Authors:

László Tabár

,

Peter B. Dean

Date of publication: 22 May 2025
Last update: 22 May 2025

Abstract

Until the mid-20th century, women or their physicians detected breast cancer through palpation, usually at an advanced and incurable stage. This led to the claim that breast cancer is a systematic disease from its inception. A major technical development in the mid-1970s, the invention of low dose film-screen mammography, made it possible to find breast cancers in their non-palpable phase and challenge the proposal that breast cancer was a systematic disease from its inception. Specifically, the proposal was that detection through regular mammography screening and treatment at an early, non-palpable phase could prevent premature death in a significant proportion of breast cancer patients. Randomized controlled trials (RCTs) were set up to measure the efficacy of invitation to regular mammography examinations. The earliest of these to mature demonstrated a 31% significantly decreased breast cancer death among those invited, proving that breast cancer was not a systemic disease from the outset and that early detection and treatment in early phase could prevent many premature deaths. Invited women who did not attend screening could not benefit from early detection, causing the RCTs to underestimate the true effect of early detection through regular participation. Women who participated regularly had their risk of dying from breast cancer reduced by 40-50 %. This triumph in clinical cancer research led to the introduction of population screening programs in many countries over a relatively short period of time, despite the vociferous opposition of individuals ideologically opposed to early diagnosis of breast cancer through population screening. Improvements in image resolution, the implementation of multidisciplinary management meetings and quality assurance standards, and the regular training of physicians and personnel have all contributed to improved patient outcomes. The detection of a large number of very early breast cancers opened up new fields of research. The remaining challenges include the development of multimodality screening and the use of imaging biomarkers as the indicator of the site of origin of breast cancer to improve patient management. Despite all our best efforts over the past half century, we still need a comprehensive re-evaluation of our current management principles and practices and a renewed commitment to quality assurance.

 

Introduction

Physicians fought a losing battle against breast cancer so long as palpation and inspection were the only means of detection, the disease being far advanced by the time of treatment. Bernard Fisher claimed that breast cancer is a systematic disease from its inception (Fisher B 1980), a statement which is incompatible with the nature of an adenocarcinoma during its early stages of development (Tabár et al 2014). A major technical development in the mid-70s, the invention of low dose film-screen mammography, made it possible to find breast cancers in their non-palpable phase, before the development of viable metastases. These developments challenged the proposal that breast cancer was a systematic disease from its inception. The strong association of advanced disease with breast cancer death indicated that a significant decrease in advanced cancers could result in a significant reduction in breast cancer mortality (Nicholas E. Day et al. 1982, Day et al. 1989). Population-based randomized controlled trials were carried out to evaluate the impact of early detection on mortality from breast cancer.

Discussion

The first RCT to document a significant decrease in breast cancer mortality used a combination of breast palpation and mammography (Shapiro et al. 1971). The pilot studies of Lundgren and colleagues using mammography as the sole detection modality (Lundgren et al. 1975, Lundgren 1976) prompted the National Board of Health and Welfare of Sweden to initiate the large, population-based randomised controlled Two-County Trial in 1977. Similar but smaller trials began in the cities of Malmö (1976), Stockholm (1981) and Gothenburg (1982). An independent end-point committee performed a blinded review of all fatal breast cancer cases and assessed the causes of death in all the Swedish population-based screening trials. This review concluded that “The cumulative mortality curves for the invited and control groups showed a similar pattern” (Nyström et al 1993). The largest RCT, the Two-County Swedish Trial, showed a 25% decrease in the rate of Stage II or more advanced breast cancers (RR 0.75 (0.65-.087)) which corresponded to a 31% significant reduction in breast cancer mortality (RR 0.69 (0.51-.092)) in the group invited to screening (participants and non-participants combined) (Tabár et al. 1985). These results led to the establishment of the first nationwide breast cancer screening programs in Finland, Sweden, the UK and in The Netherlands. The remaining EU countries established nationwide screening services over the next three decades (Screening Group 2016). Nationwide programs have also been established in Norway, Canada, Singapore, Australia and New Zealand. The prospective, population-based randomized controlled trials and service screening programs provided unequivocal evidence that the incidence rate of advanced (Stage II+) cancers is indeed a sensitive predictor of subsequent mortality (Tabár et al. 1985, Foca et al. 2013, Tabár et al. 2015, Broeders et al. 2015, IARC 2016, Duffy et al. 2020). Supporting evidence obtained from the RCTs and from nationwide, population-based service screening programs confirmed that early detection of breast cancer through mammography screening is associated with a significant reduction in the risk of dying from the disease (Nyström et al. 1993, Vainio et al. 2002, Tabár et al. 2011a, Hellquist 2011, Hofvind 2013, Coldman et al. 2014, IARC 2016, Screening Group 2016, Tabár et al. 2016, Morrell 2017, Duffy et al. 2020). All these results also confirmed that breast cancer could not be a systemic disease from its inception, contradicting the theory developed by [Bernard Fisher](@ (Fisher B 1980).

