All rights reserved. PII: S 0 8 9 9 - 7 0 7 1 ( 0 0 ) 0 0 1 8 4 - 4
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
2. Materials and methods
Table 2 The average ages and sizes of malignant and benign mammo-TP and -FN lesions
2.1. Study population The preoperative mammograms from female patients with pathology-proven, malignant and benign breast lesions were collected over the period from January 1995 to February 1999. The intervals from mammography to surgery ranged from zero to 124 days (mean = 8.1) for malignant cases and zero to 134 days (mean = 19.1) for benign cases. The follow-up period ranged from 9 to 61 months (mean = 26.8). All the mammographic examinations were performed using a GE DMR dedicated mammography unit (GE, Senographe DMR, Buc, Cedex, France) with 18 24 cm Min-R M screens in combination with Min-R M films (Eastman Kodak, Rochester, NY). The processing time was 90 s for each exposure. The first, preoperative mammographic results were obtained using the services of a single in-house radiologist and based exclusively on mammograms that conformed to specially designed mammography questionnaires. The retrospective reviews were performed by a second inhouse radiologist utilizing adequate clinical breast examination results and corresponding sonographic findings. The radiologists worked independently and blindly, and their results were not compared by each other. Comparisons of preoperative and retrospective diagnoses of mammograms were performed by two radiologists in our department (J.W. and T.T.-F.S.). As an initial step in the elaboration and exploration of the features and characteristics of breast abnormalities, the definitions for TP and FN lesions need to be established. TP malignant lesions were defined where the abnormalities were detected on mammograms at the first reading, that is, preoperatively, these lesions being determined as suspicious or definitely malignant in nature, and a diagnosis of breast cancer delivered without delay. TP benign lesions were defined where the
Table 1 Categorization of mammographic FN (mammo-FN) lesions Type
Malignant FN
Benign FN
Type I FN
Lesions cannot be identified either preoperatively or retrospectively due to poor film quality Lesions cannot be seen either preoperatively or retrospectively with acceptable film quality Lesions cannot be detected preoperatively but can be depicted retrospectively Lesions misinterpreted as benign in nature
Same as left
Type II FN
Type III FN Type IV FN
97
Same as left
Same as left
Malignant Malignant TP FN P* Agea 51.8 (year) Sizeb 2.94 (cm)
47.7 2.04
Benign Benign TP FN P**
.01 < P < .025 45.9 P < .001
2.00
43.4 1.65
.1 < P < .2 P > .1
* Student's t test, the P value for malignant lesions. ** The P value for benign lesions. a The average age of TP and FN patients. b The average size of TP and FN lesions, across the largest diameter.
lesions were distinguished preoperatively. Four types of malignant FN lesions were established: Type I FN lesions were those that could not be detected either preoperatively or postoperatively due to poor image quality related to positioning or exposure problems; Type II FN lesions were those that could not be recognized either preoperatively or retrospectively despite acceptable image quality; Type III FN lesions could not be distinguished preoperatively but were identified in retrospective mammogram review; Type IV FN lesions were recognized preoperatively but misdiagnosed as benign in nature (Table 1). Only three types of benign FN lesions were established, Types I, II and III, using the definitions above (Table 1). The classification of breast tissue patterns is taken from the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BIRADS): ACR 1, breast with predominant fat; ACR 2, breast with predominant fat and up to 25% visible fibroglandular tissue; ACR 3, heterogeneous dense breast with over 25% as visible fibroglandular tissue; ACR 4, extremely dense breast [13]. The TP and FN groups for breast cancers and benign breast lesions were compared according to the following factors: the age of the patients, size of lesions (across the largest diameter), breast tissue patterns, lesion locations, predominant mammographic features and pathology types. The TP and FN groups of malignant lesions and the TP and FN groups of benign breast lesions were analyzed separately. The relationship between age and lesion size was analyzed using Student's t test. The relationships between TP and FN classes were analyzed for breast tissue pattern, lesion location, mammographic features, and pathology type using the chi-square test (c2 test) to assess goodness of fit and binomial distribution of TP and FN lesions. The threshold value (a) below
98
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
Table 3 The breast tissue patterns of malignant and benign mammo-TP and -FN lesions ACR breast patterns
Malignant TP (%)
Malignant FN (%)
Benign TP (%)
Benign FN (%)
1 2 3 4 3+4 Number of lesions
121 27 179 30 209 357
6 2 22 8 30 38
18 6 75 8 83 107
2 1 17 5 22 25
(33.9) (7.6) (50.1) (8.4) (58.5)
(15.8) (5.3) (57.9) (21) (78.9)
(16.8) (5.6) (70.1) (7.5) (77.6)
(8) (4) (68) (20) (88)
Numbers in parentheses mean percentages. 3 + 4: sum of ACR 3 and ACR 4 lesions. Binomial distribution for malignant TP and FN lesions for 3 + 4: P < .05. c2 Test for malignant lesions: .01 < P < .025. c2 Test for benign lesions: P > .1.
