Gabriella Risso

Accuracy of fine needle aspiration cytology (FNAC) of axillary lymph nodes as a triage test in breast cancer staging

IntroductionAxillary node fine needle aspiration cytology (FNAC) has the potential to triage women with operable breast cancer to initial nodal surgical procedure. Because of variability in the reported accuracy of this test its role and clinical utility in pre-operative staging remains controversial.MethodsWe retrospectively evaluated the accuracy of ultrasound-guided axillary FNAC in all consecutive clinically T1–2 N0–1 breast cancers that had undergone this test (491 biopsies). We included subjects with clinically or sonographically indeterminate or suspicious nodes. Pathological node status was used as the reference standard (based on axillary dissection or sentinel node biopsy).ResultsSensitivity of node FNAC was 72.6% (67.3–77.9) and specificity was 95.7% (92.5–98.8) for all cases, sensitivity was lower at 64.6% (59.3–70.0) if inadequate cytology was included as a negative result. FNAC sensitivity was highest in women with clinically suspicious nodes [92.5% (88.2–96.7)] and lowest in women with sonographically abnormal and clinically negative nodes [50.0% (41.3–58.7)]. Specificity was high in both groups, 81.2% (54.5–96.0) and 97.2% (94.6–99.9), respectively. The false-negative rate was 15.3% (12.1–18.5), the false-positive rate was 1.4% (0.4–2.5), and the inadequacy rate was 10.8% (8.0–13.5). The likelihood of node FNAC being positive was significantly associated with tumour grade and stage, and the number of nodes involved with metastases.DiscussionOur data show that axillary FNAC has moderate sensitivity (which varies according to selection criteria for the test) and consistently high specificity, is associated with low inadequacy and very few false positives. We estimate that its use would have improved triage to initial nodal procedure in about one quarter of our cases. If one accepts the premise that initial surgical staging of the axilla should be based on all information available through pre-operative diagnosis, then axillary FNAC should be adopted routinely into clinical practice.

Comparison of standard reading and computer aided detection (CAD) on a national proficiency test of screening mammography

OBJECTIVE To evaluate the role of computer aided detection (CAD) in improving the interpretation of screening mammograms MATERIAL AND METHODS Ten radiologists underwent a proficiency test of screening mammography first by conventional reading and then with the help of CAD. Radiologists were blinded to test results for the whole study duration. Results of conventional and CAD reading were compared in terms of sensitivity and recall rate. Double reading was simulated combining conventional readings of four expert radiologists and compared with CAD reading. RESULTS Considering all ten readings, cancer was identified in 146 or 153 of 170 cases (85.8 vs. 90.0%; chi(2)=0.99, df=1, P=0.31) and recalls were 106 or 152 of 1330 cases (7.9 vs. 11.4%; chi(2)=8.69, df=1, P=0.003) at conventional or CAD reading, respectively. CAD reading was essentially the same (sensitivity 97.0 vs. 96.0%; chi(2)=7.1, df=1, P=0.93; recall rate 10.7 vs. 10.6%; chi(2)=1.5, df=1, P=0.96) as compared with simulated conventional double reading. CONCLUSION CAD reading seems to improve the sensitivity of conventional reading while reducing specificity, both effects being of limited size. CAD reading had almost the same performance of simulated conventional double reading, suggesting a possible use of CAD which needs to be confirmed by further studies inclusive of cost-effective analysis.

NEGLIGIBLE ADVANTAGES AND EXCESS COSTS OF ROUTINE ADDITION OF BREAST ULTRASONOGRAPHY TO MAMMOGRAPHY IN DENSE BREASTS

Aim To assess the role of breast ultrasonography as a complement to negative mammography in radiologically dense breasts. Material and methods Out of a total series of 49,044 consecutive mammograms reported as negative in asymptomatic women, 25,665 (52.3%) were coded as dense (BI-RADS D3–4) and ultrasonography was recommended. Due to organizational problems, ultrasonography was performed immediately or within 1 month only in 5,227 cases, representing the study series. Results Two cancers were detected at immediate ultrasonography (0.03%). The cancer detection rate in women aged 40–49 and 50–69 years was 0.002% and 0.07%, respectively. The benign biopsy rate was 0.5% for core biopsies and 0.02% for surgical biopsies. The cost per ultrasonography-assessed woman was € 56.05, whereas the cost per additional mammographically occult but ultrasonography-detected cancer was € 146,496.53. The mammograms of the 2 cancer cases underwent blind review by an expert reader and were confirmed as negative. Discussion Our findings show a low cancer detection rate, substantially lower compared to other clinical studies of ultrasonography in dense breasts, though in accordance with preliminary evidence from an Italian randomized clinical trial within a population-based screening program. The policy of adding ultrasonography to negative mammography in dense breasts seems to have very limited cost-effectiveness, and should not be adopted in routine practice before results of ongoing clinical trials are available.