These accomplishments led to a paradigm shift in breast cancer management. In addition to the traditional emphasis of applying various therapeutic methods to advanced disease, the new emphasis is to employ early detection to arrest disease progression to an advanced stage. We may conclude from the RCTs and from subsequent population screening results that nothing is more harmful than letting a breast cancer evolve from its preclinical, mammographically detectable and potentially curable stage to a clinically detectable stage. A cost-effectiveness analysis from The Netherlands found that the cost of screening per life-year gained was 1,600 EUR. For each breast cancer death prevented by screening, the woman will be spared the terminal stages of this disease (Malmgren et al. 2012, Health Council of the Netherlands 2014, Tabár et al. 2015). A study from Switzerland found a significantly higher incidence of advanced breast cancers in women living in cantons that did not have organized mammography screening, compared to the cantons offering screening during the years 2014-20 (Gutzeit et al. 2024). Despite numerous efforts, breast palpation as the sole detection modality in screen trials has not been effective in reducing breast cancer mortality (IARC 2016).

The Swedish Organized Service Screening Evaluation Group (SOSSEG) was established after the publication of the results from the Swedish Two-County Trial, and focused attention upon evaluating the ongoing nationwide service screening. Data on breast cancer mortality and the incidence of subsequently fatal breast cancers in women aged 40–69 years at the time of invitation to screening were analysed. The results showed that women who had attended two consecutive screenings prior to breast cancer diagnosis had a 50% reduction in breast cancers that were fatal at 10 years (RR = 0.50; 95% CI: 0.46, 0.55; P < .001) compared women who did not participate in their last two screenings before breast cancer diagnosis. Missing the last two examinations conferred a significantly higher risk of dying from breast cancer (Duffy et al. 2021). There is still a need to increase women’s awareness about the importance of regular participation in screening.

SOSSEG researchers studied breast cancer incidence and mortality in a geographic population of women aged 40-69 during the years 1958-1976 (before the RCT started), and during the RCT and service screening (1977-2015) in women who participated and did not participate in screening. This allowed historical and contemporaneous assessment of breast cancer incidence and mortality, and the relative impact of early detection and treatment. Important conclusions concerning the relationship between early diagnosis and adjuvant therapy were summarized as follows: “Although some consider that advances in adjuvant therapy and chemotherapy are mainly responsible for improved breast cancer prognosis in screened populations (Autier et al. 2011), in the modern era, we believe that it is time to focus attention on the combination of diagnosis and therapy, instead of viewing them as independent, or worse, as competing interests. Our results demonstrate that the benefit of therapy is significantly greater for women who have participated in mammography screening. Our results from precise, individual-based data covering 6 decades, should provide women and their physicians with reassurance that participating in regular, high-quality mammography screening is the best way to reduce the risk of a premature death from breast cancer” (Fig. 1)(Tabár et al. 2018). Screening has made possible the detection of a large proportion of node negative tumours less than 15 mm size (i.e. before the development of viable metastases) and there is substantial evidence that local-regional therapy is effective in these cases. The decisive factor is whether the treatment is given early or late in the natural history of the disease, rather than which treatment choice is offered to breast cancer patients. There is no substitute for finding breast cancer early in its natural history. Adjuvant systemic therapy has negligible scope to improve the survival of patients with these tumours (Eugenio Paci et al. 2005, Tabár et al. 2019).

Fig. 1. The incidence of breast cancer (upper chart) and of breast cancer fatal within 10 years (lower chart) among women who did and did not participate in mammography screening. All values indicate 5-year moving averages for women ages 40 to 69 years (data from statistics of Dalarna County, Sweden, from 1958 to 2015). Figure adapted from Tabár et al. 2019.