which statistical significance will be declared is set at 0.05 in this study. 3. Results The preoperative mammograms for 512 female patients were collected for this study. Of these, 395 malignant breast lesions were taken from 392 patients and 132 benign breast lesions were taken from 120 patients. Of the malignant lesions, there were 357 TP breast cancers from 354 patients (aged 24 to 91 years, mean 51.8 years) and 38 FN cancers from 38 patients (aged 31 to 75 years, mean 47.7 years) with an FN rate of 9.6%. The average age of TP patients and FN patients was 51.8 and 47.7 years, respectively (P < .025) (Table 2). The average size of the 357 malignant TP lesions and FN cancers were 2.93 and 2.04 cm, respectively, across the largest diameter (P < .001) (Table 2). The breast tissue patterns for malignant TP and FN lesions showed significant differences (c2 test, P < .025),
Table 5 Types and numbers of malignant and benign FN lesions Types Type I FN Type II FN Type III FN Type IV FN Total
Numbers of malignant lesions (%)
Numbers of benign lesions (%)
3 21 12 2 38
1 (4) 19 (76) 5 (20) ± 25
(7.9) (55.3) (31.6) (5.2)
Numbers in parentheses mean percentages.
the TP cancers occurred more often in fatty breasts (ACR 1), and FN cancers occurred more often in denser breasts (ACR 3 and 4) (P < .05, Table 3). For malignant breast lesions, the probability was higher that FN lesions would be located in the deep retroglandular portion of the breast, compared with TP lesions (P < .001) (Table 4). There were no statistically significant differences for the other lesion locations between the TP and FN groups (Table 4). Of the 38 FN cancers, three were classified as Type I FN lesions because they could not be identified either preoperatively or retrospectively as a result of poor mammographic techniques (Table 5) (Fig. 1). Of the remaining 35 FN lesions, 21 were classified as Type II FN lesions as the cancers could not be depicted either preoperatively or retrospectively with acceptable film quality (Fig. 2); Twelve lesions could be recognized on review (Type III FN lesions), and exhibited the following imaging features: focal discrete ill-defined mass with spiculated margin (n = 7), increased
Table 4 The lesion locations of malignant and benign mammo-TP and -FN lesions Location
Malignant Malignant TP (%) FN (%) P*
Lateral 159 (44.5) 10 (26.3) > .2 Medial 77 (21.6) 2 (5.3) > .5 Central and 39 (10.9) 3 (7.9) > .8 subareolar Deep 20 (5.6) 12 (31.6) < .001 retroglandular Othersa 62 (17.4) 11 (28.9) ±
Benign TP (%)
Benign FN (%) P * *
53 (49.5) 11 (44) > .7 22 (20.6) 2 (8) > .6 15 (14.0) 7 (28) < .025 2 (1.9) 15 (14.0)
0 (0)
±
5 (20) ±
Numbers in parentheses mean percentages. c2 Test for malignant lesions: P < .01. c2 Test for benign lesions: P > .1. * P: evaluation of binomial distribution of malignant TP and FN lesions by P value. ** P: evaluation of binomial distribution of benign TP and FN lesions by P value. a Others mean the locations crossing two or three areas mentioned above.
Fig. 1. The mammography of the right breast in MLO view of a 59-year-old woman shows no definite focal lesions even in retrospect. An infiltrating ductal carcinoma, with a 2-cm diameter, in the deep upper retroglandular portion of the right breast was discovered during surgery. The lesion was missed on mammography possibly due to poor positioning.
