Archive for the ‘Medical Device Therapies for Altzheimer’s Disease’ Category

Follow-up on Tomosynthesis

Writer & Curator: Dror Nir, PhD

Tomosynthesis, is a method for performing high-resolution limited-angle (i.e. not full 3600 rotation but more like ~500) tomography. The use of such systems in breast-cancer screening is steadily increasing following the clearance of such system by the FDA on 2011; see my posts – Improving Mammography-based imaging for better treatment planning and State of the art in oncologic imaging of breast.

Many radiologists expects that Tomosynthesis will eventually replace conventional mammography due to the fact that it increases the sensitivity of breast cancer detection. This claim is supported by new peer-reviewed publications. In addition, the patient’s experience during Tomosynthesis is less painful due to a lesser pressure that is applied to the breast and while presented with higher in-plane resolution and less imaging artifacts the mean glandular dose of digital breast Tomosynthesis is comparable to that of full field digital mammography. Because it is relatively new, Tomosynthesis is not available at every hospital. As well, the procedure is recognized for reimbursement by public-health schemes.

A good summary of radiologist opinion on Tomosynthesis can be found in the following video:

Recent studies’ results with digital Tomosynthesis are promising. In addition to increase in sensitivity for detection of small cancer lesions researchers claim that this new breast imaging technique will make breast cancers easier to see in dense breast tissue.  Here is a paper published on-line by the Lancet just a couple of months ago:

Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study

Stefano Ciatto†, Nehmat Houssami, Daniela Bernardi, Francesca Caumo, Marco Pellegrini, Silvia Brunelli, Paola Tuttobene, Paola Bricolo, Carmine Fantò, Marvi Valentini, Stefania Montemezzi, Petra Macaskill , Lancet Oncol. 2013 Jun;14(7):583-9. doi: 10.1016/S1470-2045(13)70134-7. Epub 2013 Apr 25.

Background Digital breast tomosynthesis with 3D images might overcome some of the limitations of conventional 2D mammography for detection of breast cancer. We investigated the effect of integrated 2D and 3D mammography in population breast-cancer screening.

Methods Screening with Tomosynthesis OR standard Mammography (STORM) was a prospective comparative study. We recruited asymptomatic women aged 48 years or older who attended population-based breast-cancer screening through the Trento and Verona screening services (Italy) from August, 2011, to June, 2012. We did screen-reading in two sequential phases—2D only and integrated 2D and 3D mammography—yielding paired data for each screen. Standard double-reading by breast radiologists determined whether to recall the participant based on positive mammography at either screen read. Outcomes were measured from final assessment or excision histology. Primary outcome measures were the number of detected cancers, the number of detected cancers per 1000 screens, the number and proportion of false positive recalls, and incremental cancer detection attributable to integrated 2D and 3D mammography. We compared paired binary data with McNemar’s test.

Findings 7292 women were screened (median age 58 years [IQR 54–63]). We detected 59 breast cancers (including 52 invasive cancers) in 57 women. Both 2D and integrated 2D and 3D screening detected 39 cancers. We detected 20 cancers with integrated 2D and 3D only versus none with 2D screening only (p<0.0001). Cancer detection rates were 5·3 cancers per 1000 screens (95% CI 3.8–7.3) for 2D only, and 8.1 cancers per 1000 screens (6.2–10.4) for integrated 2D and 3D screening. The incremental cancer detection rate attributable to integrated 2D and 3D mammography was 2.7 cancers per 1000 screens (1.7–4.2). 395 screens (5.5%; 95% CI 5.0–6.0) resulted in false positive recalls: 181 at both screen reads, and 141 with 2D only versus 73 with integrated 2D and 3D screening (p<0·0001). We estimated that conditional recall (positive integrated 2D and 3D mammography as a condition to recall) could have reduced false positive recalls by 17.2% (95% CI 13.6–21.3) without missing any of the cancers detected in the study population.

Interpretation Integrated 2D and 3D mammography improves breast-cancer detection and has the potential to reduce false positive recalls. Randomised controlled trials are needed to compare integrated 2D and 3D mammography with 2D mammography for breast cancer screening.

Funding National Breast Cancer Foundation, Australia; National Health and Medical Research Council, Australia; Hologic, USA; Technologic, Italy.


Although controversial, mammography screening is the only population-level early detection strategy that has been shown to reduce breast-cancer mortality in randomised trials.1,2 Irrespective of which side of the mammography screening debate one supports,1–3 efforts should be made to investigate methods that enhance the quality of (and hence potential benefit from) mam­mography screening. A limitation of standard 2D mammography is the superimposition of breast tissue or parenchymal density, which can obscure cancers or make normal structures appear suspicious. This short coming reduces the sensitivity of mammography and increases false-positive screening. Digital breast tomosynthesis with 3D images might help to overcome these limitations. Several reviews4,5 have described the development of breast tomosynthesis technology, in which several low-dose radiographs are used to reconstruct a pseudo-3D image of the breast.4–6

Initial clinical studies of 3D mammography, 6–10 though based on small or selected series, suggest that addition of 3D to 2D mammography could improve cancer detection and reduce the number of false positives. However, previous assessments of breast tomosynthesis might have been constrained by selection biases that distorted the potential effect of 3D mammography; thus, screening trials of integrated 2D and 3D mammography are needed.6

We report the results of a large prospective study (Screening with Tomosynthesis OR standard Mammog­raphy [STORM]) of 3D digital mammography. We investi­gated the effect of screen-reading using both standard 2D and 3D imaging with tomosynthesis compared with screening with standard 2D digital mammography only for population breast-cancer screening.



Study design and participants

STORM is a prospective population-screening study that compares mammography screen-reading in two sequential phases (figure)—2D only versus integrated 2D and 3D mammography with tomosynthesis—yielding paired results for each screening examination. Women aged 48 years or older who attended population-based screening through the Trento and Verona screening services, Italy, from August, 2011, to June, 2012, were invited to be screened with integrated 2D and 3D mammography. Participants in routine screening mammography (once every 2 years) were asymptomatic women at standard (population) risk for breast cancer. The study was granted institutional ethics approval at each centre, and participants gave written informed consent. Women who opted not to participate in the study received standard 2D mammography. Digital mammography has been used in the Trento breast-screening programme since 2005, and in the Verona programme since 2007; each service monitors outcomes and quality indicators as dictated by European standards, and both have published data for screening performance.11,12


study design


All participants had digital mammography using a Selenia Dimensions Unit with integrated 2D and 3D mammography done in the COMBO mode (Hologic, Bedford, MA, USA): this setting takes 2D and 3D images at the same screening examination with a single breast position and compression. Each 2D and 3D image consisted of a bilateral two-view (mediolateral oblique and craniocaudal) mammogram. Screening mammo­grams were interpreted sequentially by radiologists, first on the basis of standard 2D mammography alone, and then by the same radiologist (on the same day) on the basis of integrated 2D and 3D mammography (figure). Thus, integrated 2D and 3D mammography screening refers to non-independent screen reading based on joint interpretation of 2D and 3D images, and does not refer to analytical combinations. Radiologists had to record whether or not to recall the participant at each screen-reading phase before progressing to the next phase of the sequence. For each screen, data were also collected for breast density (at the 2D screen-read), and the side and quadrant for any recalled abnormality (at each screen-read). All eight radiologists were breast radiologists with a mean of 8 years (range 3–13 years) experience in mammography screening, and had received basic training in integrated 2D and 3D mammography. Several of the radiologists had also used 2D and 3D mammography for patients recalled after positive conventional mammography screening as part of previous studies of tomosynthesis.8,13

Mammograms were interpreted in two independent screen-reads done in parallel, as practiced in most population breast-screening programs in Europe. A screen was considered positive and the woman recalled for further investigations if either screen-reader recorded a positive result at either 2D or integrated 2D and 3D screening (figure). When previous screening mammograms were available, these were shown to the radiologist at the time of screen-reading, as is standard practice. For assessment of breast density, we used Breast Imaging Reporting and Data System (BI-RADS)14 classification, with participants allocated to one of two groups (1–2 [low density] or 3–4 [high density]). Disagreement between readers about breast density was resolved by assessment by a third reader.

