The Problem of Mammographic Breast Density – The Position of the DEGUM Working Group on Breast Ultrasound

Abstract

Mammographic breast density correlates with breast cancer risk and also with the number of false-negative calls. In the USA these facts lead to the “Breast Density and Mammography Reporting Act” of 2011. In the case of mammographically dense breasts, the Working Group on Breast Ultrasound in Germany recommends explaining the advantages of adjunct imaging to women, depending on the individual breast cancer risk. Due to the particular structure of German healthcare, quality-assured breast ultrasound would be the first choice. Possible overdiagnosis, costs, potentially increased emotional stress should be addressed. In high familial breast cancer risk, genetic counselling and an intensified early detection program should be performed.

Zusammenfassung

Die mammografisch dichte Brust ist mit einem erhöhten Risiko einerseits für die Entstehung von Brustkrebs und andererseits für die Maskierung von Karzinomen in der Mammografie korreliert. Dies hat in einer zunehmenden Zahl von Staaten der USA zur gesetzlichen Verpflichtung geführt, die mammografische Brustdichte an die Frau wie auch an den behandelnden Arzt weiterzugeben. Der Arbeitskreis Mammasonografie empfiehlt die Mitteilung der Brustdichte und die Aufklärung der betroffenen Frauen über die Vorteile individualisiert ergänzender Verfahren in Abhängigkeit vom Gesamterkrankungsrisiko der Frau; aufgrund der deutschen Gesundheitsstruktur mit Erfahrung und Qualitätssicherungsprogrammen insbesondere die ergänzende Durchführung einer Mammasonografie unter Sicherung von Struktur-, Prozess-, und Ergebnisqualität. Die Probleme möglicher Überdiagnostik, zusätzlicher Kosten und erhöhten emotionalen Stress sind bei der Aufklärung zu berücksichtigen. Bei familiärer Hochrisikokonstellation sollte eine humangenetische Beratung durchgeführt, eine genetische Testung und intensivierte Früherkennung unter Einbeziehung der MR-Tomografie erwogen werden.

Key words

breast - mammography - ultrasound - neoplasms - screening

Initial situation

Mammography is the only method for the early detection of breast cancer which was able to show a positive effect on the reduction of breast cancer mortality in different population-based studies [1]. The proportion of early mammographic detection on the one hand and treatment development on the other hand with respect to the observed breast cancer mortality reduction over the past few years is difficult to determine [2]. Nevertheless, even in times of state-of-the-art treatment concepts, the initial tumor size at diagnosis remains an essential and indisputable prognostic factor [3].

Consequently, the importance of imaging for the early detection of breast cancer remains undiminished. The effect of smaller tumor sizes on possible future therapeutic approaches will become increasingly differentiated in the future, not least in combination with molecular genetics and tumor risk categories [4]. In addition, there are indicators of an increase in the effectiveness of early detection imaging through greater individualization depending on the individual risk [5].

Breast density in diagnosis

High mammographic breast density plays an important role in two respects: increased breast cancer risk and masking of breast cancer in mammography. Firstly, a 4 – 5-fold increased risk for the development of breast cancer was detected in a meta-analysis when women with a very low breast density were compared with women who had a very high breast density [6] [7] [8] [9]. Secondly, density has an effect on the detection rate and especially on the certainty of the exclusion of breast cancer (sensitivity, negative predictive value) [10]. A decreasing sensitivity and increasing number of false-positive findings with the volumetric glandular tissue density was also recently shown for full-field digital mammography [11].

For these reasons, a law was developed in the USA in 2011 (Breast Density and Mammography Reporting Act of 2011) which stipulates that mammography facilities must inform both the referring doctor and the patient of the patient’s individual breast density (“patient's individual measure of breast density”) in writing. This law has now been passed and is in force in 21 states in the USA. Other states are currently working on a law or have already introduced it for passage [12].