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
Fig. 2. The mammography of the right CC view of a 50-year-old woman (the right-hand side of the figure indicates the lateral aspect of the right breast) shows extremely dense fibroglandular stromas with no definite focal lesions identified. An infiltrating ductal carcinoma, with a 4-cm largest diameter, in the right central subareolar portion, was discovered during surgery. The right nipple (arrows) was not projected tangentially.
focal density or focal asymmetry (n = 3) (Fig. 3), and focal architectural distortion (n = 2). Compared to the TP cancers, FN cancers tend to present as focal mass, increased focal density or focal asymmetry, and architectural distortion on mammograms, however, the sample size is too small (Table 6). Two lesions were classified as Type IV FN (Table 5) due to their smooth and circumscribed borders (Fig. 4), the pathology types of which were revealed as being papillary and mucinous carcinoma, respectively. The predominant mammographic features of TP and FN cancers are summarized in Table 6, but were not analyzed using the chi-square test as only 14 of the 38 FN cancers could have been identified retrospectively. None of the FN cancers showed mammographically distinguishable microcalcifications. Of 357 malignant TP lesions, however, 162 (45.4%) exhibited indications of malignant microcalcifications (Table 6).
99
Fig. 4. The mammography of the right CC view showed a hyperdense lobulated mass about 4 cm in diameter in the inner part of the right breast (arrow) and was misdiagnosed as a benign lesion at the first reading. However, it was proved by histopathology to be a mucinous carcinoma.
There was no significant statistical difference for pathology types between mammography-defined TP (mammo-TP) and mammography-defined FN (mammo-FN) groups for malignant lesions (c2 test, c2[df 9] = 9.92, P > .1). Of the 132 pathology-proven preoperative mammograms from benign breast lesions from 120 female patients, 107 were TP mammograms from benign lesions from 99 patients (aged 15 to 79 years, mean 45.9 years), and 25 were FN mammograms from benign lesions from 21 patients (aged 34 to 61 years, mean 43.4 years) (Table 2). Three patients revealed one TP and one FN lesion each. The FN rate for mammography for benign breast lesions was 18.9%. The average age of the benign TP and FN cases was 45.9 and 43.4 years, respectively. Although the average age of TP cases was higher than that of the FN cases, there was no statistically significant difference between these groups (Table 2). The average size of the benign TP and FN lesions was 2.00 cm and 1.65 cm, respectively, across the largest diameter. The average size of TP lesions was greater than that of their FN counterparts but without a definite statistical difference (P > .1) (Table 2). Table 6 The predominant mammographic features of malignant TP and FN lesions
Fig. 3. The mammography of bilateral MLO views of a 48-year-old woman shows a focal asymmetry with increased density in the lower part of the left breast (arrowheads). The lesion was detected retrospectively and it was an infiltrating ductal carcinoma with a 1-cm largest diameter.
Signs
TP (%)
FN (%)
Mass Microcalcifications Mass with microcalcifications Architectural distortion Skin or nipple change Increased focal density or focal asymmetry Axillary lymphadenopathy
144 (40.3) 80 (22.4) 82 (23)
9 (64.3) 0 (0) 0 (0)
12 (3.4)
2 (14.3)
4 (1.1) 34 (9.5) 1 (0.3)
Numbers in parentheses mean percentages.
0 (0) 3 (21.4) 0 (0)
100
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
Table 7 The predominant mammographic features of benign TP and FN lesions Mass Mass with microcalcifications Increased focal density or focal asymmetry Benign appearing microcalcifications Benign coarse calcifications
TP (%)
FN (%)a
73 (68.2) 16 (15.0)
2 (40) 1 (20)
7 (6.5)
2 (40)
8 (7.5)
0 (0)
3 (2.8)
0 (0)
Numbers in parentheses mean percentages. Only five FN lesions can be identified retrospectively.
a
There was no statistically significant difference for breast tissue patterns between benign TP and FN lesions (Table 3). Benign TP lesions, however, occurred most commonly in heterogeneous dense breasts (ACR 3), followed in frequency by predominantly fatty breasts (ACR 1). The benign FN lesions also occurred most frequently in heterogeneous
Fig. 5. The mammography of the bilateral MLO (A) and CC (B) views of a 61-year-old woman. A papilloma 0.9 cm in diameter was detected at the left central breast on sonograms and proved by surgery, but the lesion could not be distinguished on the mammograms even on review. The focal asymmetry in the upper-inner quadrant of the right breast seen on the mammograms (arrows in A, B) did not have definite clinical and sonographic significance, and was a normal stroma.