Our primary outcomes were the number of cancers detected, the number of cancers detected per 1000 screens, the number and percentage of false posi­tive recalls, and the incremental cancer detection rate attributable to integrated 2D and 3D mammography screening. We compared the number of cancers that were detected only at 2D mammography screen-reading and those that were detected only at 2D and 3D mammography screen-reading; we also did this analysis for false positive recalls. To explore the potential effect of integrated 2D and 3D screening on false-positive recalls, we also estimated how many false-positive recalls would have resulted from using a hypothetical conditional false-positive recall approach; – i.e. positive integrated 2D and 3D mammography as a condition of recall (screening recalled at 2D mammography only would not be recalled). Pre-planned secondary analyses were comparison of outcome measures by age group and breast density.

Outcomes were assessed by excision histology for participants who had surgery, or the complete assessment outcome (including investigative imaging with or without histology from core needle biopsy) for all recalled participants. Because our study focuses on the difference in detection by the two screening methods, some cancers might have been missed by both 2D and integrated 2D and 3D mammography; this possibility could be assessed at future follow-up to identify interval cancers. However, this outcome is not assessed in the present study and does not affect estimates of our primary outcomes – i.e. comparative true or false positive detection for 2D-only versus integrated 2D and 3D mammography.


Statistical analysis

The sample size was chosen to provide 80% power to detect a difference of 20% in cancer detection, assuming a detection probability of 80% for integrated 2D and 3D screening mammography and 60% for 2D only screening, with a two-sided significance threshold of 5%. Based on the method of Lachenbruch15 for estimating sample size for studies that use McNemar’s test for paired binary data, a minimum of 40 cancers were needed. Because most screens in the participating centres were incident (repeat) screening (75%–80%), we used an underlying breast-cancer prevalence of 0·5% to estimate that roughly 7500–8000 screens would be needed to identify 40 cancers in the study population.

We calculated the Wilson CI for the false-positive recall ratio for integrated 2D and 3D screening with conditional recall compared with 2D only screening.16 All of the other analyses were done with SAS/STAT (version 9.2), using exact methods to compute 95 CIs and p-values.

Role of the funding source

The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author (NH) had full access to all the data in the study and had final responsibility for the decision to submit for publication.


7292 participants with a median age of 58 years (IQR 54–63, range 48–71) were screened between Aug 12, 2011, and June 29, 2012. Roughly 5% of invited women declined integrated 2D and 3D screening and received standard 2D mammography. We present data for 7294 screens because two participants had bilateral cancer (detected with different screen-reading techniques for one participant). We detected 59 breast cancers in 57 participants (52 invasive cancers and seven ductal carcinoma in-situ). Of the invasive cancers, most were invasive ductal (n=37); others were invasive special types (n=7), invasive lobular (n=4), and mixed invasive types (n=4).

Table 1 shows the characteristics of the cancers. Mean tumour size (for the invasive cancers with known exact size) was 13.7 mm (SD 5.8) for cancers detected with both 2D alone and integrated 2D and 3D screening (n=29), and 13.5 mm (SD 6.7) for cancers detected only with integrated 2D and 3D screening (n=13).


Table 1

Of the 59 cancers, 39 were detected at both 2D and integrated 2D and 3D screening (table 2). 20 cancers were detected with only integrated 2D and 3D screening compared with none detected with only 2D screening (p<0.0001; table 2). 395 screens were false positive (5.5%, 95% CI 5.0–6.0); 181 occurred at both screen-readings, and 141 occurred at 2D screening only compared with 73 at integrated 2D and 3D screening (p<0.0001; table 2). These differences were still significant in sensitivity analyses that excluded the two participants with bilateral cancer (data not shown).

Table 2

5.3 cancers per 1000 screens (95% CI 3.8–7.3; table 3) were detected with 2D mammography only versus 8.1 cancers per 1000 screens (95% CI 6.2–10.4) with integrated 2D and 3D mammography (p<0.0001). The incremental cancer detection rate attributable to inte­grated 2D and 3D screening was 2.7 cancers per 1000 screens (95% CI 1.7–4.2), which is 33.9% (95% CI 22.1–47.4) of the cancers detected in the study popu­lation. In a sensitivity analysis that excluded the two participants with bilateral cancer the estimated incre­mental cancer detection rate attributable to integrated 2D and 3D screening was 2.6 cancers per 1000 screens (95% CI 1.4–3.8). The stratified results show that integrated 2D and 3D mammography was associated with an incrementally increased cancer detection rate in both age-groups and density categories (tables 3–5). A minority (16.7%) of breasts were of high density (category 3–4) reducing the power of statistical comparisons in this subgroup (table 5). The incremental cancer detection rate was much the same in low density versus high density groups (2.8 per 1000 vs 2.5 per 1000; p=0.84; table 3).

Table 3

Table 4-5

Overall recall—any recall resulting in true or false positive screens—was 6.2% (95% CI 5.7–6.8), and the false-positive rate for the 7235 screens of participants who did not have breast cancer was 5.5% (5.0–6.0). Table 6 shows the contribution to false-positive recalls from 2D mammography only, integrated 2D and 3D mammography only, and both, and the estimated number of false positives if positive integrated 2D and 3D mammography was a condition for recall (positive 2D only not recalled). Overall, more of the false-positive rate was driven by 2D mammography only than by integrated 2D and 3D, although almost half of the false-positive rate was a result of false positives recalled at both screen-reading phases (table 6). The findings were much the same when stratified by age and breast density (table 6). Had a conditional recall rule been applied, we estimate that the false-positive rate would have been 3.5% (95% CI 3.1–4.0%; table 6) and could have potentially prevented 68 of the 395 false positives (a reduction of 17.2%; 95% CI 13.6–21.3). The ratio between the number of false positives with integrated 2D and 3D screening with conditional recall (n=254) versus 2D only screening (n=322) was 0.79 (95% CI 0.71–0.87).


Our study showed that integrated 2D and 3D mam­mography screening significantly increases detection of breast cancer compared with conventional mammog­raphy screening. There was consistent evidence of an incremental improvement in detection from integrated 2D and 3D mammography across age-group and breast density strata, although the analysis by breast density was limited by low number of women with breasts of high density.

One should note that we investigated comparative cancer detection, and not absolute screening sensitivity. By integrating 2D and 3D mammography using the study screen-reading protocol, 1% of false-positive recalls resulted from 2D and 3D screen-reading only (table 6). However, significantly more false positives resulted from 2D only mammography compared with integrated 2D and 3D mammography, both overall and in the stratified analyses. Application of a conditional recall rule would have resulted in a false-positive rate of 3.5% instead of the actual false-positive rate of 5.5%. The estimated false positive recall ratio of 0.79 for integrated 2D and 3D screening with conditional recall compared with 2D only screening suggests that integrated 2D and 3D screening could reduce false recalls by roughly a fifth. Had such a condition been adopted, none of the cancers detected in the study would have been missed because no cancers were detected by 2D mammography only, although this result might be because our design allowed an independent read for 2D only mammography whereas the integrated 2D and 3D read was an interpretation of a combination of 2D and 3D imaging. We do not recommend that such a conditional recall rule be used in breast-cancer screening until our findings are replicated in other mammography screening studies—STORM involved double-reading by experienced breast radiologists, and our results might not apply to other screening settings. Using a test set of 130 mammograms, Wallis and colleagues7 report that adding tomosynthesis to 2D mammography increased the accuracy of inexperienced readers (but not of experienced readers), therefore having experienced radiologists in STORM could have underestimated the effect of integrated 2D and 3D screen-reading.

