Enhancing breast cancer detection in PTEN Hamartoma Tumor Syndrome through insights into MRI and mammography lesion features

Enhancing breast cancer detection in PTEN Hamartoma Tumor Syndrome through insights into MRI and mammography lesion features | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Enhancing breast cancer detection in PTEN Hamartoma Tumor Syndrome through insights into MRI and mammography lesion features Ritse Mann, Alma Hoxhaj, Annemieke Milants, Porjai Techanithisawat, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3813519/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Women with PTEN Hamartoma Tumor Syndrome (PHTS) have an increased breast cancer (BC) risk (up to 66%) and a relatively high prevalence of benign breast lesions (BBLs) (30–75%), necessitating annual MRI and mammography surveillance. This study aimed to describe BCs and BBLs imaging features in PHTS women to improve early BC detection. This retrospective study at Radboudumc (2001–2021) involved 65 PHTS women aged ≥ 18. Of these, 39 participated in a high-risk BC surveillance program. Breast lesion features at MRI and mammography (when available) examinations were described by two breast radiologists. Pathology reports were retrieved to assess the nature of the biopsied findings. Statistical analysis included descriptive statistics and correlation analyses, with significance set at P < 0.05. Twenty-one women were diagnosed with 35 BCs. For 11 women (52%), who were diagnosed with 17 BCs (49%), imaging examinations were available for re-reading. Of these 17 BCs, 12 (70%) were invasive. MRI examinations were available for re-reading for 10 BCs, with MRI detecting 9 of these (sensitivity 90%). The BCs identified by MRI primarily exhibited malignant features. Notably, up to 50% of BCs were visible in baseline MRI examinations. Mammography examinations were available for re-reading for 15 BCs, with mammography detecting 6 of these (sensitivity 40%). Eighty-nine BBLs were diagnosed in 23 women. Imaging examinations were available for re-reading for 31 BBLs in 16 women. MRI detected 29 (100%) out of 29 available BBLs cases, while mammography detected 15 (58%) out of 26 BBLs available cases. On MRI, BBLs often showed ambiguous enhancement features. In our study, MRI identified BCs mostly exhibited malignant features, while mammography often missed cancers. On MRI, most BCs were already visible at baseline examinations, and BBLs showed ambiguous enhancement features. These findings highlight the critical role of thorough MRI evaluation in the detection of BCs in PHTS women. Health sciences/Oncology/Cancer/Breast cancer Health sciences/Oncology/Cancer/Cancer prevention Health sciences/Oncology/Cancer/Cancer screening Health sciences/Oncology/Cancer/Cancer imaging Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Women with PTEN Hamartoma Tumor Syndrome (PHTS) face unique health challenges, notably a significantly high cumulative lifetime risk of breast cancer (BC) (up to 66%%) [ 1 ]. BC is the most prevalent hereditary cancer among this population [ 2 – 4 ]. Consequently, these women adhere to more stringent surveillance guidelines than the general population [ 5 , 6 ]. The American Cancer Society (ACS) [ 7 ] and European expert opinion-guidelines [ 8 ] recommend starting yearly breast magnetic resonance imaging (MRI) surveillance at age 25 years and adding supplemental mammography from age 30 years [ 9 ]. Recent studies have demonstrated the effectiveness of BC surveillance in women with PHTS. Notably, the cancer detection rate (CDR) achieved through annual surveillance is impressive (45 per 1000 rounds [95% CI, 20–94]) [ 10 ]. Both the sensitivity (100%) and specificity (82%) of the combined modalities were found to be high. However, consistent with findings from studies in high-risk populations (MRI: 71–96%, mammography: 19–51%) [ 11 – 13 ], MRI demonstrated superior sensitivity (100%) compared to mammography (50%) when these modalities were assessed independently [ 10 ]. Similarly, despite the individual specificity of mammography (92%) and MRI (84%) being both adequate, MRI alone was responsible for the diagnosis of BC in 3 out of 5 women who underwent both imaging modalities. These findings align with those observed in women with BRCA1/2 pathogenic variants [ 14 , 15 ], suggesting that the added value of mammography in these high-risk groups might be limited. Significant research has focused on BC imaging features at breast MRI and mammography in women with BRCA1/2 pathogenic variants [ 16 – 19 ], as well as in the general population [ 20 – 22 ]. However, the specific appearance of BCs in women with PHTS remains under-explored. Considering the relatively high prevalence of benign breast lesions (BBLs) (46%) in this group [ 10 ], studies describing both benign and malignant imaging characteristics could further increase sensitivity and specificity of the surveillance program. Additionally, such data could inform expert opinion-based guidelines and potentially lead to a reevaluation of mammography use, specifically in young women with PHTS. The primary purpose of this study was to describe the imaging and pathological characteristics of breast disease in women with PHTS. By shedding light on the most common features of breast disease in this high-risk population, radiologists' ability to identify suspicious findings and distinguish benign from malignant lesions could be improved. This could lead to lower recall and biopsy rates, and, most importantly, aid in the early detection of BC. Results In total, 21 women with PHTS were diagnosed with 35 BCs (median age at first BC diagnosis, 40 years [range, 24–59 years]). Imaging examinations for 11 women (52%), who were diagnosed with 17 BCs, were available for re-reading. Breast density was classified as B (36%), C (46%) and D (18%). Kappa statistic indicated poor agreement for breast density assessment (κ = 0.37 [95% CI -0.08-0.82]) and good agreement for BIRADS score assessment (κ = 0.67 [95% CI 0.19-1.0]). Surveillance detected 10 BCs in 7 women, while 4 BCs were incidentally found in 3 women undergoing (bilateral) prophylactic mastectomy. The remaining 3 BCs were diagnosed in 3 women outside surveillance. These women, who were symptomatic, had mammography examinations available for re-reading (Fig. 1). At pathology, 10 were invasive carcinomas of no-special type (NST), 5 were ductal carcinomas in situ (DCIS), one was an invasive lobular carcinoma (ILC), and another was an invasive papillary carcinoma. Among the 10 BCs detected in women undergoing surveillance, one BC was diagnosed in the prevalent round (baseline examinations) in one woman, and 9 BCs during incident rounds (i.e., diagnosed at subsequent surveillance rounds) in 6 women. The median interval time between baseline and detection imaging examinations was 2 years (range, 0–5 years), with no interval cancers observed. In detail, 2 BCs in one patient were identified solely through MRI (mammography was performed elsewhere and unavailable for re-reading), while 1 BC in another patient was diagnosed using only mammography (MRI was contraindicated due to a neurostimulator). Furthermore, 7 BCs were diagnosed in 5 women who had both MRI and mammography detection examinations. Regarding the 4 BCs incidentally found during (bilateral) prophylactic mastectomy, 1 BC was identified in a woman who had undergone both MRI and mammography; the remaining 3 BCs were identified in 2 women who had only mammography examinations available. These BCs were not detected during surveillance nor described at imaging re-reading (Fig. 2). Ultimately, 12 BC were described during the re-reading of imaging examinations by both readers, and one BC by only one reader. Kappa statistic revealed excellent agreement in assessing lesion visibility (κ = 0.85 [95% CI 0.0–1.0]) and lesion type (κ = 0.86 [95% CI 0.32-1.0]). The inter-observer reliability for sizes measured at imaging was excellent (ICC = 0.99 [0.97-1.0]). Pathological size data was available for 11 of these 12 BCs described by both readers, as one patient was treated with neo-adjuvant chemotherapy and achieved a pathological complete response (pCR). One case was excluded due to inconsistent size estimations between imaging and pathology. This BC was detected through mammography, when mammography was the only modality available, and was characterized as an area of global asymmetry measuring 118 mm. However, pathology revealed an invasive carcinoma NST measuring only 30 mm. The median pathological size of these 10 BCs included in the analysis was 19 mm (range, 2–41), compared to a median imaging size of 19.5 mm (range, 9.5–30), with size differences ranging from − 11 to + 28 mm. The agreement between sizes measured at imaging and at pathology is shown in the Bland-Altman plot (Fig. 3). Magnetic resonance imaging features and corresponding pathology outcome of breast cancers MRI examinations of 10 BCs diagnosed in 6 women were available for re-reading. Of these, nine BCs were identified through surveillance (one in the prevalent round and eight in incident rounds). Additionally, one BC was incidentally discovered during a contralateral prophylactic mastectomy in a woman previously diagnosed with BC. During the re-reading of the images, this incidental BC was not described either (MRI sensitivity 90%). Of the 8 BCs detected in incident rounds, 4 BCs were identified by both radiologists in both the baseline and detection MRI examinations. The median time between baseline and detection examinations for these BCs visible at baseline was 1.5 years (range, 1–2 years). In the comparison of baseline to detection MRIs, the lesions were visible but not necessarily deemed suspicious (Fig. 4). Table 1 presents the MRI features and pathological outcomes of the 9 BCs described during the re-reading of detection examinations. MRI successfully detected 9 out of 10 BCs with available MRI examinations, resulting