Fig. 6. The mammograms of the bilateral CC views showed heterogeneous dense breasts and increased focal density in the right inner breast (arrow). The lesion was not identified preoperatively but was distinguished retrospectively and was a fibroadenoma with a diameter of 2 cm.
dense breasts with occurrence in extremely dense breasts (ACR 4) the next most frequent. Benign TP lesions, however, were more likely to occur in fatty breasts as compared with FN lesions, which occurred more frequently in extremely dense breasts. There were no statistically significant differences for lesion locations in lateral and medial portions of breast between benign TP and FN groups (Table 4). Both the benign TP and FN lesions are most frequently located in the lateral part of the breast, but the benign FN lesions are more often found in the central to subareolar portions of breasts in comparison with TP lesions (P < .025) (Table 4). The predominant mammographic features for benign TP and FN lesions are listed in Table 7. There are 27 (25.3%) benign TP lesions showing mammographically evident calcifications. None of the benign TP and FN lesions present with architectural distortions on mammograms (Table 7). Of the 25 benign FN lesions, one of them (4%) was Type I FN (Table 5). Nineteen FN lesions (76%) were Type II FN (Fig. 5). Five of the 25 FN lesions (20%) were classified as Type III (Table 5). Of the five Type III FN lesions, two of them (40%) exhibited as the major feature a distinct focal well-circumscribed mass on only one view, two lesions (40%) revealed focal asymmetry or increased focal density (Fig. 6), and one lesion (20%) exhibited a focal mass with very faint microcalcifications on a poorly exposed mammogram (Table 7). There was no benign FN lesion exhibiting features of microcalcifications without the associated mass (Table 7). No statistically significant difference exists for pathology types between mammographically benign TP and FN lesions in this study (c2[df 9] = 12.51, P > .1). 4. Discussion Mammography is a useful imaging modality for breast cancer screening, since it can detect microcalcifications with
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
high sensitivity, indications of which are frequently the hallmark of noninvasive breast carcinoma [11,12]. The FN rates for mammography for detection of breast cancers vary with different series. Bird et al. [1] define FN results as pathology-derived diagnoses of breast cancer within 1 year after negative mammographic results, or more than 1 year if the cancer could be distinguished from the mammogram on a retrospective review, the FN rate from this research in a screened population being 24%. Georgen et al. [3] define a missed cancer as a cancer misdiagnosed by one, or occasionally both, of the primary screening radiologists, an FN rate from this research from a screened population being 22%. Mann et al. [6] evaluate the FN mammograms from symptomatic patients with palpable cancers with the FN rate as high as 34.2%. From the work of Kalisher [8], the lowest FN rate documented was 4.3%. The causes of FN mammograms should be the subject of discussion and analysis in order to improve the accuracy of interpretation and thus reduce the possibility of delayed diagnosis, especially for malignancies. Reviewing the literature, it can be concluded that missed breast cancers tended to occur in denser breasts, were less likely in association with malignant calcifications, were more likely to exhibit developing opacity [1], were more often smallersized cancers and of relatively low density, and that cancers visible from only one of two views were more easily missed [2,3]. A lack of knowledge of results available from the clinical examination may be an important factor in the generation of FN results [2,7]. The inherent limitations of screen-film mammography, inadequacies in technique, subtle lesion characteristics, and interpretation error may be the four main factors for FN mammograms [2]. In this study, the FN rate for mammography in detecting breast cancers was 9.6%. There were several factors influencing the detection of FN cancers. These are tabulated and analyzed in Tables 2± 4. The average age for TP cancer patients was slightly higher than for FN cancer patients. The average size for TP cancers (2.94 cm across the largest diameter) was significantly greater than that for FN cancers (2.04 cm across the largest diameter), logically therefore, smaller cancers, mostly with the size less than 2 cm across the largest diameter were more easily missed on mammograms. The percentage of dense breasts (ACR pattern 3 and 4) for FN cancers was significantly greater than that for TP lesions, indicating that the FN cancers were more prone to occur in dense breasts. Since breast fibroglandular stromas become more fatty as age increases, it seems reasonable to suggest that the breast cancers are more frequently missed in younger, denser breasts [1,6]. The FN cancers tended to be located in the deep retroglandular portion of breasts in our series, the results were comparable with those obtained by Bird et al. [1], suggesting that the deeper lesions may readily escape detection on film due to their very peripheral location and the limitations of the mammography equipment. Sometimes, only