In a US study of 9232 women in follow-up after breast cancer (therefore not originating from a population-based screening collective), no relationship was found between breast density and breast cancer mortality [13]. In contrast, in a randomized controlled trial of women with dense breasts from the Kopparberg collective of the Swedish screening program, both an increased incidence of breast cancer (relative risk increase RR 1:57) and an increased breast cancer mortality (RR 1.91) were found in 15 658 women aged between 45 and 59 years. [14]

The ACR BI-RADS standards have become largely accepted in Germany in recent years, albeit with small semantic or content modifications or comments from professional societies or consensus conference publications [15] [16] [17] [18] [19]. The standardized assessment of breast density thereby also found its way into Germany, even though it had not been previously reflected in the agreement of quality assurance measures in accordance with § 135 para. 2 SGB V for curative mammography [20]. Although the luminance in image display devices is regulated here, there is no information regarding mammographic density.

In contrast, the S3 guideline has referred to mammographic density in terms of breast cancer risk and the risk of masking a lesion since 2004 [21]. In the first update in 2008, supplementary breast ultrasound is already required after a mammogram with ACR density types III/IV [22]. Although mammography screening was introduced nationwide in Germany and with high quality standards, the striking lack of information about different breast densities is very problematic, especially for women to make an informed decision. In the official download area of the mammography screening program, brochures and leaflets are available which do not contain any reference to the issue of breast density [23]. The decision regarding participation in comprehensive, quality-assured mammography screening in Germany should be made by each woman after informed assessment of benefit and harm.

It remains to be seen whether this will change as a result of the decision made by the German Medical Assembly in 2014. In the paper, it was stated that: "The responsible doctors participating in the mammography screening program are requested to perform mammography according to the medical standard and to inform the attending doctor of the complete results." What is meant by “complete results” was not specified. It may be assumed, however, that the result classification (according to BI-RADS) and breast density are meant, but not a detailed description of the results which may be barely achievable and financeable in the context of a population-based screening program. Furthermore, reference is made in the explanatory statement that the follow-up care of patients must be guaranteed. In particular, reference is made to the Patients' Rights Act [24].

No specific reference was made to breast density in the decision of the Medical Assembly. However, this can inevitably be made from what was said above. Since breast density is an important predictor for the risk of developing breast cancer for women as well as for breast cancer detection, this has potential consequences for further care. In addition, breast density – divided into 4 levels according to the American College of Radiology – is documented in a standardized format in the mammography report. Here, the current BI-RADS lexicon shows that the subjective density assessment on 4 levels in the USA has led to uniform distribution of density documentation over many years [25].

One concern related to the relaying of breast density to German mammography screening clients could be that women would be left alone with the consequence of their breast density, as there is uncertain evidence for further procedures in such cases. This could eventually lead patients into the network of qualitatively heterogeneous providers of individual health services (IGel: individuellen Gesundheitsleistungen), the significance of which is unclear.

Very diverse opinions have been published on the basic implementation of further imaging procedures in mammographically dense breasts in asymptomatic women with normal risk [26] [27] [28].

Additional techniques for high breast density

Tomosynthesis

Digital breast tomosynthesis or 3 D mammography has shown higher sensitivity while maintaining or even increasing specificity compared to mammography in several studies in recent years, especially in women with increased breast density, but not in women with extremely dense breasts since the necessary parenchyma/fat contrast is missing [29] [30] [31] [32] [33] [34] [35]. The radiation dose for 3 D mammography/tomosynthesis, depending on the manufacturer and recording process, is typically slightly more than for a 2 D mammogram, but remains within the dosage limits for 2 D mammography [36].

Ultrasound

A number of studies proved that ultrasound can detect cancers in addition to mammography, especially in dense breasts [37] [38] [39] [40] [41] [42]. Depending on the study design and underlying risk prevalence, the number of breast cancers additionally discovered by ultrasound was stated as being up to 4.6/1000 examined women ([Table 1]). Therefore in the early detection guidance from 2008, the S3 guideline for breast cancer already called for the systematic use of ultrasound in mammographically dense breasts (ACR density 3/4) [18]. However, it must be stressed that the demand for ultrasound for ACR 3/4 breasts (evidence level of 3b) refers to general early detection and a transferal to the collective of clients within the mammography screening program (age 50 – 69 years) is only possible on an uncertain evidence base.