in a 90% detection rate at the re-reading. Table 1 Features of Breast Cancers at Magnetic Resonance Imaging in Women with PTEN Hamartoma Tumor Syndrome Features BCs (N = 9) described at detection MRI examinations (N = 6) Background parenchymal enhancement Minimal or mild 2/6 Moderate or marked 4/6 Breast Density A 0 B 2 C 2 D 2 Lesion type Mass 5 Shape Round 1/5 Oval 1/5 Irregular 3/5 Margins Circumscribed 1/5 Irregular 4/5 Mass enhancement Heterogeneous 4/5 Rim enhancement 1/5 Non-mass enhancement 4 Distributions modifiers Focal area 2/4 Segmental 1/4 Regional 1/4 Internal enhancement Heterogeneous 2/4 Clumped 2/4 Kinetic curve assessment: initial phase 1 Fast 7/7 Kinetic curve assessment: delayed phase 1 Washout 7/7 Type of breast cancer NST 6/9 ILC 1/9 DCIS 1/9 Other 1/9 ER 2 Positive 3/6 Negative 3/6 PR 2 Positive 3/6 Negative 3/6 HER2 2 Positive 1/6 Negative 5/6 Triple negative 2 No 3/6 Yes 3/6 Grade 2 1 0/6 2 3/6 3 3/6 BC = breast cancer; NST = invasive carcinoma of no-special type; ILC = invasive lobular carcinoma; DCIS = ductal carcinoma in situ; ER = estrogen receptor; PR = progesterone receptor; HER2 = human epidermal growth factor receptor 2 1 Kinetic curve assessment was available for 7 BCs with surveillance MRI examination available 2 ER, PR, HER2 status and grade were available for 6 BCs Mammographic imaging features and corresponding pathology outcome of breast cancers Mammography examinations for 15 BCs diagnosed in 10 women were available for re-reading. Of these, 12 BCs occurred in 7 women participating in the BC surveillance program, while the remaining 3 BCs were diagnosed in 3 women outside the program with only mammography examinations available. Within the surveillance group, 8 BCs were identified through surveillance, whereas 4 BCs were incidentally discovered during prophylactic mastectomy. More specifically, two were found at bilateral prophylactic mastectomy and two at contralateral prophylactic mastectomy. These were not described during the re-reading of the images either. Among the 8 BCs detected through surveillance (one BC in the prevalent round and 7 in incident rounds), one BC had only mammography examinations available, while the remaining 7 had both MRI and mammography examinations. However, 5 out of these 7 BCs in women with both imaging modalities were only visible in MRI, consistent in both the original reports and the re-readings. These 5 BCs undetected by mammography occurred in 3 women with breast density classified as C (n = 1) or D (n = 2) (Fig. 5). They were described at MRI as 3 irregular masses with irregular margins and heterogeneous enhancement patterns (3 invasive carcinomas NST), one focal NME with heterogeneous internal enhancement (invasive carcinoma NST), and one segmental NME with clumped internal enhancement (DCIS). In 4 of the 5 BCs not visible at mammography, non-suspicious round/oval masses, resembling fibroadenomas, were described at the re-readings of MRI examinations. Table 2 presents the mammographic features and pathological outcomes of the 6 BCs identified during the re-reading of detection mammography examinations. Mammography successfully detected 6 BCs out of the 15 BCs, resulting in a 40% detection rate. Table 2 Features of Breast Cancers at Mammography in Women with PTEN Hamartoma Tumor Syndrome Features BCs (N = 6) described at detection mammography examinations (N = 6) Breast Density A 0 B 3 C 2 D 1 Lesion type Mass 4 Shape Round 1/4 Irregular 3/4 Margins Circumscribed 1/4 Indistinct 1/4 Spiculated 2/4 Density High 4/4 Asymmetry 1 Global 1/1 Calcifications 1 Morphology Fine pleiomorphic 1/1 Distribution Regional 1/1 Associated features 9 Calcifications 1 Nipple retraction 1 Skin thickening 1 Trabecular thickening 2 Architectural distortion 4 Type of breast cancer NST 4/6 DCIS 1/6 Other 1/6 ER 1 Positive 3/4 Negative 1/4 PR 1 Positive 3/4 Negative 1/4 HER2 1 Positive 1/4 Negative 3/4 Triple negative 1 No 3/4 Yes 1/4 Grade 1 1 0/4 2 1/4 3 3/4 BC = breast cancer; NST = invasive carcinoma of no-special type; ILC = invasive lobular carcinoma; DCIS = ductal carcinoma in situ; ER = estrogen receptor; PR = progesterone receptor; HER2 = human epidermal growth factor receptor 2. 1 ER, PR, HER2 status and grade were available for 4 BCs. Imaging features and corresponding pathology outcome of benign breast lesions In total, 89 distinct pathologically confirmed BBLs were diagnosed within 23 women (35%), with a median age of 38 years at first diagnosis (range, 15–61 years). Imaging examinations for 31 BBLs in 16 women were available for re-reading. In five of these cases, multiple (> 20 per side) well-defined BBLs were radiologically identified during the re-reading of the imaging examinations (Fig. 6). For these women, only the three most significant lesions were described in detail. MRI examinations for 29 BBLs detected in 14 women were available for re-reading (Table 3 ). Of these, corresponding mammography examinations were available for 26 BBLs. However, 11 BBLs were not detectable in mammography and were only identified in MRI. In total, 15 (57%) of the BBLs, found in 9 women, were visible in mammography. Additionally, 3 BBLs were described in women for whom only mammography examinations were available. Table 3 Features of Benign Breast Lesions at Magnetic Resonance Imaging in Women with PTEN Hamartoma Tumor Syndrome Features BBLs (N = 29) described at MRI examinations (N = 14) Lesion type Focus 2 Mass 25 Shape Round 9/25 Oval 8/25 Irregular 8/25 Margins Circumscribed 20/25 Irregular 5/25 Mass enhancement Homogeneous 1/25 Heterogeneous 15/25 Dark internal septations 9/25 Non-mass enhancement 2 Distributions modifiers Focal area 1/2 Regional 1/2 Internal enhancement Heterogeneous 2/2 Kinetic curve assessment: initial phase 1 Slow 13/27 Medium 8/27 Fast 6/27 Kinetic curve assessment: delayed phase 1 Persistent 11/27 Plateau 13/27 Washout 3/27 Type of benign breast lesion Fibroadenoma 13/29 Fybrocystic changes 5/29 Adenosis 4/29 Fibrosis/sclerosis 3/29 Radial scar 3/29 Intraductal papilloma 1/29 BBLs = benign breast lesions 1 Kinetic curve assessment was available for 1 focus, 24 mass lesions and 2 NME Discussion In our study, breast MRI detected 90% of BCs for which MRI examinations were available. The missed BC, undetected in both the original and in the re-reading reports, was a small incidental invasive carcinoma NST (10 mm) found during prophylactic mastectomy in a woman with BC previously diagnosed in the opposite breast. Five out of the 9 (56%) BCs were described as masses at MRI. These, most frequently, showed irregular shape (60%) and irregular margins (80%), as well as a heterogeneous enhancement (80%). Four (44%) BCs presented as NMEs, most often with a heterogeneous internal enhancement pattern (75%). All the 7 BCs for which curves were available presented as type III. Mammography detected only 40% of BCs, both in the original report and in the re-reading process. The majority were identified as masses (67%) with irregular shapes (75%), spiculated margins (50%), and high density (100%). The most common associated feature was architectural distortion (56%). In our study, readers demonstrated poor agreement in breast density assessment (κ = 0.37) and good agreement in BIRADS score assessment (κ = 0.67). Several studies have shown substantial variability among radiologists in using final assessment categories [ 23 , 24 ], highlighting the need for specific training programs to increase inter-observer reliability [ 25 ]. However, the agreement was excellent for both lesion visibility (κ = 0.85) and lesion type (κ = 0.86), as was the inter-observer reliability for measuring lesion sizes through imaging (ICC = 0.99). Differences between sizes measured at imaging and pathology (Fig. 3) were shown to be relatively small, with imaging overestimating the lesion size by an average of 1.5 mm. This was consistent, as most data points were clustered around the mean difference line and within the limits of agreement. There was one outlier, involving a 30 mm enhancing area on the imaging. The discrepancy in this case occurred because the recorded size at pathology referred to the invasive BC (2 mm), not the larger surrounding area of DCIS (32 mm). BCs in PHTS women showed features typical of malignancies at MRI. This observation is in line with results from studies investigating imaging features of BCs in young women at average risk [ 20 – 22 ], but differing from what has been observed in BCs in BRCA1/2 women [ 16 ]. In BRCA women, BCs usually appear as rounded masses with sharp margins and rim-enhancement at MRI. In line with findings in both the general population and BRCA 1/2 women, all 7 BCs with available enhancement curves in our study showed a type III pattern, typical of malignant lesions [ 26 ]. The limited sensitivity of mammography in our study could be attributed to the infrequent occurrence of suspicious calcifications, an observation consistent with findings in women with BRCA1 pathogenic variants [ 19 , 27 ]. Additionally, mammography missed BCs in 5 women who had dense fibroglandular tissue. Overall, 64% (7 out of 11) of the women diagnosed with BCs in our study had dense fibroglandular tissue, which may have contributed to the reduced efficacy of mammography in detecting BCs [ 28 ]. In our study, pathology revealed that only two of the BCs detected through imaging were DCIS (15%), with the majority being invasive cancers (85%). Among the 11 invasive BCs, 54% presented with high nuclear grade, and 37% were triple negative (TN) cancers. Comparatively, Atchley et al. reported 57% high nuclear grade and 85% TN BCs in BRCA1 women, and lower percentages (56% high nuclear grade, 23% TN) in BRCA2 women. In the non-carriers group, these figures were 38% for high nuclear grade and 14% for TN BCs. Hence, the incidence of TN BCs in PHTS women appears lower than in BRCA1 carriers but higher than in BRCA2 carriers. [ 29 ]. At mammography, between 