No other population screening trials of integrated 2D and 3D mammography have reported final results (panel); however, an interim analysis of the Oslo trial17 a large population screening study has shown that integrated 2D and 3D mammography substantially increases detection of breast cancer. The Oslo study investigators screened women with both 2D and 3D mammography, but randomised reading strategies (with vs without 3D mammograms) and adjusted for the different screen-readers,17whereas we used sequential screen-reading to keep the same reader for each exam­ination. Our estimates for comparative cancer detection and for cancer detection rates are consistent with those of the interim analysis of the Oslo study.17 The applied recall methods differed between the Oslo study (which used an arbitration meeting to decide recall) and the STORM study (we recalled based on a decision by either screen-reader), yet both studies show that 3D mammog­raphy reduces false-positive recalls when added to standard mammography.

An editorial in The Lancet18 might indeed signal the closing of a chapter of debate about the benefits and harms of screening. We hope that our work might be the beginning of a new chapter for mammography screening: our findings should encourage new assessments of screening using 2D and 3D mammography and should factor several issues related to our study. First, we compared standard 2D mammography with integrated 2D and 3D mammography the 3D mammograms were not interpreted independently of the 2D mammograms therefore 3D mammography only (without the 2D images) might not provide the same results. Our experience with breast tomosynthesis and a review6 of 3D mammography underscore the importance of 2D images in integrated 2D and 3D screen-reading. The 2D images form the basis of the radiologist’s ability to integrate the information from 3D images with that from 2D images. Second, although most screening in STORM was incident screening, the substantial increase in cancer detection rate with integrated 2D and 3D mammography results from the enhanced sensitivity of integrated 2D and 3D screening and is probably also a result of a prevalence effect (ie, the effect of a first screening round with integrated 2D and 3D mammography). We did not assess the effect of repeat (incident) screening with integrated 2D and 3D mammography on cancer detection it might provide a smaller effect on cancer detection rates than what we report. Third, STORM was not designed to measure biological differences between the cancers detected at integrated 2D and 3D screening compared with those detected at both screen-reading phases. Descriptive analyses suggest that, generally, breast cancers detected only at integrated 2D and 3D screening had similar features (eg, histology, pathological tumour size, node status) as those detected at both screen-reading phases. Thus, some of the cancers detected only at 2D and 3D screening might represent early detection (and would be expected to receive screening benefit) whereas some might represent over-detection and a harm from screening, as for conventional screening mam mography.1,19 The absence of consensus about over-diagnosis in breast-cancer screening should not detract from the importance of our study findings to applied screening research and to screening practice; however, our trial was not done to assess the extent to which integrated 2D and 3D mam­mography might contribute to over-diagnosis.

The average dose of glandular radiation from the many low-dose projections taken during a single acquisition of 3D mammography is roughly the same as that from 2D mammography.6,20–22 Using integrated 2D and 3D en­tails both a 2D and 3D acquisition in one breast com­pression, which roughly doubles the radiation dose to the breast. Therefore, integrated 2D and 3D mammography for population screening might only be justifiable if improved outcomes were not defined solely in terms of improved detection. For example, it would be valuable to show that the increased detection with integrated 2D and 3D screening leads to reduced interval cancer rates at follow-up. A limitation of our study might be that data for interval cancers were not available; however, because of the paired design we used, future evaluation of interval cancer rates from our study will only apply to breast cancers that were not identified using 2D only or integrated 2D and 3D screening. We know of two patients from our study who have developed interval cancers (follow-up range 8–16 months). We did not get this information from cancer registries and follow-up was very short, so these data should be interpreted very cautiously, especially because interval cancers would be expected to occur in the second year of the standard 2 year interval between screening rounds. Studies of interval cancer rates after integrated 2D and 3D mammography would need to be randomised controlled trials and have a very large sample size. Additionally, the development of reconstructed 2D images from a 3D mammogram23 provides a timely solution to concerns about radiation by providing both the 2D and 3D images from tomosynthesis, eliminating the need for two acquisitions.

We have shown that integrated 2D and 3D mammog­raphy in population breast-cancer screening increases detection of breast cancer and can reduce false-positive recalls depending on the recall strategy. Our results do not warrant an immediate change to breast-screening practice, instead, they show the urgent need for random­ised controlled trials of integrated 2D and 3D versus 2D mammography, and for further translational research in breast tomosynthesis. We envisage that future screening trials investigating this issue will include measures of breast cancer detection, and will be designed to assess interval cancer rates as a surrogate endpoint for screening efficacy.


SC had the idea for and designed the study, and collected and interpreted data. NH advised on study concepts and methods, analysed and interpreted data, searched the published work, and wrote and revised the report. DB and FC were lead radiologists, recruited participants, collected data, and commented on the draft report. MP, SB, PT, PB, PT, CF, and MV did the screen-reading, collected data, and reviewed the draft report. SM collected data and reviewed the draft report. PM planned the statistical analysis, analysed and interpreted data, and wrote and revised the report.

Conflicts of interest

SC, DB, FC, MP, SB, PT, PB, CF, MV, and SM received assistance from Hologic (Hologic USA; Technologic Italy) in the form of tomosynthesis technology and technical support for the duration of the study, and travel support to attend collaborators’ meetings. NH receives research support from a National Breast Cancer Foundation (NBCF Australia) Practitioner Fellowship, and has received travel support from Hologic to attend a collaborators’ meeting. PM receives research support through Australia’s National Health and Medical Research Council programme grant 633003 to the Screening & Test Evaluation Program.



1       Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet 2012; 380: 1778–86.

2       Glasziou P, Houssami N. The evidence base for breast cancer screening. Prev Med 2011; 53: 100–102.

3       Autier P, Esserman LJ, Flowers CI, Houssami N. Breast cancer screening: the questions answered. Nat Rev Clin Oncol 2012; 9: 599–605.

4       Baker JA, Lo JY. Breast tomosynthesis: state-of-the-art and review of the literature. Acad Radiol 2011; 18: 1298–310.

5       Helvie MA. Digital mammography imaging: breast tomosynthesis and advanced applications. Radiol Clin North Am 2010; 48: 917–29.

6      Houssami N, Skaane P. Overview of the evidence on digital breast tomosynthesis in breast cancer detection. Breast 2013; 22: 101–08.

7   Wallis MG, Moa E, Zanca F, Leifland K, Danielsson M. Two-view and single-view tomosynthesis versus full-field digital mammography: high-resolution X-ray imaging observer study. Radiology 2012; 262: 788–96.

8   Bernardi D, Ciatto S, Pellegrini M, et al. Prospective study of breast tomosynthesis as a triage to assessment in screening. Breast Cancer Res Treat 2012; 133: 267–71.

9   Michell MJ, Iqbal A, Wasan RK, et al. A comparison of the accuracy of film-screen mammography, full-field digital mammography, and digital breast tomosynthesis. Clin Radiol 2012; 67: 976–81.

10 Skaane P, Gullien R, Bjorndal H, et al. Digital breast tomosynthesis (DBT): initial experience in a clinical setting. Acta Radiol 2012; 53: 524–29.

