Let Us Move Out of Plato’s Cave: The Greater Reality of DCIS

HomeRadiologyVol. 301, No. 1 PreviousNext Reviews and CommentaryFree AccessEditorialLet Us Move Out of Plato’s Cave: The Greater Reality of DCISChristiane K. Kuhl Christiane K. Kuhl Author AffiliationsFrom the Department of Diagnostic and Interventional Radiology, University Hospital Aachen, RWTH Pauwelsstr 30, 52074 Aachen, Germany.Address correspondence to the author (e-mail: [email protected]).Christiane K. Kuhl Published Online:Aug 3 2021https://doi.org/10.1148/radiol.2021211596MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In An earlier incorrect version of this article appeared online. This article was corrected on August 4, 2021.See also the article by Chou et al in this issue.Prof Christiane Kuhl is chair of the Department of Diagnostic and Interventional Radiology at the University Hospital of Aachen, RWTH. Her research interests focus on oncologic imaging, especially breast and hepatobiliary imaging, and interventional treatment of cancer. She has received the gold medal of ISMRM and EUSOBI, the Impact Award of the NCoBC, and the European Magnetic Resonance Award, and has been named a member of LEOPOLDINA. When she is not doing clinics, performing administrative duties, conducting research, or caring for the people in her department—the best in the world, of course—Prof Kuhl is a loving mother of three dogs and eight horses and ponies that she cares for together with her husband, Heribert Bieling.Download as PowerPointOpen in Image Viewer In this issue of Radiology, Chou and colleagues (1) report on the results of an important clinical trial by the Eastern Cooperative Oncology Group and American College of Radiology Imaging Network (EA4112) on the use of breast MRI for treatment planning and risk stratification in patients with ductal carcinoma in situ (DCIS).DCIS is a nonobligate precursor of “the real thing”—invasive breast cancer. It describes a situation where cancerous cells develop within the epithelial lining of the milk ducts that proliferate and may ultimately fill an entire milk duct system. But, for reasons entirely unknown, these cancerous cells respect the ductal basal membrane boundary and do not cross it. Since blood or lymphatic vessels do not penetrate the milk duct wall, DCIS does not have access to the usual routes of tumor cell seeding and cannot metastasize. It is therefore considered a precancerous condition, appropriately referred to as stage 0 breast cancer.There appears to be no progressive dedifferentiation in grades of DCIS. Rather, low-grade DCIS may (or may not or may only after a long period of time) progress to low-grade invasive carcinoma; high-grade DCIS will progress more likely and sooner to high-grade invasive cancer. This means that the biology of DCIS is as variable as the biology of invasive cancer that may (or may not) emerge from it (2).Detection of DCIS is considered beneficial because it enables primary prevention. Treatment of DCIS prevents the development of invasive breast cancer and is, thus, a preventive measure. The aim is not to cure the disease (DCIS is a factually benign condition) but to prevent future in-breast events (ie, DCIS or invasive breast cancer). At times, the medical community seems to lose sight of the preventive nature of DCIS treatment in that DCIS is treated with similar rigor as the disease—invasive cancer—that the treatment of DCIS aims to prevent. Since the average DCIS is larger at the time of diagnosis than the average invasive cancer (3), the fraction of women with DCIS requiring extensive surgery or mastectomy is even higher than that of women with invasive breast cancer. Women with DCIS require more than one round of surgery to achieve clear margins three times more often than women with invasive cancer (4). Like women with invasive cancer, most women with DCIS also undergo radiation therapy and, increasingly, antihormonal treatment. Thus, the degree of treatment provided for DCIS may explain why women with DCIS have difficulty realizing they do not have cancer but just its precursor—even if explicitly told so.Because often painful or even mutilating procedures are administered only for prevention, there is substantial uncertainty regarding the appropriate management stratification of women with DCIS. The uncertainties are related to two distinct issues.For one, it is