49–100% of TN BCs lack associated calcifications and are known to have a low incidence of associated DCIS [ 30 – 32 ]. Consistent with this, most BCs in our study lacked suspicious calcifications, and few were DCIS. Considering these findings and the known low sensitivity of mammography in young women with dense breasts [ 33 , 34 ], its added value in surveilling young women with PHTS appears limited. Therefore, we conclude that the age where mammography is added to a yearly breast MRI could be increased from 30 to 40 years. Conversely, meticulous evaluation of morphological and dynamic features in MRI examinations is crucial for distinguishing between malignant and benign lesions in PHTS patients, therefore improving early detection of BCs. This is particularly important considering the high rate (up to 50%) of cancers retrospectively visible at baseline MRI examinations [ 35 ]. In our study, the majority of BBLs (86%) appeared on MRI as round/oval masses (68%) with circumscribed margins (80%) and heterogenous (60%) or dark internal septation (36%) enhancement patterns. Dynamic evaluation commonly showed type I (48%) and II (30%) kinetic curves, with persistent (41%) and plateau (48%) delayed enhancement patterns. At pathology, the most confirmed types of BBLs were fibroadenomas (45%) and fibrocystic changes (18%), aligning with existing MRI descriptions of these conditions in the literature [ 36 , 37 ]. Notably, heterogenous enhancement, typically associated with malignant lesions [ 38 ], was prevalent among BBLs in women with PHTS. This complicates accurate diagnosis based solely on imaging, possibly contributing to the high biopsy rate seen in women with PHTS [ 10 ]. The primary limitations of our study were the single-institution retrospective design and the small sample size, attributable to the rarity of PHTS. As it should be noted, data was collected over a 20-year period in a national expertise center, reflecting the rarity of the syndrome. Additionally, the quality of both MRI and mammographic examinations obviously improved over time. Despite these limitations, our main objective was to describe the imaging features of malignant and benign lesions in this very specific high-risk yet understudied group of women. BI-RADS characteristics were applicable across all scans from the entire period. To improve surveillance for women with PHTS and reduce recall and biopsy rates, data pooling from multiple centers is necessary. Conclusion Understanding imaging features of PHTS-related breast disease is crucial for early detection, accurate diagnosis, effective management, and personalized treatment of BC, ultimately improving outcomes in PHTS women. Methods Ethics This retrospective single-institution study was approved by the institutional review board of the Radboud University Medical Center (CMO 2016–3045, Project 20021). The need for informed consent was waived. Authors complied with all relevant ethical regulations including the Declaration of Helsinki. Study population and design Between January 2001 and February 2021, 65 women (aged ≥ 18) with a confirmed (likely) pathogenic PTEN variant (N = 62) or a variant of uncertain significance with a clear PHTS phenotype (N = 3) were identified at the Radboud university medical center, a National and European PHTS expert center, as well as one of the European PHTS expert centers affiliated with ERN GENTURIS [ 39 ]. Women with PHTS who started surveillance at our institution (N = 39) were monitored within our high-risk BC surveillance program, in line with the ACS guidelines [ 7 ] and the national PHTS guidelines [ 40 ]. Baseline, cancer detection, and last surveillance breast MRI scans were prospectively re-evaluated from October 2020 to December 2021 by two specialized breast radiologists using the BI-RADS lexicon (5th edition) [ 41 ]. When available, surveillance mammograms were evaluated alongside MRIs to compare lesion visibility and/or assess the presence of additional findings. When a discrepancy in categorical values was noted, a majority vote based on the original report was used to resolve this. For continuous values, if the discrepancy was 5 mm, the mean between the assessment of the original report and the assessment of the reader closer to the original report was calculated. Except from the knowledge of a malignancy being present in the cancer detection imaging examination, the radiologists were blinded to any other clinical information. MRI and mammography images were reviewed concurrently. Due to the prevalence of multiple BBLs in women with PHTS (often > 20 per side), only the three most significant lesions (e.g. largest, most distinctive) were described for each case. MRI protocols, while varying over time, consistently included T1 weighted pre- and post-contrast exams, adhering to the European Society of Breast Imaging standards [ 42 ]. Assessments on a dedicated breast MRI workstation (Dynacad, Invivo, USA) included scoring lesion detection, size, morphology, and enhancement kinetics. Morphologic assessments covered lesion shape, margin appearance, and enhancement patterns. Lesion enhancement kinetics were evaluated according to the criteria described by Kuhl et al. [ 26 ]. Mammography assessment, using a full-field digital machine, included two views (mediolateral-oblique and craniocaudal). Detection, density of the lesion compared with breast tissue, lesion morphology, and lesion size (measured along the longest axis) were scored. Corresponding pathology reports were retrieved to assess the nature of imaging findings, with histopathological data sourced from local or national archives. Parameters included tumor size, type, grade, and receptor statuses (ER, PR, HER2), along with pTNM stage, or cTNM when pTNM was unavailable. For BBLs, histological types were noted. Statistical analysis Statistical analysis employed descriptive statistics for patient and tumor characteristics. Kappa statistic, Intraclass Correlation Coefficient (ICC), or Bland-Altmann plot were used to assess inter-observer reliability based on the type of data. The strength of agreement beyond chance for different κ/ICC values was rated as: poor (< 0.40), fair (0.40–0.59), good (0.60–0.74), excellent (0.75-1.00). Bootstrapping was used to calculate 95% confidence intervals (Cl) for kappa values using 1000 replications. Significance was set at a two-sided P-value below 0.05, using R software version 1.2.5001 for analyses [ 43 ]. Declarations Data availability The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Code availability The codes developed during this study are not publicly available but may be made available to qualified researchers upon reasonable request from the corresponding author. Author contributions AH: Conceptualization; Data Curation; Formal Analysis; Investigation; Methodology; Project administration; Software; Validation; Visualization; Writing-Original Draft; Writing-Review & Editing. AM: Data Curation; imaging reader. PT: Data curation; imaging reader. PB: Writing-Review & Editing. NH: Resources; Writing-Review & Editing. RMM: Conceptualization; Funding acquisition; Methodology; Resources; Supervision; Writing-Review & Editing. Acknowledgements The authors would like to thank Antonio Portaluri for his assistance in selecting the most appropriate images for this study. Funding: This work was supported by a grant of the Talent Program VIDI for Health Research and Development financed by the Dutch Research Council (NWO) and assigned to R.M.M. (grant no. 016.196.338). The funders had no role in the design or conduct of the study; in the collection, management, analysis, or interpretation of the data; in the preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication. Competing interests All authors declare that they have no competing interests, with the exception of one author. R.M. Mann reports personal fees outside the submitted work from Bayer Healthcare, Siemens Healthineers, BD, and Transonic Imaging for consultancies; grants/grants pending from Siemens Healthineers, Medtronic, Bayer Healthcare, BD, Screenpoint Medical, Seno Medical, and Koning. There are no other relationships or activities that could appear to have influenced the submitted work. 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N Engl J Med, 2007. 356(3): p. 227–36. Lowry, K.P., et al., Screening Performance of Digital Breast Tomosynthesis vs Digital Mammography in Community Practice by Patient Age, Screening Round, and Breast Density . JAMA Netw Open, 2020. 3(7): p. e2011792. Wedegärtner, U., et al., Differentiation between benign and malignant findings on MR-mammography: usefulness of morphological criteria . Eur Radiol, 2001. 11(9): p. 1645–50. Hochman, M.G., et al., Fibroadenomas: MR imaging appearances with radiologic-histopathologic correlation . Radiology, 1997. 204(1): p. 123–9. Chen, J.H., et al., Magnetic resonance imaging features of fibrocystic change of the breast . Magn Reson Imaging, 2008. 26(9): p. 1207–14. Zhang, J., L. Wang, and H.F. Liu, Imaging Features Derived From Dynamic Contrast-Enhanced Magnetic Resonance Imaging to Differentiate Malignant From Benign Breast Lesions: A Systematic Review and Meta-Analysis . J Comput Assist Tomogr, 2022. 46(3): p. 383–391. Vos, J.R., et al., Boosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes . Fam Cancer, 2019. 18(2): p. 281–284. Dutch society of Clinical Genetics (VKGN). Guideline PTEN Hamartoma Tumour Syndrome. Version 1.0. The Netherlands Comprehensive Cancer Organisation 2015.. D’Orsi CJ, S.E., Mendelson EB, et al., ACR BI-RADS Atlas, Breast Imaging Reporting and Data System , 5th ed. Reston, VA : American College of Radiology ,. 2013. Mann, R.M., et al., Breast MRI: guidelines from the European Society of Breast Imaging . Eur Radiol, 2008. 