Table 1 Studies on ultrasound of the breast as an early detection method for breast cancer.

	number of participants (analyses)/ mean age	MG before US; US before MG; doctor/tech	risk HR/IR/NR	breast density distribution	number of MG lesions	number of US lesions	number of MG&US-detected lesions	NPV without/with US	PPV without/ with US	total number of cancers	number of cancers excl. US+	Δsensitivity with/sensitivity without additional US	number of biopsies per US-detected malignancy (pos. biopsy rate for US-detected Ca)
Bae et al. [33]	106 856 pat./ 47 J. (Ca-Pat.)	100 %/ 0 %; doctor	NR 95 %	ACR 2 – 4 (11/56/33 %)	only US-detected Ca analyzed	356	?	?	?	?	329 Ca (study population)	additional detection rate with US 3.4 Ca/1000 pat., = > suspected Δ 50 %	?
Berg et al. [34]	2637/55 J.	49 %; 51 %; tech	HR/IR (53 % after breast cancer)	5-level (%): 2/11/31/37/19	> C3: 12	> C3: 12	> C3: 8	>C2: 99.2/ 99.6	>C2: 14.7/10.1	40	12	30 %	16.58
Buchberger et al. [35]	6800/49 J.; of these 6113 asympt./49 J.	100 %/ 0 %; doctor	HR/IR/NR (10v. 21 US-detect. Ca in asympt. “high-risk” pat.)	ACR 2 – 4 (768/5236/796)	75	94	66	?/ 99.2 – 100 %[1]	?/ 25.3 – 11.5 %1	103 in 96 pat.	28 in 26 pat.; including 2 “indeterminable lesions”	27 % incl. indeterminate/25 % only malignant classification	12.61 (incl. syst. lesions)
Hooley et al. [36]	14 242 / ?; 935 / 52 J.; 753 asymptomatic, 182 sympt.	Tech	HR 9.3 %; IR 15.9 %; NR 65.7 %	ACR 3 – 4; no further info.	105 BI-RADS 0	55 with 54 subsequent biopsies	0	89.06 %/94.42 %	5.4 – 6.5 % (lesions/per pt)	3	3	100 %	18
Kolb et al. [10]	11 130 / 59.6; of these 5418 US-Pat. / 54.7 J.; of these 4897 asympt. and clin./MG neg.	100 %/ 0 %; Tech	HR/IR 26.5 % der US-pat., 73.5 % NR	ACR 2 – 4	423 biopsies in 393 pat. with 113 Ca in 99 pat.	320 biopsies in 292 pat. with 33 Ca in 31 pat.	?	99.32 %/100 %	35.8 %/20.5 %	146 Ca in 130 pat.	33 Ca in 31 pat.	22.6 %	9.7
Leconte et al. [37]	4236 Pat.; 60.7 J.; 73 % asymptomatic; 24 % post BC therapy; 3 % suspicious symptoms	100 %; doctor	N. D.	ACR 1 – 4; 1/2: MG 20 Ca; US 22 Ca; 3/4: MG 14 Ca; US 22 Ca.	34 Ca	44 Ca	28 Ca	?	?	50	16	20 %	?
Weigel et al [38]	2803 asymptomatic (screening clients)/58 J.	100 %/0 %; doctor	NR 100 %	ACR 1 – 4 (4/44 /49/3 %)	392	8	?	?	20 %/33 %	403	8	2 %	3

¹ with/without counting of “indeterminate lesions”;

Ca = breast cancer; Tech = radiographer; HR = high risk; IR = intermediate risk; NR = normal risk; ACR = American College of Radiology.

In the latest guideline recommendations of the Gynecological Oncology Working Group (AGO), ultrasound is recommended as a supplementary measure for dense breasts with an evidence level of 2b and recommendation grade B [43]. In Austrian mammography screening, ultrasound is applied as optional extra imaging directly after mammography in the case of an indication defined by the initial reader (dense breast or unclear results) [44]. Ultrasound has thus become an integral part of Austrian mammography screening.

Conversely, the IGeL (individual health services) monitor rated “ultrasound of the breast for the early detection of cancer in women with unknown breast density” as “unclear” [45]. Interestingly, individual statutory health insurance companies on the other hand promote breast ultrasound for early detection as part of special programs as a reimbursable service [46].