101
the anterior part of a deep lesion is detected on mammograms so these types of lesions may be overlooked. The detection rate for such cases may be improved through the use of various additional views, for example: axillary tail view for far-lateral superior lesions, cleavage view for deep-medial lesions, lumpogram for extreme-upper lesions, and caudocranial view for lowermost lesions. Combining the use of identification markers can also be helpful. None of the FN cancers on mammograms presented as microcalcifications (Table 6). Mammography is a highly sensitive tool for detecting calcifications, high-contrast images achievable with low kilovolt peak (kVp) setting permitting the differentiation of fine breast structures and densities, especially for the delineation of microcalcifications. Essentially, all the mammograms collected in this study were obtained with a modern, dedicated mammographic unit and high-contrast images were obtained in almost all of the films, with the exception of two of three Type I FN cancers and one benign Type I FN lesion. Subtle, very faint microcalcifications may exist in these lesions but they escaped identification due to poor contrast. Among the 12 Type III FN cancers, the most common mammographic feature detected in retrospect was ``focal mass'' with all the mass exhibiting spiculated, poorly defined margins. Other features in decreasing order of frequency are signs of increased density or focal asymmetry, and architectural distortion. This suggests that missed radiologist diagnoses are sometimes do occur though the indicator of mass is more easily recognized than other imaging features. The causes of missed diagnoses in such lesions may be due to disbelief or distraction while reading the films [2], or relatively low density of the mass [3]. From some workers, Type III FN cancers, (i.e., lesions distinguished in retrospect) were more common than other types of missed lesions [1,5,10]. This, however, is not the case in our study, where Type III FN cancers are less common than Type I and Type II lesions. The reasons for the difference remain unclear, however, it could be argued that most of the mammography-defined FN cancers in our series present as noncalcified masses in dense breasts, so there is no distinct ``contrast'' between the lesion and adjacent fibroglandular tissues to provide better delineation. The pathology types do not play a distinctive role in the differentiation of malignant TP and FN lesions, this conclusion compatible with some studies [1,3] but contradictory to other series [4,7]. Turning to benign mammograms for TP and FN lesions, the only statistically significant factor in the occurrence of TP and FN lesions was ``central and subareolar location,'' the percentage of centrally located FN lesions being significantly higher than that of TP lesions. This difference may be attributable to the fact that fibroglandular tissue in central subareolar portions of breast is denser than tissue in other locations for most patients. Ergo, a lesion is more easily missed if it is superimposed on, or hidden in the central and subareolar breast. There were no benign mam-
102
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103
mo-FN lesions and only two benign TP lesions located in deep retroglandular tissue, the result in contrast to the situation for malignant lesions. This contrast may be explained by two factors, the relatively small sample size for benign lesions in this study, and, the fact that most benign lesions tend to manifest as a well-circumscribed mass that may be clearly delineated if located in the deep retroglandular part of the breast, some distance from adjacent fibroglandular tissue. The malignant lesions seated in deep retroglandular part can sometimes be missed as a result of a manipulation of film exposure aimed at producing adequate density for retroareolar glandular tissue [2,3]. this can result in the density of lesions in deep retroglandular parts appearing to be relatively lower, and the relatively spiculated margin of malignant lesions may be mistaken for normal fibroglandular stromas, with the result that the lesions are more liable to be overlooked. Whilst there was no statistically significant difference for average age, size and breast tissue pattern between benign mammographic TP and FN lesions using the chi-square test, although some clinical differences do exist. The average age for benign TP patients was greater than that for FN cases and the average size across the largest diameter for benign TP lesions was greater than that for benign FN lesions in this study. The percentage of ACR 4 (extremely dense) breast tissue patterns occurring for benign FN lesions was greater than that for benign TP lesions. There was a tendency for smaller-sized lesions in extremely dense breasts to be missed on mammograms. The pathology type is not significant in the relationship between TP and FN lesions for both benign and malignant lesions. In the review of the 25 benign FN lesions, only five (20%) can be distinguished retrospectively. When compared for mammographic feature of ``focal asymmetry or increased focal