18(7): p. 1307–18. RStudio Team (2020). RStudio: Integrated Development for R. RStudio, PBC, Boston, MA URL http://www.rstudio.com/ . Additional Declarations There is a conflict of interest R.M. Mann reports personal fees outside the submitted work from Bayer Healthcare, Siemens Healthineers, BD, and Transonic Imaging for consultancies; grants/grants pending from Siemens Healthineers, Medtronic, Bayer Healthcare, BD, Screenpoint Medical, Seno Medical, and Koning. There are no other relationships or activities that could appear to have influenced the submitted work. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3813519","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":276150306,"identity":"954b5710-71b9-4f00-ace5-22b976211762","order_by":0,"name":"Ritse Mann","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYBAC+2Y4k/kAAwMbEDMkgLkyuLQYHGaGMdkSULTw4NRyAK6Fx4BILcf5D3/4wLBN3ly659uHH2V35AyO55hu+MFwB6cW+2ZmNskZDLcNd845u3lmz7lnxgZn3pjd7GF4hlOLHTMzGzMPw23GDTdyNzPwth1O3HAjx+w2A8NhnFqMmZmZP/9huG0PVPmY8S8xWgybmRmkGRhug1QyMxNlCzCQzSR7DG4nb7iRZswsA/SL5JlnZTd7DPBoOX/w8YcfFbdtN9xIfsz4BhhifMeTt934UXFYDpcWqEYiREbBKBgFo2AUkAAA51JewutH99AAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-8111-1930","institution":"Radboud University Medical Centre","correspondingAuthor":true,"prefix":"","firstName":"Ritse","middleName":"","lastName":"Mann","suffix":""},{"id":276150307,"identity":"42732cc8-e503-4423-a895-d22a34569f5f","order_by":1,"name":"Alma Hoxhaj","email":"","orcid":"https://orcid.org/0000-0002-8553-863X","institution":"Radboudumc","correspondingAuthor":false,"prefix":"","firstName":"Alma","middleName":"","lastName":"Hoxhaj","suffix":""},{"id":276150308,"identity":"7edcdcea-a9fd-40df-9e61-392d6bd5c4ea","order_by":2,"name":"Annemieke Milants","email":"","orcid":"","institution":"Vitaz","correspondingAuthor":false,"prefix":"","firstName":"Annemieke","middleName":"","lastName":"Milants","suffix":""},{"id":276150309,"identity":"b904bd9c-71d3-4af8-bd04-119a23e2a28f","order_by":3,"name":"Porjai Techanithisawat","email":"","orcid":"","institution":"Queen Sirikit Centre of Breast Cancer- King Chualalongkorn Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Porjai","middleName":"","lastName":"Techanithisawat","suffix":""},{"id":276150310,"identity":"09efac06-700e-4ac6-91b7-9f5c5e4fdad5","order_by":4,"name":"Peter Bult","email":"","orcid":"","institution":"Radboud university medical center","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Bult","suffix":""},{"id":276150311,"identity":"175998e9-9910-4395-8e52-e508437ceb42","order_by":5,"name":"Nicoline Hoogerbrugge","email":"","orcid":"","institution":"Radboudumc","correspondingAuthor":false,"prefix":"","firstName":"Nicoline","middleName":"","lastName":"Hoogerbrugge","suffix":""}],"badges":[],"createdAt":"2023-12-27 19:35:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3813519/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3813519/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52039745,"identity":"45d44d49-1df6-4dff-806d-8ef9551df02c","added_by":"auto","created_at":"2024-03-05 17:42:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":180383,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the distribution of breast cancers (BCs) among women who enrolled in the BC surveillance program and women who did not enroll\u003c/p\u003e\n\u003cp\u003e1 Two women were diagnosed with 2 BCs in 2 breasts by means of surveillance and opted for contralateral prophylactic mastectomy which revealed a contralateral BC.\u003c/p\u003e\n\u003cp\u003e2 One woman previously diagnosed with one BC (unknown detection mode) was later diagnosed with a contralateral BC during mammographic follow-up\u003c/p\u003e\n\u003cp\u003e3 One woman opted for contralateral prophylactic mastectomy because of prior diagnosis of a symptomatic BC\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-3813519/v1/870b1e94dcea645bee72607e.png"},{"id":52039742,"identity":"255ed8de-f0d5-4072-94d3-1528c9c3a34b","added_by":"auto","created_at":"2024-03-05 17:42:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":178643,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of breast cancers (BCs) detected by means of surveillance\u003c/p\u003e\n\u003cp\u003e1 This woman had been diagnosed with 2 biopsy proven malignant lesions, detected by means of MRI and not visible at mammography. A third BC in the same breast was detected during mastectomy.\u003c/p\u003e\n\u003cp\u003e2 One woman was diagnosed with 1 BC by means of imaging examination (both MRI and mammography). After opting for prophylactic mastectomy of the contralateral breast, one incidental BC was diagnosed in this breast.\u003c/p\u003e\n\u003cp\u003e3 One woman was diagnosed with 1 BC by means of imaging examination (only mammography performed). After opting for prophylactic mastectomy of the contralateral breast, one incidental BC was diagnosed in this breast.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-3813519/v1/789ca4921b72ce5781003bc6.png"},{"id":52039746,"identity":"5c3d9475-3051-4f07-8810-5ef9a797128c","added_by":"auto","created_at":"2024-03-05 17:42:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":121436,"visible":true,"origin":"","legend":"\u003cp\u003eBland-Altmann plot for the agreement between sizes measured at imaging and sizes measured at pathology\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-3813519/v1/38a91d7e2c0c902804ad3678.png"},{"id":52039743,"identity":"116ace78-83c6-4cd5-b241-d40997842bd0","added_by":"auto","created_at":"2024-03-05 17:42:06","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":574785,"visible":true,"origin":"","legend":"\u003cp\u003ea. One BC showed no change in size (30 mm), features (non-mass enhancement), or enhancement curves (type III) from baseline to detection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eb. One BC showed changes in size, features and enhancement curves from baseline (5 mm, focus, type I) to detection (18 mm, oval mass, type III).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ec. \u0026amp; d. Two BCs exhibited changes in features and enhancement curves from baseline (oval masses, type I) to detection (irregular masses, type III).\u003c/p\u003e","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-3813519/v1/6a47051a5a335d5c132124a6.png"},{"id":52040365,"identity":"9d7139fc-5e4c-438e-a9c6-1e5306d586f0","added_by":"auto","created_at":"2024-03-05 17:50:06","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":466135,"visible":true,"origin":"","legend":"\u003cp\u003eImages show a woman with dense breasts in which a lesion was not identified or deemed suspicious during mammography. However, MRI revealed a segmental, clumped non-mass enhancement (NME) lesion in the left breast, characterized by a type III curve. This lesion was subsequently confirmed to be DCIS by pathology.\u003c/p\u003e","description":"","filename":"Fig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-3813519/v1/17585c8bec8f81341e87033d.png"},{"id":52039747,"identity":"4976def6-1661-4e19-a866-700fd7e1e106","added_by":"auto","created_at":"2024-03-05 17:42:06","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":661086,"visible":true,"origin":"","legend":"\u003cp\u003eMRI examinations of two women with multiple benign breast lesions in both breasts.\u003c/p\u003e","description":"","filename":"Fig.6.png","url":"https://assets-eu.researchsquare.com/files/rs-3813519/v1/7c28c88bcb3bf300f2055853.png"},{"id":62273422,"identity":"45e834a7-f632-4076-b7e4-f26621453a93","added_by":"auto","created_at":"2024-08-12 10:43:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3362985,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3813519/v1/5022a128-c038-4446-9709-0d9d0b22c388.pdf"}],"financialInterests":"There is a conflict of interest\nR.M. Mann reports personal fees outside the submitted work from Bayer Healthcare, Siemens Healthineers, BD, and Transonic Imaging for consultancies; grants/grants pending from Siemens Healthineers, Medtronic, Bayer Healthcare, BD, Screenpoint Medical, Seno Medical, and Koning. There are no other relationships or activities that could appear to have influenced the submitted work.","formattedTitle":"Enhancing breast cancer detection in PTEN Hamartoma Tumor Syndrome through insights into MRI and mammography lesion features","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWomen with \u003cem\u003ePTEN\u003c/em\u003e Hamartoma Tumor Syndrome (PHTS) face unique health challenges, notably a significantly high cumulative lifetime risk of breast cancer (BC) (up to 66%%) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. BC is the most prevalent hereditary cancer among this population [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Consequently, these women adhere to more stringent surveillance guidelines than the general population [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The American Cancer Society (ACS) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and European expert opinion-guidelines [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] recommend starting yearly breast magnetic resonance imaging (MRI) surveillance at age 25 years and adding supplemental mammography from age 30 years [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies have demonstrated the effectiveness of BC surveillance in women with PHTS. Notably, the cancer detection rate (CDR) achieved through annual surveillance is impressive (45 per 1000 rounds [95% CI, 20\u0026ndash;94]) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Both the sensitivity (100%) and specificity (82%) of the combined modalities were found to be high. However, consistent with findings from studies in high-risk populations (MRI: 71\u0026ndash;96%, mammography: 19\u0026ndash;51%) [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], MRI demonstrated superior sensitivity (100%) compared to mammography (50%) when these modalities were assessed independently [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Similarly, despite the individual specificity of mammography (92%) and MRI (84%) being both adequate, MRI alone was responsible for the diagnosis of BC in 3 out of 5 women who underwent both imaging modalities. These findings align with those observed in women with BRCA1/2 pathogenic variants [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], suggesting that the added value of mammography in these high-risk groups might be limited.