Despite this accumulating evidence, some individuals failed to understand or refused to accept the implications of these results. Edwin Fisher, a pathologist, claimed: “There is no evidence that delay in diagnosis unfavorably influences the survival of patients with breast cancer” (Fisher ER 1988). Bernard Fisher, a surgeon, stated, “Local therapy and local disease control cannot affect survival outcomes” (Fisher B 1999). Their statements were based on their proposal that breast cancer was a “systemic disease from its inception”, and they concluded that surgical therapy could not be curative without adjuvant therapy. This proposal proved to be mistaken by evidence from the randomized controlled trials and service screening programs, which provided substantial data that local-regional therapy is effective for screen-detected, impalpable node negative tumours smaller than 15 mm, and that adjuvant systemic therapy has negligible scope to improve the outcome of patients with these tumours. The persuasiveness of the Fisher brothers regarding early surgical intervention has led to the nearly universal use of adjunctive therapeutic methods such as radiotherapy after breast conserving surgery, anti-estrogen therapy for tumours with sufficiently positive estrogen receptor immunochemistry results and the frequent use of chemotherapy.

A number of physicians have opposed the concept of early diagnosis of breast cancer through population screening, arguing that healthy, asymptomatic women should not be screened for breast cancer due to the alleged “harms” of screening, and questioning the benefits. Some have attempted to prevent the establishment of screening programs and have urged women not to attend ongoing programs. One of the first was John C Bailar 3rd, an internist and editor of the JNCI, who published an article claiming that the radiation exposure of mammography would cause more deaths than could be prevented by early diagnosis (Bailar 1976). His calculations were shown to have been faulty, and also, the radiation exposure of mammography decreased exponentially during the next decade through technical advances. Concern over radiation exposure prompted the Swedish government to follow the advice of radiologist Bengt Lundgren to use only single-view (mediolateral oblique) image for each breast (Lundgren 1976) with a three-year interscreening interval in the Two-County screening program.

Petr Skrabanek, an internist and lecturer in medical ethics, argued forcefully against all forms of government sponsored screening programs. “One of my duties is to protect people against the harm that over-enthusiastic doctors and misguided politicians can inflict upon them” (Skrabanek 1988a). He opposed cancer screening as a dangerous government interference in people’s lives, an example of what he called “coercive healthism”. He claimed that screening provided no benefit since overall mortality was not significantly reduced and he exaggerated the perceived harms (Skrabanek 1988b). Anthony B. Miller, an internist and a harsh critic of mammography screening, led the Canadian National Breast Screening Study (CNBSS), which was not a population study and had serious epidemiological, quality assurance, medical and ethical problems (Kopans et al. 1993, Boyd et al. 1993, Burhenne et al. 1993, Miller et al. 2014, Heywang-Köbrunner, et al. 2015, Yaffe et al. 2022, Seely et al. 2022). Despite these serious deficiencies, this discredited study has negatively influenced screening organisation for decades.

In 1997, Peter C. Gøtzsche, a Danish physician and Director of the Nordic Cochrane Centre, expressed opposition to all forms of screening, “The studies also raise a pertinent ethical issue: do we wish to turn the world's healthy citizens into fearful patients-to-be who, in the not too distant future, might be asked to deliver, for example, annual samples of faeces, urine, sputum, vaginal smear, and blood, and undergo X-ray and ultrasound examination with all it entails in terms of psychological morbidity and the potential for harm because of further testing and interventions due to false positive findings? If we compare with the considerable risks the citizens expose themselves to because of smoking and other unhealthy lifestyles, I believe that the answer should be no.” (Gøtzsche 1997). He subsequently compromised himself in his Cochrane Review from 2002-2012 by stating in his Declaration of Interest, “None. We had no a priori opinion on the effect of screening for breast cancer when we were asked by the Danish National Board of Health in 1999 to review the randomised trials.” (Olsen et al. 2001, Gøtzsche et al. 2013). These two conflicting statements speak for themselves to describe his character. He claimed, “Screening for breast cancer with mammography is unjustified” (Gøtzsche et al. 2000). His approach was based on a selective and personal interpretation of RCTs without gaining a sufficient understanding of the basics of screening epidemiology. In a BBC radio interview in 2012 he stated, "What women should do is, as they have always done, if they find something unusual, go and see a doctor, but don't examine yourself regularly. It has no effect and it doubles the number of biopsies and it also induces a lot of anxiety of course...so, so, there is general agreement now that women should not be advised to examine themselves every month. That’s against recommendation" (Gøtzsche 2012a). He published a book in which he claimed, “The most effective way to decrease women’s risk of becoming a breast cancer patient is to avoid attending screening” (Gøtzsche 2012b). His approach included selective citation of the scientific literature by reporting failed or mediocre results from mammography screening and reports detailing purported “harms” of screening. Reports demonstrating the benefits of mammography screening were either ignored, incorrectly cited, or cited but declared as biased using novel criteria, and ignored in his conclusions. He made many elementary errors in screening epidemiology, repeating these same errors despite having them repeatedly pointed out in letters to the editor (Paci et al. 2002, Dean 2004, Duffy et al. 2010b, Puliti et al. 2012, Duffy et al. 2013). In a perceptive review of the RCTs in 2004 (Freedman et al. 2004,), the authors stated, “The basis for the Gøtzsche–Olsen critique turns out to be simple. Studies that found a benefit from mammography were discounted as being of poor quality; remaining negative studies were combined by meta-analysis. The critique therefore rests on judgements of study quality, but these judgements are based on misreadings of the data and the literature.”