Breast fine-needle aspiration malondialdehyde deoxyguanosine adduct in breast cancer

Abstract This study has analysed the generation of 3-(2-deoxy-β-D-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine adduct [M1dG], a biomarker of oxidative stress and lipid peroxidation, in breast fine-needle aspirate samples of 22 patients with breast cancer, at different clinical stages, in respect to 13 controls. The multivariate analysis show that M1dG adduct was higher in cases than in controls (Mean Ratio (MR) = 5.26, 95% CI = 3.16–8.77). Increased M1dG was observed in women with a tumour grade 3 and a pathological diameter 2 (MR = 7.61, 95% CI = 3.91–14.80 and MR = 5.75, 95% CI = 3.13–10.59, respectively). A trend with increasing tumour grade and pathological diameter was present (MR = 1.98, 95% CI = 1.57–2.50 and MR = 2.44, 95% CI = 1.71–3.48, respectively). Not significant effects of age and smoking habit were found (MR = 1.58, 95% CI = 0.92–2.72 and MR = 1.68, 95% CI 0.88–3.20, respectively). An increment over the background frequency of M1dG can contribute to breast cancer development. Increasing severity of breast tumour can influence DNA damage level.

The role of arbitration of discordant reports at double reading of screening mammograms

Objective: To asses the effectiveness of arbitration of discordant double readings in mammography screening. Design: A retrospective study of 1217 consecutive arbitrations. Setting: A subset of discordant double readings from the Florence screening programme underwent arbitration by a third reader. Results: Positive arbitration of 1217 discordant double readings prompted assessment in 476 cases (39.2%), detecting 30 cancers (6.3%). Of 741 negative arbitrations (60.8%), 311 have been followed up thus far, and two cancers (0.64%) occurred in the site previously suspected at one of the two independent readings. Arbitration had a sensitivity of 86.3% and a negative predictive value of 99.3%. Arbitration reduced the overall referral rates from 3.82% to 2.59% (relative decrease 32.1%). Due to false-negative arbitration, cancers detected per 1000 women screened would decrease from 4.58 to 4.50 (relative decrease 1.7%). For every cancer missed due to false-negative arbitration, 151 unnecessary recalls and €21,248 would have been saved, whereas the saved cost per screened woman due to arbitration was €1.72. Discussion: Arbitration of discordant double reading would substantially reduce referral rates with a limited reduction in cancer detection rate, and may be recommended as a routine procedure. Greater benefit from arbitration might be expected in the presence of high referral rates at independent double reading, a common scenario in a newly implemented service screening.

Accuracy of needle biopsy of breast lesions visible on ultrasound: audit of fine needle versus core needle biopsy in 3233 consecutive samplings with ascertained outcomes.

INTRODUCTION Core needle biopsy (CNB) has progressively replaced fine needle aspiration cytology (FNAC) in the diagnosis of breast lesions. Less information is available on how these tests perform for biopsy of ultrasound (US) visible breast lesions. This study examines the outcomes of CNB and FNAC in a large series ascertained with surgical histology or clinical-imaging follow-up. MATERIALS AND METHODS Retrospective five-year audit of 3233 consecutive US-guided needle samplings of solid breast lesions, from self-referred symptomatic or asymptomatic subjects, performed by six radiologists in the same time-frame (2003-2006): 1950 FNAC and 1283 CNB. The probability of undergoing CNB as a first test instead of FNAC was evaluated using logistic regression. Accuracy and inadequacy were calculated for each of CNB and FNAC performed as first test. Accuracy measures included equivocal or borderline/atypical lesions as positive results. RESULTS The probability of CNB as a first test instead of FNAC increased significantly over time, when there was a pre-test higher level of suspicion, in younger (relative to older) women, with increasing lesion size on imaging, and for palpable (relative to impalpable) lesions. Inadequacy rate was lower for CNB (B1 = 6.9%) than for FNAC (C1 = 17.7%), p < 0.001, and specifically in malignant lesions (B1 = 0.9% vs. C1 = 4.5%; p < 0.001). False negative rate was equally low for both CNB and FNAC (1.7% each test). CNB performed significantly better than FNAC for absolute sensitivity (93.1% vs. 74.4%; p < 0.001) and complete sensitivity (97.4% vs. 93.8%; p = 0.001), however specificity was lower for CNB than FNAC (88.3% vs. 96.4%; p < 0.001). Absolute diagnostic accuracy was higher for CNB than FNAC (84.5% vs. 71.9; p < 0.001) while FNAC performed better than CNB for complete diagnostic accuracy (95.4% vs. 93.2; p < 0.008). In the small subgroup assessed with CNB after an inconclusive initial FNAC (231 cases) there was improved complete sensitivity (from 93.8% to 97.0%) however this also increased costs. CONCLUSION FNAC and CNB were generally performed in different patients, thus our study reported indirect comparisons of these tests. Although FNAC performed well (except for relatively high inadequacy), CNB had significantly better performance based on measures of sensitivity, but this was associated with lower specificity for CNB relative to FNAC. Overall, CNB is the more reliable biopsy method for sonographically-visible lesions; where FNAC is used as the first-line test, inadequate or inconclusive FNAC can be largely resolved by using repeat sampling with CNB.