\u003c/p\u003e \u003cp\u003eSignificant research has focused on BC imaging features at breast MRI and mammography in women with BRCA1/2 pathogenic variants [\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], as well as in the general population [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, the specific appearance of BCs in women with PHTS remains under-explored. Considering the relatively high prevalence of benign breast lesions (BBLs) (46%) in this group [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], studies describing both benign and malignant imaging characteristics could further increase sensitivity and specificity of the surveillance program. Additionally, such data could inform expert opinion-based guidelines and potentially lead to a reevaluation of mammography use, specifically in young women with PHTS.\u003c/p\u003e \u003cp\u003eThe primary purpose of this study was to describe the imaging and pathological characteristics of breast disease in women with PHTS. By shedding light on the most common features of breast disease in this high-risk population, radiologists' ability to identify suspicious findings and distinguish benign from malignant lesions could be improved. This could lead to lower recall and biopsy rates, and, most importantly, aid in the early detection of BC.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn total, 21 women with PHTS were diagnosed with 35 BCs (median age at first BC diagnosis, 40 years [range, 24\u0026ndash;59 years]). Imaging examinations for 11 women (52%), who were diagnosed with 17 BCs, were available for re-reading. Breast density was classified as B (36%), C (46%) and D (18%). Kappa statistic indicated poor agreement for breast density assessment (κ\u0026thinsp;=\u0026thinsp;0.37 [95% CI -0.08-0.82]) and good agreement for BIRADS score assessment (κ\u0026thinsp;=\u0026thinsp;0.67 [95% CI 0.19-1.0]). Surveillance detected 10 BCs in 7 women, while 4 BCs were incidentally found in 3 women undergoing (bilateral) prophylactic mastectomy. The remaining 3 BCs were diagnosed in 3 women outside surveillance. These women, who were symptomatic, had mammography examinations available for re-reading (Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eAt pathology, 10 were invasive carcinomas of no-special type (NST), 5 were ductal carcinomas in situ (DCIS), one was an invasive lobular carcinoma (ILC), and another was an invasive papillary carcinoma.\u003c/p\u003e \u003cp\u003eAmong the 10 BCs detected in women undergoing surveillance, one BC was diagnosed in the prevalent round (baseline examinations) in one woman, and 9 BCs during incident rounds (i.e., diagnosed at subsequent surveillance rounds) in 6 women. The median interval time between baseline and detection imaging examinations was 2 years (range, 0\u0026ndash;5 years), with no interval cancers observed. In detail, 2 BCs in one patient were identified solely through MRI (mammography was performed elsewhere and unavailable for re-reading), while 1 BC in another patient was diagnosed using only mammography (MRI was contraindicated due to a neurostimulator). Furthermore, 7 BCs were diagnosed in 5 women who had both MRI and mammography detection examinations. Regarding the 4 BCs incidentally found during (bilateral) prophylactic mastectomy, 1 BC was identified in a woman who had undergone both MRI and mammography; the remaining 3 BCs were identified in 2 women who had only mammography examinations available. These BCs were not detected during surveillance nor described at imaging re-reading (Fig.\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eUltimately, 12 BC were described during the re-reading of imaging examinations by both readers, and one BC by only one reader. Kappa statistic revealed excellent agreement in assessing lesion visibility (κ\u0026thinsp;=\u0026thinsp;0.85 [95% CI 0.0\u0026ndash;1.0]) and lesion type (κ\u0026thinsp;=\u0026thinsp;0.86 [95% CI 0.32-1.0]). The inter-observer reliability for sizes measured at imaging was excellent (ICC\u0026thinsp;=\u0026thinsp;0.99 [0.97-1.0]). Pathological size data was available for 11 of these 12 BCs described by both readers, as one patient was treated with neo-adjuvant chemotherapy and achieved a pathological complete response (pCR). One case was excluded due to inconsistent size estimations between imaging and pathology. This BC was detected through mammography, when mammography was the only modality available, and was characterized as an area of global asymmetry measuring 118 mm. However, pathology revealed an invasive carcinoma NST measuring only 30 mm. The median pathological size of these 10 BCs included in the analysis was 19 mm (range, 2\u0026ndash;41), compared to a median imaging size of 19.5 mm (range, 9.5\u0026ndash;30), with size differences ranging from \u0026minus;\u0026thinsp;11 to +\u0026thinsp;28 mm. The agreement between sizes measured at imaging and at pathology is shown in the Bland-Altman plot (Fig.\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eMagnetic resonance imaging features and corresponding pathology outcome of breast cancers\u003c/p\u003e \u003cp\u003eMRI examinations of 10 BCs diagnosed in 6 women were available for re-reading. Of these, nine BCs were identified through surveillance (one in the prevalent round and eight in incident rounds). Additionally, one BC was incidentally discovered during a contralateral prophylactic mastectomy in a woman previously diagnosed with BC. During the re-reading of the images, this incidental BC was not described either (MRI sensitivity 90%).\u003c/p\u003e \u003cp\u003eOf the 8 BCs detected in incident rounds, 4 BCs were identified by both radiologists in both the baseline and detection MRI examinations. The median time between baseline and detection examinations for these BCs visible at baseline was 1.5 years (range, 1\u0026ndash;2 years). In the comparison of baseline to detection MRIs, the lesions were visible but not necessarily deemed suspicious (Fig.\u0026nbsp;4).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the MRI features and pathological outcomes of the 9 BCs described during the re-reading of detection examinations. MRI successfully detected 9 out of 10 BCs with available MRI examinations, resulting in a 90% detection rate at the re-reading.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFeatures of Breast Cancers at Magnetic Resonance Imaging in Women with PTEN Hamartoma Tumor Syndrome\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eFeatures\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u003cem\u003eBCs (N\u0026thinsp;=\u0026thinsp;9) described at detection MRI examinations (N\u0026thinsp;=\u0026thinsp;6)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBackground parenchymal enhancement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMinimal or mild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerate or marked\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e4/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast Density\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eA\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eB\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eC\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesion type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eMass\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eShape\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRound\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003eOval\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eIrregular\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e3/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMargins\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eCircumscribed\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eIrregular\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e4/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMass enhancement\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eHeterogeneous\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e4/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRim enhancement\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eNon-mass enhancement\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eDistributions modifiers\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eFocal area\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2/4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSegmental\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRegional\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eInternal enhancement\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eHeterogeneous\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2/4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eClumped\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2/4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKinetic curve assessment: initial phase\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eFast\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e7/7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKinetic curve assessment: delayed phase\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eWashout\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e7/7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of