A group of 41 screening experts, exasperated by the steady flow of non-scientific criticism, published a letter in The Lancet: "Although the wider scientific community has long embraced the benefits of population-based breast screening, there seems to be an active anti-screening campaign orchestrated in part by members of the Nordic Cochrane Centre. These contrary views are based on erroneous interpretation of data from cancer registries and peer reviewed articles. Their specific aim seems to be to support a pre-existing opposition to all forms of screening” (Bock et al. 2011). Gøtzsche was dismissed in 2018 from his position as Director of the Nordic Cochrane Centre, as a Head Physician at the Copenhagen University Hospital (Rigshospitalet), and as Professor of Clinical Research Design and Analysis at the University of Copenhagen for his combative behavior and questionable scientific conduct (Lund 2020). He continues his polemics outside the academic community, stating, “You should not trust your doctor. You should look up the evidence yourself.” and has recently opposed COVID-19 vaccination (Kolitz 2020, Lund 2020, Gorski 2023).

H. Gilbert Welch, an internist and a critic of screening for cancer, co-authored a publication with the pediatric oncologist Archie Bleyer stating, “Screening is having, at best, only a small effect on the rate of death from breast cancer” (Bleyer et al. 2012). Although published in a prominent journal, their misleading conclusions were made without knowledge of which woman was or was not screened, or how often, or, even if a breast cancer was diagnosed in a woman who did or did not get a mammogram. These authors admitted: "Unfortunately, because the [Surveillance, Epidemiology, and End Results (SEER)] program does not collect data on the method of detection, we were unable to distinguish screening-detected from clinically detected cancers." These authors admitted to the following deficiencies in their New England Journal of Medicine 2012 publication: "Tables 1 and 2, however, are based on assumptions ..." ”We were forced to make some assumptions ..." "The simplest approach was to assume ..." "In our best-guess estimate ..." "Our assumption ... was admittedly arbitrary ..." "Fourth, our best-guess estimate ..." "Our method did not allow us to disentangle the two. We did, however, estimate ...". These terms of imprecision were used more than 71 times in that NEJM article. Bleyer and Welch described that their opinions were "a view from space." (Bleyer et al. 2012). Welch and Frankel wrote, "we were forced to make an assumption to capture the downstream benefit of screening.” (Welch et al. 2011). In 2018 Welch left Dartmouth University amid charges of research fraud.

The physicians actively opposing screening have several features in common, the most important being the ideology that healthy people should not undergo medical examinations, which serves as a “justification” for opposing the early detection of cancer. Few of them has personal expertise in cancer screening or even a basic understanding of the epidemiology of cancer screening, as in their published critiques they confuse invitation to screening with participation in screening, reducing the true effect of participation by approximately 50%. Since the reviewers and editors of general and internal medicine journals are also often unaware of these distinctions, many authors opposing early detection have been successful in publishing their opinions, as the journals encourage “controversy” to enhance their impact factors, circulation numbers, and finances. In response to complaints that such publications were not properly evaluated, the editors of Breast Cancer Screening (IARC Working Group on the Evaluation of Cancer-Preventive Strategies 2016) responded: “most ecologic studies that compared mortality between regions or time periods were judged to be uninformative, since they did not control adequately for potential confounding by secular trends or population characteristics. Modeling studies were not considered for the evaluation of effectiveness.” (Lauby-Secretan et al. 2015).