impossible to predict the likelihood with which a DCIS will ever progress to invasive cancer. Nuclear grading and gene expression profiling do provide hints; however, there is no tool available to foretell the future behavior of a DCIS (prognostication) with sufficient accuracy (5).For another, the diagnostic methods currently used to detect DCIS and guide its treatment are insufficient. Therefore, we fail to identify DCIS early enough. Hence, DCIS is usually larger than invasive cancer at the time of diagnosis. And hence, most cancers diagnosed at mammographic screening are detected only when they are already in the invasive stage, which implies that we failed to detect them during their respective DCIS stage. Last, this also leads to our failure to delineate the actual extent of known DCIS, hence the need for repetitive surgery in women with DCIS. Thus, although overdiagnosis of DCIS remains an issue, underdiagnosis of DCIS (ie, failure to detect it early enough and to depict its true extent) may be an even greater challenge.For the time being, virtually all DCIS included in clinical trials on treatment stratification in DCIS were diagnosed with mammography. In other words, the world of DCIS as we know it is shaped by the subset of mammography-visible DCIS. However, the medical community seems mostly unaware that this is indeed only a subset and that, in accordance with Plato (Greek philosopher 428–348 BC), a “greater reality” of DCIS exists that we cannot see with mammography.This lack of awareness when it comes to DCIS and mammography is understandable. The link between mammography and DCIS is so strong that it has become a “mammographic disease.” The depiction of microcalcifications and detection of DCIS have become virtually synonymous. The fact that MRI is unable to depict microcalcifications has therefore been perceived as synonymous with MRI being inferior to mammography for DCIS detection. This was fueled by early reports that directly compared the diagnostic accuracy of MRI with that of mammography in women with DCIS and that had found a lower sensitivity for MRI. However, because only mammography was and is used for screening, these studies included only individuals who all had DCIS diagnosed with mammography. It was likely the conjecture that there is no DCIS outside the realm of mammography that explains why there was little, if any, awareness that such a study design suffers from selection bias. With this biased design, however, it was literally impossible for MRI to achieve a higher sensitivity than mammography since mammography was the method used to identify eligible patients.The true sensitivity of MRI in the diagnosis of DCIS was only discovered when MRI and mammography were compared in unselected cohorts. Our group published such a systematic comparison and found that breast MRI is much more sensitive than mammography in the diagnosis of DCIS (6). Over half of all DCIS cases are not associated with microcalcifications and are therefore only visible at MRI. This finding is in good agreement with the observation that over half of the invasive breast cancers detected with mammography are not associated with microcalcifications. Possibly, these invasive cancers emerged from noncalcified DCIS that were undetectable with mammography—more indirect evidence for underdiagnosis of DCIS with mammographic screening.The results of the recent EA1141 study on the use of abbreviated MRI versus digital breast tomosynthesis serve to reconfirm that MRI improves the detection of DCIS to the same extent as invasive breast cancer (7). The only difference between invasive breast cancer and DCIS in terms of MRI versus mammographic detectability is that, whereas it is exceedingly rare for invasive breast cancer to be detected with mammography but not MRI, this does happen in the case of DCIS. About 20% of DCIS associated with microcalcifications on mammograms are not associated with enhancement on breast MRI scans; the majority of these lesions are low-grade DCIS.The bottom line is that with usual mammography or digital breast tomosynthesis screening, we identify only about half of the existing DCIS and ignore the other half that only MRI can depict. Accordingly, differences regarding the selection of the respective study cohorts (full range of DCIS or only the mammography-detectable subset) can explain discrepant findings