breast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNST\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e6/9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eILC\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1/9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eDCIS\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1/9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eOther\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1/9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e3/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e3/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e3/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e3/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e5/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriple negative\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e3/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e3/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e3/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e3/6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eBC\u0026thinsp;=\u0026thinsp;breast cancer; NST\u0026thinsp;=\u0026thinsp;invasive carcinoma of no-special type; ILC\u0026thinsp;=\u0026thinsp;invasive lobular carcinoma; DCIS\u0026thinsp;=\u0026thinsp;ductal carcinoma in situ; ER\u0026thinsp;=\u0026thinsp;estrogen receptor; PR\u0026thinsp;=\u0026thinsp;progesterone receptor; HER2\u0026thinsp;=\u0026thinsp;human epidermal growth factor receptor 2\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e1\u003c/sup\u003e Kinetic curve assessment was available for 7 BCs with surveillance MRI examination available\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e2\u003c/sup\u003e ER, PR, HER2 status and grade were available for 6 BCs\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMammographic imaging features and corresponding pathology outcome of breast cancers\u003c/p\u003e \u003cp\u003eMammography examinations for 15 BCs diagnosed in 10 women were available for re-reading. Of these, 12 BCs occurred in 7 women participating in the BC surveillance program, while the remaining 3 BCs were diagnosed in 3 women outside the program with only mammography examinations available. Within the surveillance group, 8 BCs were identified through surveillance, whereas 4 BCs were incidentally discovered during prophylactic mastectomy. More specifically, two were found at bilateral prophylactic mastectomy and two at contralateral prophylactic mastectomy. These were not described during the re-reading of the images either.\u003c/p\u003e \u003cp\u003eAmong the 8 BCs detected through surveillance (one BC in the prevalent round and 7 in incident rounds), one BC had only mammography examinations available, while the remaining 7 had both MRI and mammography examinations. However, 5 out of these 7 BCs in women with both imaging modalities were only visible in MRI, consistent in both the original reports and the re-readings. These 5 BCs undetected by mammography occurred in 3 women with breast density classified as C (n\u0026thinsp;=\u0026thinsp;1) or D (n\u0026thinsp;=\u0026thinsp;2) (Fig.\u0026nbsp;5). They were described at MRI as 3 irregular masses with irregular margins and heterogeneous enhancement patterns (3 invasive carcinomas NST), one focal NME with heterogeneous internal enhancement (invasive carcinoma NST), and one segmental NME with clumped internal enhancement (DCIS). In 4 of the 5 BCs not visible at mammography, non-suspicious round/oval masses, resembling fibroadenomas, were described at the re-readings of MRI examinations.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the mammographic features and pathological outcomes of the 6 BCs identified during the re-reading of detection mammography examinations. Mammography successfully detected 6 BCs out of the 15 BCs, resulting in a 40% detection rate.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFeatures of Breast Cancers at Mammography in Women with PTEN Hamartoma Tumor Syndrome\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eFeatures\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eBCs (N\u0026thinsp;=\u0026thinsp;6) described at detection mammography examinations (N\u0026thinsp;=\u0026thinsp;6)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast Density\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eA\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eB\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eC\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesion type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eMass\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eShape\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRound\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eIrregular\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMargins\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eCircumscribed\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eIndistinct\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSpiculated\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eDensity\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eHigh\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAsymmetry\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eGlobal\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eCalcifications\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMorphology\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eFine pleiomorphic\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eDistribution\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRegional\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAssociated features\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e9\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eCalcifications\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNipple retraction\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSkin thickening\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eTrabecular thickening\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eArchitectural distortion\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of breast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNST\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eDCIS\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eOther\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriple negative\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eBC\u0026thinsp;=\u0026thinsp;breast cancer; NST\u0026thinsp;=\u0026thinsp;invasive carcinoma of no-special type; ILC\u0026thinsp;=\u0026thinsp;invasive lobular carcinoma; DCIS\u0026thinsp;=\u0026thinsp;ductal carcinoma in situ; ER\u0026thinsp;=\u0026thinsp;estrogen receptor; PR\u0026thinsp;=\u0026thinsp;progesterone receptor; HER2\u0026thinsp;=\u0026thinsp;human epidermal growth factor receptor 2.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e1\u003c/sup\u003e ER, PR, HER2 status and grade were available for 4 BCs.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eImaging features and corresponding pathology outcome of benign breast lesions\u003c/p\u003e \u003cp\u003eIn total, 89 distinct pathologically confirmed BBLs were diagnosed within 23 women (35%), with a median age of 38 years at first diagnosis (range, 15\u0026ndash;61 years). Imaging examinations for 31 BBLs in 16 women were available for re-reading. In five of these cases, multiple (\u0026gt;\u0026thinsp;20 per side) well-defined BBLs were radiologically identified during the re-reading of the imaging examinations (Fig.\u0026nbsp;6). For these women, only the three most significant lesions were described in detail.\u003c/p\u003e \u003cp\u003eMRI examinations for 29 BBLs detected in 14 women were available for re-reading (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Of these, corresponding mammography examinations were available for 26 BBLs. However, 11 BBLs were not detectable in mammography and were only identified in MRI. In total, 15 (57%) of the BBLs, found in 9 women, were visible in mammography. Additionally, 3 BBLs were described in women for whom only mammography examinations were available.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFeatures of Benign Breast Lesions at Magnetic Resonance Imaging in Women with PTEN Hamartoma Tumor Syndrome\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eFeatures\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eBBLs (N\u0026thinsp;=\u0026thinsp;29) described at MRI examinations (N\u0026thinsp;=\u0026thinsp;14)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesion type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eFocus\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eMass\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e25\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eShape\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRound\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9/25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eOval\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eIrregular\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMargins\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eCircumscribed\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20/25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eIrregular\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMass enhancement\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eHomogeneous\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eHeterogeneous\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15/25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eDark internal septations\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9/25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eNon-mass enhancement\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eDistributions modifiers\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eFocal area\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRegional\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eInternal enhancement\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eHeterogeneous\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKinetic curve assessment: initial phase \u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSlow\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13/27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eMedium\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eFast\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKinetic curve assessment: delayed phase \u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePersistent\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11/27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePlateau\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13/27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eWashout\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of benign breast lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eFibroadenoma\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13/29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eFybrocystic changes\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eAdenosis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eFibrosis/sclerosis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRadial scar\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eIntraductal papilloma\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eBBLs\u0026thinsp;=\u0026thinsp;benign breast lesions\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e1\u003c/sup\u003e Kinetic curve assessment was available for 1 focus, 24 mass lesions and 2 NME\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our study, breast MRI detected 90% of BCs for which MRI examinations were available. The missed BC, undetected in both the original and in the re-reading reports, was a small incidental invasive carcinoma NST (10 mm) found during prophylactic mastectomy in a woman with BC previously diagnosed in the opposite breast. Five out of the 9 (56%) BCs were described as masses at MRI. These, most frequently, showed irregular shape (60%) and irregular margins (80%), as well as a heterogeneous enhancement (80%). Four (44%) BCs presented as NMEs, most often with a heterogeneous internal enhancement pattern (75%). All the 7 BCs for which curves were available presented as type III. Mammography detected only 40% of BCs, both in the original report and in the re-reading process. The majority were identified as masses (67%) with irregular shapes (75%), spiculated margins (50%), and high density (100%). The most common associated feature was architectural distortion (56%).\u003c/p\u003e \u003cp\u003eIn our study, readers demonstrated poor agreement in breast density assessment (κ\u0026thinsp;=\u0026thinsp;0.37) and good agreement in BIRADS score assessment (κ\u0026thinsp;=\u0026thinsp;0.67). Several studies have shown substantial variability among radiologists in using final assessment categories [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], highlighting the need for specific training programs to increase inter-observer reliability [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. However, the agreement was excellent for both lesion visibility (κ\u0026thinsp;=\u0026thinsp;0.85) and lesion type (κ\u0026thinsp;=\u0026thinsp;0.86), as was the inter-observer reliability for measuring lesion sizes through imaging (ICC\u0026thinsp;=\u0026thinsp;0.99). Differences between sizes measured at imaging and pathology (Fig.\u0026nbsp;3) were shown to be relatively small, with imaging overestimating the lesion size by an average of 1.5 mm. This was consistent, as most data points were clustered around the mean difference line and within the limits of agreement. There was one outlier, involving a 30 mm enhancing area on the imaging. The discrepancy in this case occurred because the recorded size at pathology referred to the invasive BC (2 mm), not the larger surrounding area of DCIS (32 mm).\u003c/p\u003e \u003cp\u003eBCs in PHTS women showed features typical of malignancies at MRI. This observation is in line with results from studies investigating imaging features of BCs in young women at average risk [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], but differing from what has been observed in BCs in BRCA1/2 women [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In BRCA women, BCs usually appear as rounded masses with sharp margins and rim-enhancement at MRI. In line with findings in both the general population and BRCA 1/2 women, all 7 BCs with available enhancement curves in our study showed a type III pattern, typical of malignant lesions [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe limited sensitivity of mammography in our study could be attributed to the infrequent occurrence of suspicious calcifications, an observation consistent with findings in women with BRCA1 pathogenic variants [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Additionally, mammography missed BCs in 5 women who had dense fibroglandular tissue. Overall, 64% (7 out of 11) of the women diagnosed with BCs in our study had dense fibroglandular tissue, which may have contributed to the reduced efficacy of mammography in detecting BCs [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, pathology revealed that only two of the BCs detected through imaging were DCIS (15%), with the majority being invasive cancers (85%). Among the 11 invasive BCs, 54% presented with high nuclear grade, and 37% were triple negative (TN) cancers. Comparatively, Atchley et al. reported 57% high nuclear grade and 85% TN BCs in BRCA1 women, and lower percentages (56% high nuclear grade, 23% TN) in BRCA2 women. In the non-carriers group, these figures were 38% for high nuclear grade and 14% for TN BCs. Hence, the incidence of TN BCs in PHTS women appears lower than in BRCA1 carriers but higher than in BRCA2 carriers. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAt mammography, between 49\u0026ndash;100% of TN BCs lack associated calcifications and are known to have a low incidence of associated DCIS [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Consistent with this, most BCs in our study lacked suspicious calcifications, and few were DCIS. Considering these findings and the known low sensitivity of mammography in young women with dense breasts [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], its added value in surveilling young women with PHTS appears limited. Therefore, we conclude that the age where mammography is added to a yearly breast MRI could be increased from 30 to 40 years. Conversely, meticulous evaluation of morphological and dynamic features in MRI examinations is crucial for distinguishing between malignant and benign lesions in PHTS patients, therefore improving early detection of BCs. This is particularly important considering the high rate (up to 50%) of cancers retrospectively visible at baseline MRI examinations [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, the majority of BBLs (86%) appeared on MRI as round/oval masses (68%) with circumscribed margins (80%) and heterogenous (60%) or dark internal septation (36%) enhancement patterns. Dynamic evaluation commonly showed type I (48%) and II (30%) kinetic curves, with persistent (41%) and plateau (48%) delayed enhancement patterns. At pathology, the most confirmed types of BBLs were fibroadenomas (45%) and fibrocystic changes (18%), aligning with existing MRI descriptions of these conditions in the literature [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Notably, heterogenous enhancement, typically associated with malignant lesions [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], was prevalent among BBLs in women with PHTS. This complicates accurate diagnosis based solely on imaging, possibly contributing to the high biopsy rate seen in women with PHTS [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe primary limitations of our study were the single-institution retrospective design and the small sample size, attributable to the rarity of PHTS. As it should be noted, data was collected over a 20-year period in a national expertise center, reflecting the rarity of the syndrome. Additionally, the quality of both MRI and mammographic examinations obviously improved over time. Despite these limitations, our main objective was to describe the imaging features of malignant and benign lesions in this very specific high-risk yet understudied group of women. BI-RADS characteristics were applicable across all scans from the entire period. To improve surveillance for women with PHTS and reduce recall and biopsy rates, data pooling from multiple centers is necessary.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eUnderstanding imaging features of PHTS-related breast disease is crucial for early detection, accurate diagnosis, effective management, and personalized treatment of BC, ultimately improving outcomes in PHTS women.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eEthics\u003c/p\u003e \u003cp\u003e This retrospective single-institution study was approved by the institutional review board of the Radboud University Medical Center (CMO 2016\u0026ndash;3045, Project 20021). The need for informed consent was waived. Authors complied with all relevant ethical regulations including the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eStudy population and design\u003c/p\u003e \u003cp\u003eBetween January 2001 and February 2021, 65 women (aged\u0026thinsp;\u0026ge;\u0026thinsp;18) with a confirmed (likely) pathogenic \u003cem\u003ePTEN\u003c/em\u003e variant (N\u0026thinsp;=\u0026thinsp;62) or a variant of uncertain significance with a clear PHTS phenotype (N\u0026thinsp;=\u0026thinsp;3) were identified at the Radboud university medical center, a National and European PHTS expert center, as well as one of the European PHTS expert centers affiliated with ERN GENTURIS [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWomen with PHTS who started surveillance at our institution (N\u0026thinsp;=\u0026thinsp;39) were monitored within our high-risk BC surveillance program, in line with the ACS guidelines [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and the national PHTS guidelines [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Baseline, cancer detection, and last surveillance breast MRI scans were prospectively re-evaluated from October 2020 to December 2021 by two specialized breast radiologists using the BI-RADS lexicon (5th edition) [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. When available, surveillance mammograms were evaluated alongside MRIs to compare lesion visibility and/or assess the presence of additional findings. When a discrepancy in categorical values was noted, a majority vote based on the original report was used to resolve this. For continuous values, if the discrepancy was \u0026lt;\u0026thinsp;5 mm, the mean value between assessments of the two readers was used, while if the discrepancy was \u0026gt;\u0026thinsp;5 mm, the mean between the assessment of the original report and the assessment of the reader closer to the original report was calculated.