11 Pellegrini M, Bernardi D, Di MS, et al. Analysis of proportional incidence and review of interval cancer cases observed within the mammography screening programme in Trento province, Italy. Radiol Med 2011; 116: 1217–25.

12 Caumo F, Vecchiato F, Pellegrini M, Vettorazzi M, Ciatto S, Montemezzi S. Analysis of interval cancers observed in an Italian mammography screening programme (2000–2006). Radiol Med 2009; 114: 907–14.

13 Bernardi D, Ciatto S, Pellegrini M, et al. Application of breast tomosynthesis in screening: incremental effect on mammography acquisition and reading time. Br J Radiol 2012; 85: e1174–78.

14 American College of Radiology. ACR BI-RADS: breast imaging reporting and data system, Breast Imaging Atlas. Reston: American College of Radiology, 2003.

15  Lachenbruch PA. On the sample size for studies based on McNemar’s test. Stat Med 1992; 11: 1521–25.

16  Bonett DG, Price RM. Confidence intervals for a ratio of binomial proportions based on paired data. Stat Med 2006; 25: 3039–47.

17  Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population-based screening program. Radiology 2013; published online Jan 3. http://dx.doi.org/10.1148/ radiol.12121373.

18  The Lancet. The breast cancer screening debate: closing a chapter? Lancet 2012; 380: 1714.

19  Biesheuvel C, Barratt A, Howard K, Houssami N, Irwig L. Effects of study methods and biases on estimates of invasive breast cancer overdetection with mammography screening: a systematic review. Lancet Oncol 2007; 8: 1129–38.

20  Tagliafico A, Astengo D, Cavagnetto F, et al. One-to-one comparison between digital spot compression view and digital breast tomosynthesis. Eur Radiol 2012; 22: 539–44.

21  Tingberg A, Fornvik D, Mattsson S, Svahn T, Timberg P, Zackrisson S. Breast cancer screening with tomosynthesis—initial experiences. Radiat Prot Dosimetry 2011; 147: 180–83.

22  Feng SS, Sechopoulos I. Clinical digital breast tomosynthesis system: dosimetric characterization. Radiology 2012; 263: 35–42.

23  Gur D, Zuley ML, Anello MI, et al. Dose reduction in digital breast tomosynthesis (DBT) screening using synthetically reconstructed projection images: an observer performance study. Acad Radiol 2012; 19: 166–71.

A very good and down-to-earth comment on this article was made by Jules H Sumkin who disclosed that he is an unpaid member of SAB Hologic Inc and have a PI research agreement between University of Pittsburgh and Hologic Inc.

The results of the study by Stefano Ciatto and colleagues1 are consistent with recently published prospective,2,3 retrospective,4 and observational5 reports on the same topic. The study1 had limitations, including the fact that the same radiologist interpreted screens sequentially the same day without cross-balancing which examination was read first. Also, the false-negative findings for integrated 2D and 3D mammography, and therefore absolute benefit from the procedure, could not be adequately assessed because cases recalled by 2D mammography alone (141 cases) did not result in a single detection of an additional cancer while the recalls from the integrated 2D and 3D mammography alone (73 cases) resulted in the detection of 20 additional cancers. Nevertheless, the results are in strong agreement with other studies reporting of substantial performance improvements when the screening is done with integrated 2D and 3D mammography.

I disagree with the conclusion of the study with regards to the urgent need for randomised clinical trials of integrated 2D and 3D versus 2D mammography. First, to assess differences in mortality as a result of an imaging-based diagnostic method, a randomised trial will require several repeated screens by the same method in each study group, and the strong results from all studies to date will probably result in substantial crossover and self-selection biases over time. Second, because of the high survival rate (or low mortality rate) of breast cancer, the study will require long follow-up times of at least 10 years. In a rapidly changing environment in terms of improvements in screening technologies and therapeutic inter­ventions, the avoidance of biases is likely to be very difficult, if not impossible. The use of the number of interval cancers and possible shifts in stage at detection, while appropriately accounting for confounders, would be almost as daunting a task. Third, the imaging detection of cancer is only the first step in many management decisions and interventions that can affect outcome. The appropriate control of biases related to patient management is highly unlikely. The arguments above, in addition to the existing reports to date that show substantial improvements in cancer detection, particularly with the detection of invasive cancers, with a simultaneous reduction in recall rates, support the argument that a randomised trial is neither necessary nor warranted. The current technology might be obsolete by the time results of an appropriately done and analysed randomised trial is made public.

In order to better link the information given by “scientific” papers to the context of daily patients’ reality I suggest to spend some time reviewing few of the videos in the below links:

  1. The following group of videos is featured on a website by Siemens. Nevertheless, the presenting radiologists are leading practitioners who affects thousands of lives every year – What the experts say about tomosynthesis. – click on ECR 2013
  2. Breast Tomosynthesis in Practice – part of a commercial ad of the Washington Radiology Associates featured on the website of Diagnostic Imaging. As well, affects thousands of lives in the Washington area every year.

The pivotal questions yet to be answered are:

  1. What should be done in order to translate increase in sensitivity and early detection into decrease in mortality?

  2. What is the price of such increase in sensitivity in terms of quality of life and health-care costs and is it worth-while to pay?

An article that summarises positively the experience of introducing Tomosynthesis into routine screening practice was recently published on AJR:

Implementation of Breast Tomosynthesis in a Routine Screening Practice: An Observational Study

Stephen L. Rose1, Andra L. Tidwell1, Louis J. Bujnoch1, Anne C. Kushwaha1, Amy S. Nordmann1 and Russell Sexton, Jr.1

Affiliation: 1 All authors: TOPS Comprehensive Breast Center, 17030 Red Oak Dr, Houston, TX 77090.

Citation: American Journal of Roentgenology. 2013;200:1401-1408



OBJECTIVE. Digital mammography combined with tomosynthesis is gaining clinical acceptance, but data are limited that show its impact in the clinical environment. We assessed the changes in performance measures, if any, after the introduction of tomosynthesis systems into our clinical practice.

MATERIALS AND METHODS. In this observational study, we used verified practice- and outcome-related databases to compute and compare recall rates, biopsy rates, cancer detection rates, and positive predictive values for six radiologists who interpreted screening mammography studies without (n = 13,856) and with (n = 9499) the use of tomosynthesis. Two-sided analyses (significance declared at p < 0.05) accounting for reader variability, age of participants, and whether the examination in question was a baseline were performed.

RESULTS. For the group as a whole, the introduction and routine use of tomosynthesis resulted in significant observed changes in recall rates from 8.7% to 5.5% (p < 0.001), nonsignificant changes in biopsy rates from 15.2 to 13.5 per 1000 screenings (p = 0.59), and cancer detection rates from 4.0 to 5.4 per 1000 screenings (p = 0.18). The invasive cancer detection rate increased from 2.8 to 4.3 per 1000 screening examinations (p = 0.07). The positive predictive value for recalls increased from 4.7% to 10.1% (p < 0.001).

CONCLUSION. The introduction of breast tomosynthesis into our practice was associated with a significant reduction in recall rates and a simultaneous increase in breast cancer detection rates.

Here are the facts in tables and pictures from this article

Table 1 AJR

Table 2-3 AJR


Table 4 AJR


p1 ajr

p2 ajr

Other articles related to the management of breast cancer were published on this Open Access Online Scientific Journal:

Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need!

Introducing smart-imaging into radiologists’ daily practice.

Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

New Imaging device bears a promise for better quality control of breast-cancer lumpectomies – considering the cost impact

Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com

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Controlling focused-treatment of Prostate cancer with MRI

Writer and reporter: Dror Nir, PhD.