between studies on the diagnostic performance of MRI in the diagnosis of DCIS, or on MRI phenotyping of DCIS.Chou et al (1) provide further evidence that MRI could help with planning surgery of DCIS: Breast MRI depicts DCIS diagnosed with conventional imaging with a larger median span than mammography, has an additional cancer detection rate of 6.2%, and may assist with planning of wide local excision at an acceptably high positive predictive value (32%).However, in the future, MRI may also help with the first clinical need mentioned previously—the prognostication and thus the treatment stratification of DCIS—for the following reason.There is communication between the DCIS cells inside and the world outside the milk duct, known as the periductal space. Intraductal cancerous cells release proangiogenic and prolymphangiogenic factors that lead to an increased periductal vessel density. This vessel density appears to increase with DCIS grading, and the role of angiogenesis as a driver of DCIS biology and prognosis is consolidating (8,9). Since blood vessels do not penetrate the basal membrane of the milk duct wall, there is no direct perfusion of DCIS; instead, DCIS cells need to be fed by diffusion over wide distances. To promote this diffusion (ie, to ensure supply with oxygen and nutrients, including larger protein molecules), especially high-grade DCIS cells release local protease that increases the permeability of the milk duct wall.All these factors explain the MRI appearance of DCIS. The angiogenic activity of DCIS increases the density and leakiness of periductal vessels, leading to increased extravasation of a contrast agent at the site of the DCIS. From there, the contrast agent must diffuse into the intraductal space, yielding the typical ductal enhancement observed at MRI. Accordingly, after the extravasation, there is another step to take for contrast agents to reach their final destination (ie, the intraductal space). Thus, enhancement in DCIS is usually more gradual compared with invasive cancers where there is direct intratumoral perfusion. It is remarkable that it is at all possible for a large macromolecule like a gadolinium chelate to diffuse into the intraductal space. The healthy milk duct has a very tight basal membrane that acts as an effective barrier. Contrast enhancement of DCIS therefore proves presence of a drastically increased permeability of the ductal basal membrane and is thus a marker for both angiogenic and protease activity of DCIS (10).Therefore, beyond diagnostic information, breast MRI provides information about the biology of DCIS, or the “oncologic toolbox” that the intraductal cancerous cells have at their discretion. Those DCIS able to (a) communicate with the other side of the milk duct wall, (b) successfully engage in angiogenic activity to promote the periductal vascular network, and (c) release protease to overcome the barrier of the milk duct might also be the ones that have the tools to grow invasively. Therefore, we need clinical trials where the MRI phenotype of DCIS is used for treatment stratification. For instance, absence of enhancement of a DCIS may be a more useful predictor for the future behavior of a DCIS than the pure morphologic changes described in histopathology.Accordingly, we are only at the beginning of exploiting breast MRI for DCIS management. The allegory on the cave by Plato essentially states that reality is what people have been brought up to believe, while the true reality might be something entirely different. Because we are happy with our idea of reality, and because we cannot imagine something beyond this, we “remain in the cave” and try to make sense of what we see from there. Radiologists should therefore take the lead, explore the world outside Plato’s cave, and help the medical community readdress the conundrum of DCIS. Maybe the true “greater reality” of DCIS is much less enigmatic than the mammographically visible part of it.Disclosures of Conflicts of Interest: C.K.K. receives honoraria from Bayer, Bracco, and Guerbet.References1. Chou SHS, Romanoff J, Lehman CD, et al. Preoperative Breast MRI for Newly Diagnosed Ductal Carcinoma in Situ: Imaging Features and Performance in a Multicenter Setting (ECOG-ACRIN E4112 Trial). Radiology 2021.https://doi.org/10.1148/radiol.2021204743. Published online August 3, 2021. Link, Google Scholar2. Bombonati