Individuals opposing the early diagnosis of breast cancer, and who have succeeded in publishing ecologic and modelling studies based on statistical manipulation of published data and registry data, none of which had access to individual patient data, were thus unable to differentiate invited women from those actually participating in screening. These include Göran Sjönell, a general practitioner, Mette Kalager, a surgeon, Per-Henrik Zahl, a statistician, Jan Mæhlen, a pathologist, Hans-Olov Adami, a surgeon, Michael Bretthauer, a gastroenterologist, Laura Esserman, a surgeon, Philippe Autier, a specialist in tropical medicine and epidemiologist, Karsten Jørgensen, a physician and close associate of Gøtzsche, and Michael Baum, a surgeon (Sjönell et al. 1999, Zahl et al. 2009, Esserman et al. 2009, Kalager et al. 2010, Esserman et al. 2013, Adami et al. 2020, Autier et al. 2024, Baum 2024). Zahl and colleagues, using statistical manipulation of registry data, have speculated that “the natural course of some screen-detected invasive breast cancers is to spontaneously regress” (Zahl et al. 2008). Kalager and colleagues use their own methodology to claim that only 1/3 of the beneficial effect of mammography screening is the result of early diagnosis, concluding that there is “Too much mammography. Long term follow-up does not support screening women under 60” (Kalager et al. 2014). Baum recently claimed that “Breast cancer screening does not improve length or quality of life” (Baum 2024). In reply to the criticisms by Gøtzsche, Jørgensen and Zahl (Gøtzsche et al. 2010) of a publication (Duffy et al. 2010a) analysing British and Swedish breast cancer incidence and mortality, Stephen E. Duffy and colleagues carefully explained these authors’ failure to understand basic facts of breast cancer biology, epidemiology, and statistical procedures, as well as their misleading citations of the literature, and pointed out (once again) the inherent contradictions in their calculations of overdiagnosis, concluding with the following statement about potential bias, “Professor Gøtzsche has had longstanding negative views about screening, (Gøtzsche 1997) predating his interest in mammography. We appreciate that secondary research inevitably contains a major interpretative component, but there appears to be a tendency on the part of Gøtzsche and colleagues towards preoccupation with what they consider SHOULD happen after the introduction of a breast cancer screening programme, based on their views and assumptions. This may be the reason for the factual errors in Gøtzsche and colleagues’ arguments about overdiagnosis, as noted above, and may explain the use of the unobserved 15% estimate of the mortality reduction in the Cochrane review, smaller than the 20% actually observed. We suggest that more emphasis be given to what actually DID happen. When we introduced a screening programme in England, breast cancer mortality fell by 28% more than it would have in the absence of screening (similar to that expected from the trial evidence), and the number of deaths prevented outnumbered the overdiagnosed cases by more than two to one.” (Duffy et al. 2010b).

Despite the combined efforts of these opponents of early diagnosis, breast cancer screening with mammography continues to reach ever-wider populations due to the acceptance of the scientific evidence by decision makers. It is unfortunate that a few physicians have interfered with this progress, as there is an untold number of women whom they have dissuaded from attending screening by their arguments, including those who were subsequently diagnosed and treated for late-stage breast cancer.

The benefits and harms of breast cancer screening need to be viewed as part of the overall management of breast cancer patients. “Although much attention has been devoted to the potential ‘harms’ of participating in regular screening, little attention has been given to the harms of not participating in regular screening, the greatest harm being a significantly increased risk of death from breast cancer. In addition, women who choose not to participate in screening will experience a significantly higher rate of advanced breast cancers, a greater need for more extensive surgery, a greater risk of upper body impairments (including lymphedema), and more extensive radiotherapy and chemotherapy, for which many women experience significant, enduring adverse physical and cognitive effects. For each breast cancer death prevented by screening, a woman will be spared the terminal stages of this disease, and she will gain an average of 16.5 life-years” (Health Council of the Netherlands 2014, Tabár et al. 2019).