In recent years there is a growing trend of treating prostate cancer in a way that will preserve, at least partially, the functionality of this organ. When patients are presenting at biopsy a low-grade localized disease, they might be offered focused treatment of the cancer lesion. One of the option is treatment by high-intensity focused ultrasound (HIFU).

The offering of such treatments created the need of controlling their outcome while the prostate is still inside the patient’s body. The most commonly used protocol is following up the patient’s PSA levels and performing “control” biopsies. The biopsies part is at best case; extremely unpleasant. It also bears some risk for complications.

Therefore, urologists are constantly seeking an imaging based protocol that will enable them to assess the treatment outcome without the need for biopsy. The publication I bring below presents the possibility of using MRI for this task. Although it is not recent, it contains many images that makes the story very clear for the reader.  The main weakness of the study is the small number of patients – only 15.

MR Imaging of Prostate after Treatment with High-Intensity Focused Ultrasound

Alexander P. S. Kirkham, FRCR, Mark Emberton, FRCS, Ivan M. Hoh, MRCS, Rowland O. Illing, MRCS, A. Alex Freeman, FRCP and Clare Allen, FRCR

From the Department of Imaging, University College London Hospitals NHS Foundation Trust, England (A.P.S.K., C.A.); Institute of Urology (M.E., I.M.H., R.O.I.) and Department of Histopathology (A.A.F.), University College London, England.

Address correspondence to A.P.S.K., Imaging Department, University College Hospital, 235 Euston Road, London, England NW1 2BU (e-mail: alexkirkham@yahoo.com).

Radiology March 2008; 246 (3) – 833-844.


Purpose: To prospectively evaluate magnetic resonance (MR) imaging findings after high-intensity focused ultrasound (HIFU) treatment of the prostate and to correlate them with clinical and histologic findings.

Materials and Methods: Local ethics committee approval and informed consent were obtained. Fifteen consecutive men aged 46–70 years with organ-confined prostate cancer underwent ultrasonographically guided ablation of the whole prostate. Postoperative MR images were obtained within 1 month (12 patients), at 1–3 months (five patients), and in all patients at 6 months. Prostate volume was measured on T2-weighted images, and enhancing tissue was measured on dynamic images after intravenous administration of gadopentetate dimeglumine. Prostate-specific antigen (PSA) level was measured at regular intervals, and transrectal biopsy was performed in each patient at 6 months after treatment.

Results: Initial post-HIFU images showed a central nonenhancing area, surrounded by an enhancing rim. At 6 months, the prostate was small (median volume reduction, 61%) and was of predominantly low signal intensity on T2-weighted images. The volume of prostate enhancing on the initial posttreatment image correlated well with serum PSA level nadir (Spearman r = 0.90, P < .001) and with volume at 6 months (Pearsonr = 0.80, P = .001). The three patients with the highest volume of enhancing prostate at the initial posttreatment acquisition had persistent cancer at 6-month biopsy.

Conclusion: MR imaging results of the prostate show a consistent sequence of changes after treatment with HIFU and can provide information to the operator about completeness of treatment.

There is currently little to offer men with localized prostate cancer between the two extremes of watchful waiting and radical treatment—most commonly prostatectomy or radiation therapy (1). Ablation of the gland has been proposed as an alternative that has the potential to completely treat the tumor while minimizing the sexual and urinary morbidity that still accompany established radical therapies (2). Several techniques have been used in the prostate—including microwave (3) and radiofrequency (4) ablation, cryotherapy (5), photodynamic therapy (6), and high-intensity focused ultrasound (HIFU) treatment (7).

HIFU is, in several respects, ideally suited to the prostate. In contrast to extracorporeal devices for the liver and kidney (8), with the transrectal approach, there is little movement of the target because of respiration or reflection by overlying bone. A focal distance of 3 or 4 cm allows the generation of coagulative necrosis in treatment voxels less than 0.2 mL and allows a treatment volume that conforms to the shape of the prostate (9)—a degree of precision that may be beyond that of other techniques. Even so, complete ablation is likely to affect periprostatic tissues, including the neurovascular bundles containing the cavernosal nerves (10) and the external urethral sphincter. Preservation of these structures—and the patient’s erectile and urinary function—must be balanced against full treatment of the gland.

Although impotence rates after HIFU treatment approach 50% (11), it is likely that in its current clinical implementation, the prostate is not being fully ablated: In published series, the recurrence rates for cancer range between 25% and 38% (7,11,12). To our knowledge, no groups have reported mean reductions in prostate volume of more than 50% (12,13), and several groups have found it difficult to treat the anterior gland (14).

If we are to improve outcomes, a fundamental requirement for HIFU treatment (and ablative technologies in general) is a method that provides anatomic information to the operator about areas that have been over- or undertreated. This might lead to modifications in future technique, and if obtained soon after treatment, might indicate the need for further ablation. Such a method might also help predict outcome earlier than established measures, such as prostate-specific antigen (PSA) measurement and biopsy.

Magnetic resonance (MR) imaging has great potential in this setting, and Rouviere et al (14) have described the appearance of the prostate on contrast material–enhanced MR images obtained up to 5 months after HIFU treatment. Rouviere et al found a good correlation between the theoretical treatment volume and the volume of nonenhancing prostate on a subsequent acquisition. The aim of our study was to prospectively evaluate MR imaging findings after HIFU treatment of the prostate and to correlate them with clinical and histologic findings.



Misonix (the European distributors of the Sonablate device) funded the phase-II European study and provided equipment and reimbursed the hospital for costs. The company has funded two authors (I.M.H. and R.O.I.) through educational awards. One author (M.E.) has acted as a paid consultant to Misonix and also received honoraria for training and teaching. Authors other than I.M.H., R.O.I., and M.E. had control of the information and data submitted for publication. Misonix was not involved in the analysis of data or the writing of this article.


We included the first 15 men at University College Hospital (age range, 46–70 years; mean age, 59 years) who were taking part in a registered phase-II multicenter European study of HIFU therapy for organ-confined prostate cancer (Table 1). The study was approved by the local ethics committee, and full written consent was obtained from each patient. The patients understood that HIFU is an experimental treatment whose long-term outcome is unknown and were offered full conventional treatment as an alternative. The study was limited to men with a serum PSA level 15 μg/L or less, Gleason score less than 8, prostate volume less than 40 mL, life expectancy more than 5 years, and age less than 80 years. There was no limit to the number of biopsy cores that had a positive finding or the amount of cancer in each core removed. Patients with a history of previous prostate surgery were excluded, as were men who had undergone androgen deprivation therapy in the 6 months prior to recruitment or had intragland prostatic calcification more than 1 cm in diameter.

Table 1.  Patients and Demographics

 table 1

 * Ratio of cores with a positive finding to cores obtained.

 † Image not available for analysis; volume was calculated by using US measurements.

The Sonablate 500 (Focus Surgery, Indianapolis, Ind) consists of a power generator, water cooling system (the Sonachill), a treatment probe, and a positioning system. The probe contains two curved rectangular piezoceramic transducers with a driving frequency of 4 MHz and focal lengths of 30 and 40 mm. During treatment, these may be driven at low energy to provide real-time diagnostic imaging or at high energy for therapeutic ablation (in situ intensity, 1300–2200 W/cm2). The probe is covered with a condom, under which cold (17°–18°C) degassed water is circulated to help protect the rectum from thermal injury.