density,'' the benign FN lesions exhibited this feature more frequently than benign TP lesions. Compared for the feature of focal mass, the TP lesions tended to exhibit mass that are more discernible than those exhibit in FN lesions, since most of the TP masses show well-circumscribed borders. This may explain why an obvious benignappearing mass is rarely overlooked on a mammogram, and focal asymmetry or increased focal density are more subtle lesion characteristics than focal mass, since the focal asymmetry or increased density are mostly interpreted as normal on mammograms. Many studies stress the importance of independent double reading for mammography, because this can increase the cancer detection rate by up to 15% [14 ±18]. Only single readings were performed in our department preoperatively, and the second readings were performed retrospectively by another radiologist with the benefit of detailed clinical information. If the Type III and IV FN cancers are categorized as ``warranting second reading,'' there are 36.8% FN cancers that can be recognized at the ``second reading.'' If the Type III benign FN lesions are referred to as the results of ``the second reading,'' there are additional 20% benign
FN lesions that will be detected at the ``second reading.'' However, this is just a supposition. Knowledge of clinical findings may indeed improve the detection rate, and this is especially beneficial for malignant cases [2]. Knight et al. [19], however, demonstrated that while clinical findings had an influence on radiologists' patterns of referral, such findings did not influence the accuracy of cancer detection. In conclusion, mammographically FN cancers revealed the following characteristics: a tendency to occur at younger ages, in smaller sizes, denser breasts, and deeper locations with analysis of these factors revealing statistically significant differences when compared to mammographically TP cancers. The benign mammographically FN lesions tended to occur in central subareolar locations with a statistically significant difference. There were no significant differences for pathology types for malignant and benign TP and FN lesions. Calcified lesions are rarely missed on mammograms but noncalcified masses may sometimes be mammographically occult. The FN rate for mammography for breast cancers was less than that for the benign equivalent, perhaps because more breast cancers present as calcifications and thus more easily identified on mammograms. References [1] Bird RE, Wallace TW, Yankaskas BC. Analysis of cancers missed at screening mammography. Radiology 1992;184:613 ± 7. [2] Huynh PT, Jarolimek AM, Daye S. The false-negative mammogram. RadioGraphics 1998;18:1137 ± 54. [3] Goergen SK, Evans J, Cohen GPB, et al. Characteristics of breast carcinomas missed by screening radiologists. Radiology 1997;204: 131 ± 5. [4] Holland R, Hendriks JHCL, Marvunac M, et al. Mammographically occult breast cancer: a pathologic and radiologic study. Cancer 1983;52:1810 ± 9. [5] Martin JE, Moskowitz M, Milbrath JR. Breast cancer missed by mammography. Am J Roentgenol 1979;132:737 ± 9. [6] Mann BD, Giuliano AE, Bassett LW, et al. Delayed diagnosis of breast cancer as a result of normal mammograms. Arch Surg 1983; 118:23 ± 4. [7] Wallis MG, Walsh MT, Lee JR. A review of false negative mammography in a symptomatic population. Clin Radiol 1991;44:13 ± 5. [8] Kalisher L. Factors influencing false negative rates in xeromammography. Radiology 1979;133:297 ± 301. [9] Feig SA, Shaber GS, Patchefsky A, et al. Analysis of clinically occult and mammographically occult breast tumors. Am J Roentgenol 1977;128:403 ± 8. [10] Cahill CJ, Boulter PS, Gibbs NM, et al. Features of mammographically negative breast tumors. Br J Surg 1981;68:882 ± 4. [11] Bassett LW, Jahan R, Fu YS, et al. Diagnosis of Diseases of the Breast. 1st edn. PA: Saunders, 1997. pp. 447 ± 8. [12] Kopans DB. Breast Imaging. 2nd edn. PA: Lippincott-Raven, 1998. p. 388. [13] Kopans DB. Breast Imaging. 2nd edn. PA: Lippincott-Raven, 1998. p. 245. [14] Ciatto S, Turco MRD, Morrone D, et al. Independent double reading of screening mammograms. J Med Screening 1995;2:99 ± 101. [15] Linver MN, Paster SB, Rosenberg RD, et al. Improvement in mammography interpretation skills in a community radiology practice after dedicated teaching courses: 2-year medical audit of 38.633 cases. Radiology 1992;184:39 ± 43.
J. Wang et al. / Journal of Clinical Imaging 24 (2000) 96±103 [16] Thurfjell EL, Lernevall KA, Taube AA. Benefit of independent double reading in a population-based mammography screening program. Radiology 1994;191:241 ± 4. [17] Hulka CA, Slanetz PJ, Halpern EF, et al. Patients' opinion of mammography screening services: immediate results versus delayed results due to interpretation by two observers. Am J Roentgenol 1997;168:1085 ± 9.
103
[18] Brown J, Bryan S, Warren R. Mammography screening: an incremental cost effectiveness analysis of double versus single reading of mammograms. Br Med J 1996;312:809 ± 12. [19] Knight JA, Libstug AR, Moravan V, et al. An assessment of the influence of clinical breast examination reports on the interpretation of mammograms in a breast screening program. Breast Cancer Res Treat 1998;48:65 ± 71.