The potential “harms” of mammography screening have been considered to be a) radiation exposure b) discomfort and anxiety due to false-positives, c) false-negatives and d) unnecessary treatment due to overdiagnosis. These alleged harms have been carefully evaluated and shown to be of minimal concern compared to the overwhelming benefits of early detection (Di Maria et al. 2024, Duffy et al. 2013, IARC 2016).

We discuss here four recurring issues, radiation induced breast cancers, overdiagnosis, all-cause mortality and the claim that mammography screening fails to benefit women with more aggressive cancers. The radiation issue has been thoroughly investigated and evaluated soon after the introduction of low-dose film-screen mammography (Lester 1977), and later on by Feig and Ehrlich, (Feig et al. 1990) who found the risk to be negligible compared to the proven benefits of annual mammography screening beginning at age 40. The definition of overdiagnosis is that screening detects cancers that would not have been diagnosed in the host’s lifetime if screening had not taken place and would not have affected the patient’s health. The existence of such cancers can be estimated by statistical analysis that requires adjustment for the known influences on incidence. When calculating overdiagnosis one must adjust for a) increasing incidence occurring independently from screening and b) lead time from screening. Failure to apply appropriate methodology leads to overestimating overdiagnosis. Studies that fail to take full account of lead time and of underlying incidence trends tend to estimate high rates of overdiagnosis in the order of 30–50%, whereas those that do take account of these phenomena obtain much lower rates, in the order of 1-5 % (Duffy et al. 2005, Hellquist et al. 2012, Puliti et al. 2012, Tabár et al. 2017, Chaltiel et al. 2021).

The claim that mammography screening is successful only when it reduces all-cause mortality significantly in all women invited to screening is illogical because screening cannot have any impact on all other causes of mortality. All-cause mortality is a valid measurement only in women with breast cancer and has been shown to be significantly reduced by invitation to breast cancer screening (19%) ((RR 0.81, CI 0.72-0.90, p<0.001) (Tabár 2002).

It has been asserted that mammography screening preferentially detects less aggressive cancers. The SOSSEG team reviewed the impact of mammography screening on mortality by histologic malignancy grade. Contrary to these claims, there was a major reduction in mortality from Grade 3 tumours (RR = 0.65, 95% CI 0.53-0.80, p<0.001), and more deaths prevented from Grade 3 tumours (N=95) than Grade 1 and 2 tumours combined (N=48) in the invited group (Tabár et al. 2018).

Fig. 2. A, Cumulative breast cancer mortality over time in women invited to screening, i.e. attended and not attended combined, active study population (ASP) and women not invited to screening, i.e. control group, passive study population (PSP) for invasive breast cancers of histologic grade 1. B, Cumulative breast cancer mortality over time in the ASP and in the PSP for invasive breast cancers of histologic grade 2. C, Cumulative breast cancer mortality over time in the ASP and PSP for invasive breast cancers of histologic grade 3. Adapted from Tabár et al. 2018.

Breast cancer screening and the large number of very small breast cancers detected provided investigators with a wealth of previously unavailable material, enabling a re-evaluation of the sites of origin of breast cancer. The most valuable insights have arisen from correlative imaging-histopathologic studies including thick section, 3D histopathology (Marcum et al. 1969, Wellings et al. 1975, Tabár et al. 2004). Based on these observations and the long-term follow-up of a geographically defined population, with full access to the imaging, histopathology and death registry data of all breast cancer patients over a period of more than four decades, the SOSSEG team found three separate sites of origin of breast cancer. They also found serious inconsistencies in the current histopathologic nomenclature and traced the misconceptions arising during the past century that led to these inconsistencies. In approximately 75% of cases, breast cancer originates from the epithelial cells of the terminal ductal lobular unit (TDLU), i.e. from the cells of the lobule (László Tabár series 2023). Unfortunately, the currently used histopathologic terminology uses the misleading term "ductal" to describe these tumours, based on the use of the antiquated word “ductule” to describe the acini of the breast lobule (Dawson 1933). The SOSSEG research group suggests unifying the terminology of all fluid-producing organs and use the site of tumour origin in describing breast cancer subgroups, as is already the case for conventional histopathology terminology of the cancers of other fluid producing organs, the prostate and salivary glands. Cancers originating from the epithelial cells of the lobular acini should be termed acinar adenocarcinoma of the breast (AAB).