Patients were prepared before the procedure with two phosphate enemas to empty the rectum. Oral bowel preparation was used in some patients. Treatment was performed with general anesthesia in the lithotomy position and was performed or closely supervised in every case by an author (M.E., 2 years of experience in HIFU treatment). After gentle dilation of the anal sphincter, the treatment probe was introduced with a covering of ultrasonographic (US) gel to couple it to the rectal mucosa and was held in position with an articulated arm attached to the operating table. A 16-F Foley urethral catheter was inserted using sterile technique, and a 10-mL balloon was inflated to allow the bladder neck and median sagittal plane to be seen accurately. It was removed before treatment began.

Treatment was planned by using US-acquired volumes consisting of stacks of both sagittal and transverse sections (voxel size, 2 × 3 × 30 mm) and was applied in rows that extended in the craniocaudal axis, interleaved to avoid interference from adjacent, recently treated areas. After each 3-second period of ablation, diagnostic transverse and sagittal images in the plane of treatment were obtained to permit tailoring of the energy delivery in the next voxel according to visible changes on the gray-scale image. This is an important difference from the device used by Rouviere’s group (14), in which power is planned before the treatment begins. We aimed to set the power for each voxel at a level that produced hyperechoic change due to cavitation (as described by Illing et al [15]), and we invariably treated the whole anterior prostate. Neurovascular bundles were not identified at treatment (the Sonablate device does not yet have color Doppler capability); rather, we aimed to avoid treating outside the capsule where they lie posterolaterally (10). The time between the first ablation and the point at which treatment was considered complete was 3.0–4.4 hours (mean, 3.6 hours). A 16-F urethral catheter was placed immediately after the treatment and was left in place for 2 weeks.

MR Imaging

For most preoperative examinations and for all post-HIFU imaging, we used an MR machine (Symphony or Avanto; Siemens, Erlangen, Germany) with 1.5-T magnet and a pelvic-phased array coil. Except where stated, a full protocol of T1- and T2-weighted turbo spin-echo (Siemens) images and a dynamic fat-saturated postcontrast volume acquisition were used for both preoperative diagnostic and planning imaging and for postoperative assessment of HIFU treatment (Table 2). The contrast material used was 20 mL of gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany) given intravenously at 3 mL/sec.

Table 2. MR Sequences Used at Prostate Imaging

table 2

We aimed to image patients less than 1 month after treatment and did so in 12 patients. The remaining three patients were imaged between 1 and 3 months after treatment. Two patients were imaged in both time periods. Every patient underwent a 6-month MR examination.

Image Analysis

All volume measurements (except where stated) were acquired by using planimetry of contiguous 3-mm sections (16). T2-weighted images were used for measurement of prostatic volume both before and after treatment. The amount of intermediate- or high-signal-intensity material (ie, higher than muscle) remaining within the prostate was also measured on the 6-month posttreatment T2-weighted image.

The volume of nonenhancing prostate tissue at the post-HIFU acquisition was measured by using the final dynamic postcontrast image. On the initial posttreatment image, we also measured the volume of extraprostatic tissue that was both of low signal intensity on the T1-weighted image and nonenhancing. The distance between this tissue and the rectal mucosa was measured at its narrowest point. The mean thickness of the enhancing rim surrounding the treatment volume was measured on transverse postcontrast T1-weighted spin-echo images and was calculated by dividing the area of the rim by its circumference.

The volume of persistently enhancing prostate tissue on the initial image was calculated by subtracting the nonenhancing volume from the total volume of prostate on the T2-weighted image. This could be calculated in 13 patients; one patient did not receive contrast material at the post-HIFU MR acquisition, and the other was imaged more than 2 months after treatment.

All measurements were performed by a first-year radiology fellow (A.P.S.K.) without knowledge of PSA and histologic results. Two other observers independently measured the three key parameters that were used for correlation calculations for each patient: (a) the volume of nonenhancing prostate on the initial image, (b) the total volume of the prostate on the initial image, and (c) the final prostate volume at 6 months. One was a consultant uroradiologist with more than 10 years of experience in the interpretation of prostate MR images (C.A.); the other was a third-year urology research fellow with an interest in prostate imaging (R.O.I.). For each parameter, the mean of the three observers’ measurements was calculated and used for further analysis.

PSA Measurement and Prostate Biopsy

Serum PSA level was measured before and at 1.5, 3, and 6 months after HIFU treatment. The nadir was defined as the lowest of the three values.

Biopsies were performed by an author (A.P.S.K., with 4 years of experience in prostate biopsy) by using a transrectal approach with US guidance and an 18-gauge needle with a 2-cm throw soon after the 6-month MR examination. The number of cores obtained depended on the amount of residual prostate and varied between two and 10 (median, eight cores).

Erectile Function and Continence

The International Index of Erectile Function was used to assess erectile function both before and 3 months after HIFU treatment in each patient (17). The most important question was, “How often were your erections hard enough for penetration [with or without phosphodiesterase type 5 inhibitors]?” A score of 2 (a few times in 4 weeks) to 5 (always) was, for the purposes of this article, considered evidence of intact erectile function.

Men were asked to complete the International Continence Society–validated continence function questionnaire at baseline and at 3 and 6 months after therapy. The question deemed to be most informative was how often the patient required the use of pads or adult diapers. Responses could include “never,” “not more than one per day,” “1–2 per day,” or “more than 3 per day.”

Statistical Analysis

To assess the variance of results between observers, we used the intraclass correlation coefficient (18) applied to measurements obtained by three observers of the calculated volume of enhancing prostate on the initial post-HIFU image and the 6-month prostate volume.

The Spearman rank test was used to assess the correlation between enhancing prostate volume and serum PSA level nadir, and the Pearson test was used to examine the correlation between initial enhancing prostate volume and final prostate volume. Only the patients who were imaged less than 1 month after treatment were included in the analysis. These tests were performed by using software (GraphPad Prism for Mac, version 3; http://www.graphpad.com).

Because some of the covariance of volumes measured after treatment was likely to be due to their correlation with pretreatment prostate volume, we also applied a correction: The values were expressed as a proportion of the pretreatment volume, and a further correlation measurement was performed by using the Pearson test. In each case, a P value of less than .02 was considered to indicate a significant difference.



Up to 1 Month After Treatment

T2-weighted images.—Compared with that on the preoperative image, the prostate volume increased in every case (Table 1 and Table E1, Fig 1). The signal intensity from the prostate on T2-weighted images within the first month was always heterogeneous and variable. It was impossible to predict from the findings on T2-weighted images which areas of the prostate would enhance after intravenous contrast material administration. The periprostatic fat was also heterogeneous in signal intensity, which was consistent with edema (Fig 2).

Figure 1: Graph of change in prostate volume after HIFU treatment. Volume rises initially (less than 1 month after treatment) and is reduced in all cases at 6 months. Numbers = patient numbers.


Figure 2: MR images in patient 1 (a–d) and (e–h) patient 8 show low volume of enhancing prostate at initial imaging and small residual prostate at 6 months. Posttreatment serum PSA level was less than 0.05 μg/L in both cases.

Figure 2a:


Figure 2b:


Figure 2c:


Figure 2d:


Figure 2e:


Figure 2f:


Figure 2g:


Figure 2h:


T1-weighted images.—The prostate was of predominantly low signal intensity, although patchy areas of intermediate or high signal intensity, likely to represent hemorrhage, were a constant finding within the gland and in all but one of 28 seminal vesicles.

Postcontrast images.—In each patient, the postcontrast images showed a central area of nonenhancing tissue. This conformed to the treatment volume and was surrounded by an enhancing rim of mean thickness of 2–8 mm (median, 4 mm) that was continuous around the prostate in most patients (Fig 2; Table E1,).