Florence–Sydney Breast Biopsy Study: sensitivity of ultrasound-guided versus freehand fine needle biopsy of palpable breast cancer

Background. Fine needle aspiration biopsy (FNAB) is widely used in the diagnosis of breast cancer. It is unknown whether, for palpable cancers, ultrasound-guided FNAB is more accurate than freehand FNAB, and practice varies between physicians, services and countries.Methods. From consecutive women attending a major cancer centre in Florence, we prospectively recruited subjects who had a definitely palpable lump which was solid on ultrasound and suspicious of malignancy (n=102). All subjects were investigated using both ultrasound-guided and freehand FNAB (one aspirate with each method). Radiologists skilled in both sampling techniques performed all clinical examinations and aspirations, and for each subject the same radiologist obtained both FNAB samples. Sequence of aspiration method was randomised. Cytological interpretation was blinded to method of sampling. Comparative sensitivity (and insufficiency) for FNAB using the two methods was calculated in all cancers (n=97).Results. Ultrasound-guided FNAB resulted in 13.6% (5–22%) less insufficient aspirates than freehand FNAB (χ2=7.58; p=0.006). When insufficient aspirates are included and considered as negative, ultrasound-guided FNAB has a 14.6% (5.8–23%) or a 16.5% (7.6–25.4%) significantly better sensitivity than freehand FNAB (for cytology 3–5 positive or cytology 4–5 positive respectively). When insufficient aspirates are excluded from the analysis, ultrasound-guided FNAB has a 1.4% (−1.2 to 3.9%) or a 2.6% (−2.5 to 7.8%) higher sensitivity than freehand FNAB (for cytology 3–5 positive or cytology 4–5 positive respectively) but this difference in the sensitivity of the two methods is not statistically significant.Conclusion. Our data suggest that ultrasound-guided FNAB has better sensitivity than freehand FNAB in palpable breast cancer, which is predominantly an effect of a significant reduction in insufficient aspirates, but in part an effect of ‘upgrading’ cytological classification of cancers.

8-Oxo-7,8-dihydro-2′-deoxyguanosine and other lesions along the coding strand of the exon 5 of the tumour suppressor gene P53 in a breast cancer case-control study

The next-generation sequencing studies of breast cancer have reported that the tumour suppressor P53 (TP53) gene is mutated in more than 40% of the tumours. We studied the levels of oxidative lesions, including 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), along the coding strand of the exon 5 in breast cancer patients as well as in a reactive oxygen species (ROS)-attacked breast cancer cell line using the ligation-mediated polymerase chain reaction technique. We detected a significant ‘in vitro’ generation of 8-oxodG between the codons 163 and 175, corresponding to a TP53 region with high mutation prevalence, after treatment with xanthine plus xanthine oxidase, a ROS-generating system. Then, we evaluated the occurrence of oxidative lesions in the DNA-binding domain of the TP53 in the core needle biopsies of 113 of women undergoing breast investigation for diagnostic purpose. An increment of oxidative damage at the −G− residues into the codons 163 and 175 was found in the cancer cases as compared to the controls. We found significant associations with the pathological stage and the histological grade of tumours. As the major news of this study, this largest analysis of genomic footprinting of oxidative lesions at the TP53 sequence level to date provided a first roadmap describing the signatures of oxidative lesions in human breast cancer. Our results provide evidence that the generation of oxidative lesions at single nucleotide resolution is not an event highly stochastic, but causes a characteristic pattern of DNA lesions at the site of mutations in the TP53, suggesting causal relationship between oxidative DNA adducts and breast cancer.