On the other hand, when breast cancer originates from the epithelial cells of the major ducts, the histopathologic terminology is ductal carcinoma in situ (DCIS). Using the word "ductal" is correct, but these cancers often act as duct forming invasive cancers, which are newly formed, contain no acini, and were not previously present in the breast and thus clearly not in situ. These invasive, duct-forming malignancies propagate through the process of neoductgenesis, comprise approximately 20 % of breast cancers and have a 30 % risk of causing death from breast cancer. These malignancies should be termed ductal adenocarcinoma of the breast, (DAB), corresponding to the DAP describing ductal adenocarcinoma of the prostate and parotid glands. Finally, the term diffusely infiltrating "lobular" carcinoma is incorrect, because the term implies that the origin is in the lobular acini. There is recent cell culture evidence showing that this peculiar type of breast malignancy originates from the hybrid stem cells of the breast mesenchyme, and not from the epithelial cells of the lobular acini. The suggested term is breast cancer of mesenchymal origin (BCMO). These comprise approximately 5-8 % of breast malignancies and have a 40 % risk of causing death from breast cancer. This fatality risk has not been affected by improvements in breast cancer management over the past half century (László Tabár series 2023, Tabár et al. 2023).

In order to maintain and improve the benefits of early detection of breast cancer, much still need to be done, including the following:

1. The introduction of large-scale, population-based mammography screening of asymptomatic women added a new dimension to the traditional interaction between pathologists, surgeons, oncologists and radiologists, necessitating further improvements in interdisciplinary cooperation.

2. Taking the site of tumour origin into account in every aspect of diagnosis and treatment planning gives a strong scientific basis to modern breast cancer management. The histopathology terminology needs to undergo a revolution similar to the one that has already occurred in breast imaging. The currently used ductal/lobular dichotomy is an anatomically incorrect and misleading terminology, which leads to the underdiagnosis and undertreatment of diffusely infiltrating breast cancers, which are also the more fatal subtypes. This outdated terminology also causes women with minimally fatal breast cancers to be subjected to overtreatment. A thorough overhaul of this terminology is badly needed. Breast cancer management should be closely correlated with imaging biomarkers, which are based on the apparent anatomic site of origin of breast cancer. The long-term patient outcome appears to be largely determined by the site of origin of breast cancer, emphasizing the need for the use of imaging biomarkers in breast cancer management (László Tabár series 2023, Tabár et al. 2023).

3. Management of multifocal and diffusely infiltrating breast cancers, which are the more fatal, using breast conserving surgery is compromised by the use of small section histopathology which cannot adequately map the full extent of these tumours (Tabár et al. 2011b, László Tabár series 2023). Larger histopathologic sections are essential for adequate radiologic-histopathologic correlation, especially in the multifocal AAB cases, and in the diffusely infiltrating breast malignancies (DAB and BCMO), as well as for more comprehensive determination of the surgical margin.

4. The large number of screen-detected, non-palpable breast cancers provides an opportunity to study all aspects of the earliest phase of this disease. This opportunity has not been previously available.

5. Training followed by further education of breast physicians and personnel at regular intervals is necessary to maintain and improve competence. This can be done more effectively by correlating imaging with large format histopathology of each breast cancer case.

6. The benign and malignant breast diseases are complex and heterogeneous. In addition, breast tissue is unique in having a wide range of parenchymal patterns, which greatly affect the sensitivity of imaging methods. This challenge can be met by introducing the multimodality approach to breast cancer screening.

7. Serious research on artificial intelligence (AI) is needed to find out the extent to which AI can assist the screening radiologist.

Conclusions

Earlier diagnosis in organized population screening programs has had considerable success over the past five decades in reducing morbidity and mortality from breast cancer. This success could not have happened without a combination of earlier diagnosis with improved therapeutic approaches. There are still many obstacles to overcome, the greatest being the lack of access to population screening and up-to-date diagnostic and therapeutic management by a large proportion of women in many countries. Diagnostic methods are steadily improving but are hampered by the small section histopathology technique. Therapeutic efforts are hampered by the anatomically misleading breast cancer terminology, subjecting patients to underdiagnosis and undertreatment of highly malignant tumours, as well as overtreatment of the less malignant tumours. A serious reappraisal of histopathology terminology is sorely needed.

Acknowledgements

The authors are greatly indebted to the fellow members of the Swedish Organized Service Screening Evaluation Group for their active scientific collaboration over the past four decades.

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