The enhancing prostate varied in size and position. Part of the enhancing rim usually lay within the prostatic capsule and continued to the prostatic apex where there was almost always some enhancing tissue between the nonenhancing prostate and the external urethral sphincter. In many patients, more central areas of enhancement were seen: at the apex or base, either posteriorly or anteriorly (Table E1), and were almost always in continuity with the rim.

In every patient, the nonenhancing, low signal intensity within the prostate extended outside the gland and involved the periprostatic fat and the levator ani muscle, particularly anterolaterally (Table E1, Figs 23). This varied considerably and tended to be most prominent in those who had no residual gland enhancement and had an undetectable serum PSA level after HIFU treatment (Table E1). In several patients, the nonenhancing area extended to involve the Denonvilliers fascia. (The distance between its margin and the rectal muscle is listed in Table E1.) In one patient, a proportion of the rectal wall enhanced avidly, but in no patient was there loss of rectal wall enhancement to suggest necrosis.

Figure 3: MR images obtained near the prostate apex show incomplete treatment and persisting high signal intensity in prostate. Serum PSA level nadir = 0.61 μg/L.

Figure 3a: Patient 4:


 Figure 3b: Patient 4:


Figure 3c: Patient 4:


Figure 3d: Patient 4:


At 1–3 Months

In three patients, there was a “double rim” (Fig 4) on postcontrast images obtained at 36 and 56 days after HIFU treatment. The inner component lay within the prostate and the outer at the prostatic capsule; the intervening part was of low signal intensity on both T1- and T2-weighted images.

 Figure 4: MR images of “double rim” at 56 days after HIFU treatment.

Figure 4a: Patient 3:


Figure 4b: Patient 3:


Figure 4c: Patient 3:


Six-month Appearance

T2-weighted images.—In every patient, the volume of the prostate was reduced by more than 45% (median, 61% reduction) (Table E1). On T2-weighted images, the majority of the persisting prostate was of low signal intensity, with poor definition to the capsule and with persisting heterogeneous signal intensity to the surrounding fat. However, in 12 of 15 patients, there was persisting high or intermediate signal intensity of the prostate—up to 5.34 mL in volume and most often seen posteriorly and at the apex (Table E1, Figs 3 and 5). In many patients (for example, those in Fig 2), low-signal-intensity prostate of reduced volume surrounded a capacious prostatic cavity continuous with the urethra, which is similar to the cavity seen after transurethral resection (19).

Figure 5: MR images of incomplete treatment of tumor and positive biopsy findings in three of 10 cores at 6 months (in right lateral midzone, right lateral base, and right parasagittal base samples). Serum PSA level nadir = 1.19 μg/L.

Figure 5a: Patient 13:


Figure 5b: Patient 13:


Figure 5c: Patient 13:


Figure 5d: Patient 13:


Figure 5e: Patient 13:


Postcontrast images.—Some small areas of nonenhancing tissue persisted in eight of 14 patients, but this was less than 1 mL in all but one (patient 13, in whom 4 mL of the gland volume of 18.7 mL was nonenhancing). The levator muscle showed a normal signal intensity.

Correlation Between Initial Imaging and Later Findings

In the 12 patients who underwent the initial acquisition within 1 month of HIFU treatment, the volume of enhancing tissue on the initial posttreatment image was positively correlated with the serum PSA level nadir (Fig 6) (Spearman r = 0.90, P < .001) and with the amount of residual tissue at 6 months (including all low-signal-intensity material that was likely to represent fibrosis or necrosis) (Fig 7) (Pearson r = 0.80, P = .001).

 Figure 6: Graph of relationship between the proportion of the prostate still enhancing on initial image and serum PSA level nadir. There is a significant positive correlation (Spearman r = 0.90, P < .001). * = patient 13, who was included in graph but not in analysis (imaged 56 days after HIFU treatment). Patients 14 and 15 are not included because they did not undergo contrast-enhanced acquisition within 2 months of HIFU treatment. μgl−1 = μg/L.


Figure 7: Graph of relationship between the proportion of the prostate still enhancing on initial image and final volume of prostate. There is a significant positive correlation between the variables (Pearson r = 0.80, P = .001). * = patient 13, who was included in graph but not in analysis (imaged 56 days after HIFU treatment). Patients 14 and 15 are not included because they did not undergo contrast-enhanced acquisition within 2 months of HIFU treatment.


When posttreatment volumes are expressed as a proportion of pretreatment prostate volume, the correlation between enhancing tissue volume on the initial posttreatment image and the 6-month prostate volume persists (Pearson r = 0.70, P = .001).

Interobserver Correlation

The interobserver variation was excellent for the calculated volume of prostate enhancing on the initial post-HIFU image, with an intraclass correlation coefficient of 0.92, and was good for final prostate volume (intraclass correlation coefficient = 0.73).

Clinical Findings

In five patients (patients 1, 3, 8, 11, and 13), there was imaging evidence (at MR imaging or retrograde urethrography) of a stricture in the mid- or distal prostatic urethra, which was confirmed by using flow rate studies and treated by using self-catheterization or with graded urethral dilators. None have required formal urethrotomy. Patient 14 developed a bladder neck stricture, which was treated successfully by incision.

Before treatment, no men required pads or adult diapers for incontinence. At 6 months after the treatment, four men still required not more than one pad per day. In two cases, this was for reassurance rather than actual leakage.

In the 14 patients in whom there was intact erectile function (score 2–5 for the question, “How often were your erections hard enough for penetration?”) before HIFU treatment, it was intact in nine patients after the procedure. One patient had stopped trying to achieve erections, and four could not achieve penetration.

Histologic Findings

In the three patients in whom there was no high-signal-intensity peripheral zone at 6 months and with serum PSA level less than 0.05 μg/L, there was either no prostatic tissue or only a small group of acini in one core. The remaining patients had a variable amount of residual prostate at core biopsy.

Five patients had residual tumor. In three patients, it was seen in at least two cores (Table E1), and these three patients also had the largest volume of enhancing prostate on the initial post-HIFU MR image (Figs 6 and 7) and more than 2 mL of intermediate- or high-signal-intensity gland on T2-weighted images at 6 months.

In four of five patients with residual cancer, it could not be identified on either contrast-enhanced or T2-weighted images. In one patient (Fig 4), the early dynamic images showed prominent enhancement in the anterior gland, which was consistent with residual cancer found at the distal (ie, nonrectal) end of three right-sided biopsy cores. Such enhancement was not seen in patients with no cancer found at core biopsy.



We found a consistent sequence of changes at MR imaging after HIFU treatment of the whole prostate. The proportion of enhancing tissue on the initial posttreatment MR image was predictive of gland volume at 6 months and serum PSA level nadir. A strong statistical relationship between the latter and outcome has recently been demonstrated (20).

Most patients with residual cancer had evidence of incomplete ablation early (a large volume of enhancing prostate on the initial image) and late (a large volume of high-signal-intensity residual prostate on T2-weighted images at 6 months).

In some patients it was possible to achieve an undetectable serum PSA level at 6 months and entirely low signal intensity on T2-weighted images in the region of the prostate. These patients had either no or a small amount of viable prostate in one core at biopsy.

Conversely, in spite of reductions in prostate volume of more than 45% at 6 months, the majority of patients had histologic evidence of persisting viable prostate, and in a group of patients with organ-confined disease but no limit to the volume of cancer pretreatment, one-third had evidence of residual tumor.

Persisting enhancing prostatic tissue usually occurred at the periphery (or extended toward the center of the gland from it) and was particularly common at the apex and near the rectum.