\u003c/p\u003e \u003cp\u003eExcept from the knowledge of a malignancy being present in the cancer detection imaging examination, the radiologists were blinded to any other clinical information. MRI and mammography images were reviewed concurrently. Due to the prevalence of multiple BBLs in women with PHTS (often\u0026thinsp;\u0026gt;\u0026thinsp;20 per side), only the three most significant lesions (e.g. largest, most distinctive) were described for each case. MRI protocols, while varying over time, consistently included T1 weighted pre- and post-contrast exams, adhering to the European Society of Breast Imaging standards [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAssessments on a dedicated breast MRI workstation (Dynacad, Invivo, USA) included scoring lesion detection, size, morphology, and enhancement kinetics. Morphologic assessments covered lesion shape, margin appearance, and enhancement patterns. Lesion enhancement kinetics were evaluated according to the criteria described by Kuhl et al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Mammography assessment, using a full-field digital machine, included two views (mediolateral-oblique and craniocaudal). Detection, density of the lesion compared with breast tissue, lesion morphology, and lesion size (measured along the longest axis) were scored.\u003c/p\u003e \u003cp\u003eCorresponding pathology reports were retrieved to assess the nature of imaging findings, with histopathological data sourced from local or national archives. Parameters included tumor size, type, grade, and receptor statuses (ER, PR, HER2), along with pTNM stage, or cTNM when pTNM was unavailable. For BBLs, histological types were noted.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis employed descriptive statistics for patient and tumor characteristics. Kappa statistic, Intraclass Correlation Coefficient (ICC), or Bland-Altmann plot were used to assess inter-observer reliability based on the type of data. The strength of agreement beyond chance for different κ/ICC values was rated as: poor (\u0026lt;\u0026thinsp;0.40), fair (0.40\u0026ndash;0.59), good (0.60\u0026ndash;0.74), excellent (0.75-1.00). Bootstrapping was used to calculate 95% confidence intervals (Cl) for kappa values using 1000 replications. Significance was set at a two-sided P-value below 0.05, using R software version 1.2.5001 for analyses [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe codes developed during this study are not publicly available but may be made available to qualified researchers upon reasonable request from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAH: Conceptualization; Data Curation; Formal Analysis; Investigation; Methodology; Project administration; Software; Validation; Visualization; Writing-Original Draft; Writing-Review \u0026amp; Editing. AM: Data Curation; imaging reader. PT: Data curation; imaging reader. PB: Writing-Review \u0026amp; Editing. NH: Resources; Writing-Review \u0026amp; Editing. RMM: Conceptualization; Funding acquisition; Methodology; Resources; Supervision; Writing-Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eThe authors would like to thank Antonio Portaluri for his assistance in selecting the most appropriate images for this study.\u003c/li\u003e\n \u003cli\u003eFunding: This work was supported by a grant of the Talent Program VIDI for Health Research and Development financed by the Dutch Research Council (NWO) and assigned to R.M.M. (grant no. 016.196.338). The funders had no role in the design or conduct of the study; in the collection, management, analysis, or interpretation of the data; in the preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no competing interests, with the exception of one author. R.M. Mann reports personal fees outside the submitted work from Bayer Healthcare, Siemens Healthineers, BD, and Transonic Imaging for consultancies; grants/grants pending from Siemens Healthineers, Medtronic, Bayer Healthcare, BD, Screenpoint Medical, Seno Medical, and Koning. There are no other relationships or activities that could appear to have influenced the submitted work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHendricks, L.A.J., et al., \u003cem\u003eCancer risks by sex and variant type in PTEN hamartoma tumor syndrome\u003c/em\u003e. J Natl Cancer Inst, 2023. 115(1): p.\u0026nbsp;93\u0026ndash;103.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNieuwenhuis, M.H., et al., \u003cem\u003eCancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome\u003c/em\u003e. Fam Cancer, 2014. 13(1): p.\u0026nbsp;57\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBubien, V., et al., \u003cem\u003eHigh cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome\u003c/em\u003e. J Med Genet, 2013. 50(4): p.\u0026nbsp;255\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan, M.H., et al., \u003cem\u003eLifetime cancer risks in individuals with germline PTEN mutations\u003c/em\u003e. Clin Cancer Res, 2012. 18(2): p.\u0026nbsp;400\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith, R.A., et al., \u003cem\u003eAmerican Cancer Society guidelines for breast cancer screening: update 2003\u003c/em\u003e. CA Cancer J Clin, 2003. 53(3): p.\u0026nbsp;141\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerry, N., et al., \u003cem\u003eEuropean guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition\u0026ndash;summary document\u003c/em\u003e. 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RStudio, PBC, Boston, MA URL\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.rstudio.com/\u003c/span\u003e\u003cspan address=\"http://www.rstudio.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3813519/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3813519/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWomen with \u003cem\u003ePTEN\u003c/em\u003e Hamartoma Tumor Syndrome (PHTS) have an increased breast cancer (BC) risk (up to 66%) and a relatively high prevalence of benign breast lesions (BBLs) (30\u0026ndash;75%), necessitating annual MRI and mammography surveillance. This study aimed to describe BCs and BBLs imaging features in PHTS women to improve early BC detection. This retrospective study at Radboudumc (2001\u0026ndash;2021) involved 65 PHTS women aged\u0026thinsp;\u0026ge;\u0026thinsp;18. Of these, 39 participated in a high-risk BC surveillance program. Breast lesion features at MRI and mammography (when available) examinations were described by two breast radiologists. Pathology reports were retrieved to assess the nature of the biopsied findings. Statistical analysis included descriptive statistics and correlation analyses, with significance set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Twenty-one women were diagnosed with 35 BCs. For 11 women (52%), who were diagnosed with 17 BCs (49%), imaging examinations were available for re-reading. Of these 17 BCs, 12 (70%) were invasive. MRI examinations were available for re-reading for 10 BCs, with MRI detecting 9 of these (sensitivity 90%). The BCs identified by MRI primarily exhibited malignant features. Notably, up to 50% of BCs were visible in baseline MRI examinations. Mammography examinations were available for re-reading for 15 BCs, with mammography detecting 6 of these (sensitivity 40%). Eighty-nine BBLs were diagnosed in 23 women. Imaging examinations were available for re-reading for 31 BBLs in 16 women. MRI detected 29 (100%) out of 29 available BBLs cases, while mammography detected 15 (58%) out of 26 BBLs available cases. On MRI, BBLs often showed ambiguous enhancement features. In our study, MRI identified BCs mostly exhibited malignant features, while mammography often missed cancers. On MRI, most BCs were already visible at baseline examinations, and BBLs showed ambiguous enhancement features. These findings highlight the critical role of thorough MRI evaluation in the detection of BCs in PHTS women.\u003c/p\u003e","manuscriptTitle":"Enhancing breast cancer detection in PTEN Hamartoma Tumor Syndrome through insights into MRI and mammography lesion features","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-05 17:42:01","doi":"10.21203/rs.3.rs-3813519/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3bd918c9-637e-4647-addb-4f0d6b9e4145","owner":[],"postedDate":"March 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":29106476,"name":"Health sciences/Oncology/Cancer/Breast cancer"},{"id":29106477,"name":"Health sciences/Oncology/Cancer/Cancer prevention"},{"id":29106478,"name":"Health sciences/Oncology/Cancer/Cancer screening"},{"id":29106479,"name":"Health sciences/Oncology/Cancer/Cancer imaging"}],"tags":[],"updatedAt":"2024-08-12T10:35:41+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-05 17:42:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3813519","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3813519","identity":"rs-3813519","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}