It is important to note the actual definition of the individual health care service. A quote from the IGeL monitor: “IGeLs are all medical services which by law do not belong to the statutory health insurance’s specified service catalog. This includes tasks that are not covered per se in the statutory health insurance area such as certificates or travel vaccinations. To a large extent, IGeLs are medical measures for the prevention, early detection and treatment of diseases, for which an essential prerequisite demanded by law has not been officially established, namely that they conform to the accepted medical standard” [47].

Since an increased cancer detection rate with additional breast sonography is accompanied by a higher biopsy rate, the question of the personal benefit to the individual woman remains open and the cost-benefit ratio for the statutory health insurance is critical. In a risk-adapted or individualized early detection situation, however, the clearly increased sensitivity of ultrasound, which has significantly better availability compared to the above-named methods, in combination with the existing quality assurance measures in Germany (KBV, DEGUM) provides a clear rationale for ultrasound (see also further information in [48] [49]).

The interventional assessment of unclear ultrasound results (which can be performed without delay in Germany, unlike stereotactic, tomosynthetic or even MRI assessment) allows for a significantly shorter delay of diagnosis compared to alternative methods. The mental stress in the waiting period in particular is one of the main arguments in terms of a possible detriment to women as a result of overdiagnosis.

Magnetic resonance imaging

MRI of the breasts, which was developed in Germany during the mid-1980 s by W. A. Kaiser and S. H. Heywang, was able to prove its higher sensitivity in comparison to other methods [50]. However, as a result of a possible decrease in specificity, an increased number of non-malignant findings can be classified as requiring clarification, which can lead to additional procedures and unnecessary biopsies. The typical costs of MRI are currently about 10-times higher than typical ultrasound costs and 5-times higher than typical mammography costs. Internationally as well as in Germany, MRI of the breasts is recommended for early detection for women at very high risk (> 20 – 30 % lifetime risk of breast cancer) [51] [52] [53]. Several experts also recommend MRI for women with intermediate risk (15 – 30 %) and dense breasts [8] [54].

Recommendation for women with dense breasts

The recommendations for evaluation are clear. Here, ultrasound plays the undisputed central role in diagnosis and image-guided assessment using needle biopsy. This can be seen, for example, in the clear data ratios of ultrasound versus stereotactic biopsies, even in mammography screening. In an evaluation report from 2010, 10 691 ultrasound-guided biopsies and 6725 biopsies under X-ray guidance were specified for the initial examinations after primary mammographic abnormality [55]. For the recalled women (PPV I), the cancer rate was 13.9 %. For women who still had a biopsy indication after further assessment including ultrasound, the carcinoma proportion (PPV II) increased by 3.6 times to 50.4 %.It follows that ultrasound, used for the correct indication and with quality-assured application, is obviously able to increase PPV and will not, as some authors would have us believe, decrease the PPV sui generis. Similar experiences seem to have been made in the USA after the introduction of compulsory density notification and consecutive supplementary ultrasound, where reports of a learning curve and declining false-positive results have been published [56] [57].

What can now be recommended to women with dense breasts [ACR density 3/4 and C/D) in the early detection situation (individual prevention or screening)? Given the extensive nationwide experience with ultrasound, good availability, existing quality assurance criteria, the proven breast cancer detection rates with ultrasound, the possibility of timely assessment of a suspicious lesion, the low physical burden on women due to the lack of ionizing radiation and contrast media and last but not least the progressive development of “advanced” ultrasound techniques as well as the ever-improving high frequency B-scan display, ultrasound is preferentially recommended for women with an average risk constellation who are seeking advice if they have dense breasts and wish to have an additional increase in the negative predictive value. The greater the pre-test probability (i. e. the individual risk of the disease at the time of presentation), the more likely it will be – considering the medical constellation as well as the different aspects of German supply reality – that MRI will position itself as the first choice in the early detection strategy.

Needless to say, this recommendation is linked to the fulfilment of qualitative investigator standards and it should always be given to women seeking advice in their search for quality-assured facilities (KBV agreement/DEGUM/DRG qualifications).

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