Results of one previously published study (14) of post-HIFU appearances with MR imaging show a similar sequence of acute changes, although there was no attempt to quantify prostate volume at 6 months. There is also a large body of work on the MR imaging appearances with thermotherapy (whether laser [21,22] or radiofrequency [23]) and cryotherapy (24) within the prostate and other organs. The hyperenhancing rim of tissue is a constant finding in several tissues, including the liver (25), the kidney (26), and the brain (27). In the liver and the kidney, it is thin (1 mm or less) and, in most cases, has disappeared by 2 months after ablation (28). Within the prostate, the hyperenhancing rim has been shown to occur after laser ablation of benign prostatic hyperplasia (21,22) and after HIFU treatment (14).

Histologic evidence in animal models—including rabbit and porcine liver (29)—suggests that the enhancing rim corresponds to an area of inflammation and then fibrosis, with a variable amount of residual, viable tissue. How much of the rim will be viable after ablation of the prostate in humans remains uncertain. On the one hand, after HIFU treatment, core biopsy results show “partial or complete necrosis” in the rim (14). On the other, after laser ablation of benign prostatic hyperplasia, the volume of coagulative necrosis at histologic examination correlates very well with the central nonenhancing region at MR imaging, not including the rim (22). The answer is likely to be that a variable amount of the rim contains viable tissue (depending on the organ being imaged [30], the nature of the treatment, and the interval before the acquisition), and the implication is that the only reliably necrotic area at MR imaging is that which does not enhance. We have avoided the term necrosis for the nonenhancing areas of prostate seen in our current study, but from these data it is likely that the areas of prostate without enhancement are truly necrotic.

The distribution of enhancing prostate on posttreatment MR images fits with histologic evidence that “ventral, lateral and dorsal sides of the prostate” have residual viable prostatic tissue at histologic examination after HIFU treatment (31). What all of these areas have in common is proximity to the more richly vascular prostatic capsule. Is it possible that increased vascularity here results in reduced efficacy? This is another area that has been addressed by Rouviere’s group (32), who did not find a correlation between successful ablation and prostate vascularity by using power Doppler US; they conclude, as others have (33,34), that short (3-second) high-intensity bursts of focused ultrasound are unlikely to be markedly affected by blood flow. An alternate explanation is a geometric one: Centrally lying voxels are easier to treat because they may be rendered necrotic either by direct treatment or by damage to supplying vessels in the periphery.

An implication of these results is that the best strategies for minimizing complications while ensuring destruction of the cancer are likely to involve a degree of targeting: If the tumor can be imaged with MR imaging, the patient might be treated with higher power and wider margins (including periprostatic fat, muscle, or even neurovascular bundles) at the site of the cancer and with a standard intensity to the rest of the gland. An analogous approach is the wide excision, including a unilateral neurovascular bundle, of bulky tumors at radical prostatectomy (35). Such an approach may well have benefited our patients 7 and 13.

One methodologic issue that is currently unresolved relates to the timing of MR imaging. A detailed within-patient study of MR imaging changes after HIFU treatment is needed to properly describe the longitudinal changes in the appearance of the prostate. Rouviere et al (14) found that the area of nonenhancing tissue decreases by 50% at 1 month compared with that at an immediate (<1 week) post-HIFU acquisition, which suggests that for an accurate assessment of necrosis volume, the prostate should be imaged as soon as possible after treatment. Of course, perfusion would ideally be assessed during HIFU treatment so that undertreated areas could be further ablated. There is some evidence that Doppler or contrast-enhanced US (36) could play this role, but, to our knowledge, there are no studies on the correlation of immediate findings with later clinical data, such as serum PSA level or histologic examination.

We used fast low-angle shot sequences to assess enhancement because we found that the subjective assessment (together with objective measurements of signal intensity) of the dynamic series helped us identify truly nonenhancing tissue. However, the T1-weighted spin-echo postcontrast sequence would have been adequate, and we consider, as others do (22), dynamic contrast-enhanced sequences not to be an essential part of the protocol for postablation assessment. What is certain is that unenhanced T2-weighted sequences are inadequate for assessing necrosis (14,22).

Our results differ from those of other published series of HIFU treatment in the marked reduction in gland volume and absence of zonal anatomy in many patients observed at 6 months. In contrast to the study of post-HIFU MR imaging by Rouviere et al (14) who used a different device, we did not find that “HIFU-induced abnormalities seem to disappear within 3–5 months.” Rather, in several patients, it was difficult to discern any residual prostate at all at both MR and US studies. The difference probably lies in the power used for treatment and the completeness of gland coverage. The stricture rate of six of 15 is high when compared with that in published series (7,37,38) and may be related to the power used, the degree of fibrosis occurring in the prostate, and the strategy for catheterization. The latter is considered likely to be important, and we have recently changed to using a suprapubic catheter (rather than urethral) after treatment. The rate of impotence after treatment is similar to that in published series (11), as is grade I incontinence.

Our work has implications for the conduct of HIFU. The finding that the volume of enhancing prostate on the initial posttreatment image correlates well with intermediate measures, such as serum PSA level nadir and biopsy evidence of residual cancer, suggests that MR imaging can provide the operator with feedback on the effectiveness of the intervention. This information might enable modification of the technique to treat areas that have been incompletely ablated in previous patients—in our series, those areas encompassed the apex and posterior gland and rarely anterior tissue (in contrast to other study results [14]). Conversely, we might have reduced power or treatment volume at the anterolateral aspect of the gland adjacent to the levator muscle. Such feedback has been cited as a desirable attribute for ablation technology (39) and up to now has been missing.

Our study had several limitations. Although it is likely that nonenhancing areas at MR imaging represent necrosis, we do not have direct histologic evidence. Sampling error and misregistration limit the utility of core biopsies in this context. We have shown that the MR imaging appearances soon after HIFU treatment correlate with findings at 6 months, but this is not the same as outcome. A considerably longer follow-up and a larger number of patients will be necessary to determine both the ultimate efficacy of HIFU treatment and the ability of MR imaging to help predict outcome. Last, while our findings suggest that MR imaging soon after treatment may be useful to assess areas of under- and overtreatment, this is not real-time feedback and does not allow modification of the treatment as it progresses.

In summary, MR imaging results in the first 6 months after HIFU treatment show a consistent sequence of changes, and appearances in the 1st month correlate with serum PSA level nadir and imaging findings at 6 months. Such imaging results hold promise for providing feedback to the operator about the effectiveness of treatment.



  • Treatment of prostate cancer by using ablation with high-intensity focused ultrasound (HIFU) results in a consistent series of changes within the gland during 6 months seen at contrast-enhanced MR imaging.
  • Within 1 month after treatment, a central nonenhancing area is surrounded by an enhancing rim of tissue lying variably within and outside the prostate.
  • At 6 months, the gland is markedly smaller and of partly or completely low signal intensity on T2-weighted images.
  • The amount of enhancing prostate on the initial image correlates with several findings at 6 months, including serum prostate-specific antigen level nadir and prostate volume.



  • MR imaging after HIFU treatment may provide information about completeness of tumor ablation and the need for early retreatment or close monitoring in cases of incomplete coverage.



  • Trial registration: This trial started recruiting before the trial registration requirements of the International Committee of Medical Journal Editors were formalized.

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, A.P.S.K., I.M.H., C.A.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, A.P.S.K., M.E., I.M.H., R.O.I., C.A.; clinical studies, A.P.S.K., R.O.I., C.A.; statistical analysis, A.P.S.K.; and manuscript editing, all authors

Abbreviations:HIFU = high-intensity focused ultrasoundPSA = prostate-specific antigen



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