A, Sgroi DC. The molecular pathology of breast cancer progression. J Pathol 2011;223(2):307–317. Crossref, Medline, Google Scholar3. Cutuli B, Lemanski C, De Lafontan B, et al. Ductal Carcinoma in Situ: A French National Survey. Analysis of 2125 Patients. Clin Breast Cancer 2020;20(2):e164–e172. Crossref, Medline, Google Scholar4. Langhans L, Jensen MB, Talman MM, Vejborg I, Kroman N, Tvedskov TF. Reoperation Rates in Ductal Carcinoma In Situ vs Invasive Breast Cancer After Wire-Guided Breast-Conserving Surgery. JAMA Surg 2017;152(4):378–384. Crossref, Medline, Google Scholar5. Nagasawa S, Kuze Y, Maeda I, et al. Genomic profiling reveals heterogeneous populations of ductal carcinoma in situ of the breast. Commun Biol 2021;4(1):438. Crossref, Medline, Google Scholar6. Kuhl CK, Schrading S, Bieling HB, et al. MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. Lancet 2007;370(9586):485–492. Crossref, Medline, Google Scholar7. Comstock CE, Gatsonis C, Newstead GM, et al. Comparison of Abbreviated Breast MRI vs Digital Breast Tomosynthesis for Breast Cancer Detection Among Women With Dense Breasts Undergoing Screening. JAMA 2020;323(8):746–756. Crossref, Medline, Google Scholar8. Wülfing P, Kersting C, Buerger H, et al. Expression patterns of angiogenic and lymphangiogenic factors in ductal breast carcinoma in situ. Br J Cancer 2005;92(9):1720–1728. Crossref, Medline, Google Scholar9. Carpenter PM, Chen WP, Mendez A, McLaren CE, Su MY. Angiogenesis in the progression of breast ductal proliferations. Int J Surg Pathol 2011;19(3):335–341. Crossref, Medline, Google Scholar10. Jansen SA, Paunesku T, Fan X, et al. Ductal carcinoma in situ: X-ray fluorescence microscopy and dynamic contrast-enhanced MR imaging reveals gadolinium uptake within neoplastic mammary ducts in a murine model. Radiology 2009;253(2):399–406. Link, Google ScholarArticle HistoryReceived: June 24 2021Revision requested: June 29 2021Revision received: July 9 2021Accepted: July 12 2021Published online: Aug 03 2021Published in print: Oct 2021 FiguresReferencesRelatedDetailsCited ByUS, Mammography, and Histopathologic Evaluation to Identify Low Nuclear Grade Ductal Carcinoma in SituSi Eun Lee, Ga Ram Kim, Kyunghwa Han, Eun Hwa Kim, Eun-Kyung Kim, Min Jung Kim, Jung Hyun Yoon, Vivian Youngjean Park, Hee Jung Moon, 15 February 2022 | Radiology, Vol. 303, No. 2Ductal Carcinoma in Situ: State-of-the-Art ReviewLars J. Grimm, Habib Rahbar, Monica Abdelmalak, Allison H. Hall, Marc D. Ryser, 21 December 2021 | Radiology, Vol. 302, No. 2Breast cancers originating from the major lactiferous ducts and the process of neoductgenesis: Ductal Adenocarcinoma of the Breast, DABLászlóTabár, Peter B.Dean, F.Lee Tucker, Amy Ming-FangYen, Rene Wei-JungChang, Chen-YangHsu, Robert A.Smith, Stephen W.Duffy, Tony Hsiu-HsiChen2022 | European Journal of Radiology, Vol. 153Accompanying This ArticlePreoperative Breast MRI for Newly Diagnosed Ductal Carcinoma in Situ: Imaging Features and Performance in a Multicenter Setting (ECOG-ACRIN E4112 Trial)Aug 3 2021RadiologyLet Us Move Out of Plato’s Cave: The Greater Reality of DCISSep 20 2021RadiologyRecommended Articles Contrast-enhanced Mammography: Current Applications and Future DirectionsRadioGraphics2019Volume: 39Issue: 7pp. 1907-1920Recall and Outcome of Screen-detected Microcalcifications during 2 Decades of Mammography Screening in the Netherlands National Breast Screening ProgramRadiology2020Volume: 294Issue: 3pp. 528-537Ductal Carcinoma in Situ: State-of-the-Art ReviewRadiology2021Volume: 302Issue: 2pp. 246-255Tumor Characteristics and Molecular Subtypes in Breast Cancer Screening with Digital Breast Tomosynthesis: The Malmö Breast Tomosynthesis Screening TrialRadiology2019Volume: 293Issue: 2pp. 273-281Breast Cancer Tissue Markers, Genomic Profiling, and Other Prognostic Factors: A Primer for RadiologistsRadioGraphics2018Volume: 38Issue: 7pp. 1902-1920See More RSNA Education Exhibits 2021: A Breast OdysseyDigital Posters2020Contrast-Enhanced Mammography: Current Indications and Future Directions Â Digital Posters2019Non-Contrast-Enhanced Breast MR Screening for Women with Dense BreastsDigital Posters2019 RSNA Case Collection Primary breast amyloidosisRSNA Case Collection2020Mixed Mucinous Breast Carcinoma RSNA Case Collection2022Invasive Lobular CarcinomaRSNA Case Collection2021 Vol. 301, No. 1 Metrics Altmetric Score PDF download