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Background: Breast cancer is the second important cause of cancer-related adults that mostly affects female. There are different diagnostic methods for detecting breast lesions, the specificity and sensitivity of which are very important in identifying multifocal lesions, since very few studies have been done on this issue so far, this study was done with the aims to Comparison identifying imaging diagnosis methods in multifocal and multicentric breast cancer patients. Materials and Methods: The current systematic review was done based on the Strengthening the Reporting of Observationally Studies in Epidemiology and Meta-Analyses of Observational Studies in Epidemiology. The primary keywords were published in reliable databases such as Pubmed, Elsevier, SID, Wiley in English were searched until the end of 2022. Two authors independently examined the articles in terms of data extraction, inclusion criteria, and quality assessment of the articles. Results: The age range from 496 samples was 57.3. Using the results of 5 published articles for MG and CESM, the overall specificity and sensitivity were 89% and 85%, respectively and for MRI, the overall specificity and sensitivity were 81% and 85%, respectively. Conclusion: The MRI method is the most sensitive tool for diagnosing BC in patients, but if a combination of new methods is used together, we will definitely achieve better results.
Breast cancer (BC) is the second important cause of cancer-related death a leading cause of death in female adults that mostly affects females [1]. In 2021, 280,000 cases of BC were diagnosed in the US, leading to over 43,000 deaths[2]. The BC prevalence in Iranian women is nearly 120 per 100000 people with an age-standardized rate of 33.21 per 100 000 people. The BC peak age is in the 4th and 5th decades [3].
The selection of systemic and local treatment for patients with BC depends on factors such as tissue type and tumor grade, primary tumor progress, lymph node status, presence of metastasis, and the status of tumor markers at the time of diagnosis [3,4]. The Multicentric and Multifocality of neoplastic lesions are decisive factors in choosing the type of treatment [5,6]. When there are 2 or more foci in one-quarter of the breast, it is called multi-focal type lesions, and when foci occur in different quadrants, it is called multi-focal type lesions [7,8]. The prevalence of multicentric and multifocal BC varies highly in the literature (6 - 60%) [9]. The main imaging modalities are magnetic resonance imaging (MRI), ultrasound (US), mammogram (MGM), and. Each modality has specific weaknesses and strengths in breast tumor evaluation [10,11]. Thus, multifocal (MF) and multicentric (MC) BC cases are increasing [12].
Among different attainable imaging techniques, mammography can detect neoplastic lesions in the breast as an inexpensive, reproducible, and available method [13]. Mammography (MG) sensitivity is associated with the breast structure. It reduces and ranges between 45% and about 60% in breasts, with a predominance of glandular tissue [14]. Particularly in women with dense breasts and young women, US is superior to MG, and differentiation between cysts and solid tumors is easier [15]. The specificity and sensitivity of US or MG are higher if US and MG are combined [16].
MRI, MG, extended with diffusion imaging (DWI/ADC) has a high level of septicity and sensitivity (over 85%) (18-20). In Akbari et al.’s study, the high sensitivity of MRI in identifying benign and malignant lesions is emphasized. Nonetheless, it has some limitations, such as false-positive results, leading to more aggressive treatment and management than necessary [17]. Opposite to MG, which underestimates the tumor size leading to incomplete resection, MRI is highly precise for the local extent of BC, carcinoma region, and tumor size. Also, some foci and carcinomas can be observed merely on breast MRI images [18].
Contrast-enhanced spectral mammography (CESM) as a novel recently developed technique was accepted by the FDA for clinical application in the US in 2011 [19]. It works based on imaging of tumor neoangiogenesis using a contrast compound (chelated iodine-associated X-ray contrast compound) [20]. The CESM sensitivity in diagnosing BC is over 90% [21]. As a result, in the present meta-analysis study, we had a comparison identifying imaging diagnosis methods such as ultrasound, MG, and MRI methods that were investigated for patients with multifocal and multicentric BC.
The current systematic review was done based on the Strengthening the Reporting of Observationally Studies in Epidemiology (STROBE) and Meta-Analyses of Observational Studies in Epidemiology (MOOSE) instructions for the review of analytical observational articles (cohort and case-control) [22,23].
All original studies were searched in Web of Science, Medline (PubMed), EMBASE, Scopus, and CINHAL from January 2017 to June 2022 with no language limitation. The keywords were BC, MRI, MG, US, and Multifocal. The included studies were observational studies on humans.
The initial search findings were reviewed, leading to the removal of some papers. Exclusion and inclusion criteria were set by two investigators separately (Figure 1).
(1) The original article, (2) human population, (3) Studies that only examined multifocal lesions in BC patients, (4) Studies that investigated the sensitivity and specificity of the methods considered in this study in multifocal lesions. (5) The detection power in the tumor size was not considered, only in the efficiency studies, the sensitivity and specificity of the method were the criteria for selecting the articles. Studies that investigated lesions other than multifocal in BC patients and did not report the sensitivity and specificity of the methods in identifying multifocal lesions were excluded from the study.
We detected 100 articles in databases. Duplicates (N = 20) were excluded. Based on the selection criteria, 80 abstracts were screened and 30 Records were excluded based on title/abstract. We detected 50 relevant published articles but after reading their full texts, 30 cases were excluded because of Reports excluded (n = 10), inconsistency with the objectives of the study (n = 7), not available full text (n = 3), and Review article (n = 4). Finally, 6 articles remained which include 1 cohort and 4 retrospective and 1 prospective (Figure 1).
The Quality Assessment Tool [24] assessed the quality of the quantitative studies. Using the STROBE list (Table 1), the quality of 30 articles was evaluated, and at least six appropriate articles were included. The examination of full-text articles was done before data extraction. The used list is the version developed based on an instrument designed by the Effective Public Health Practice Project [24].
| Title and abstract | 1 | (a) Indicate the study’s design with a commonly used term in the title or the abstract |
| (b) Provide in the abstract an informative and balanced summary of what was done and what was found | ||
| Introduction | ||
| Background/rationale | 2 | Explain the scientific background and rationale for the investigation being reported |
| Objectives | 3 | State specific objectives, including any prespecified hypotheses |
| Methods | ||
| Study design | 4 | Present key elements of study design early in the paper |
| Setting | 5 | Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection |
| Participants | 6 | (a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants |
| (b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposed Case-control study—For matched studies, give matching criteria and the number of controls per case |
||
| Variables | 7 | Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable |
| Data sources/ measurement |
8* | For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group |
| Bias | 9 | Describe any efforts to address potential sources of bias |
| Study size | 10 | Explain how the study size was arrived at |
| Quantitative variables | 11 | Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why |
| Statistical methods | 12 | (a) Describe all statistical methods, including those used to control for confounding |
| (b) Describe any methods used to examine subgroups and interactions | ||
| (c) Explain how missing data were addressed | ||
| (d) Cohort study—If applicable, explain how loss to follow-up was addressed | ||
| (c) Explain how missing data were addressed | ||
| (d) Cohort study—If applicable, explain how loss to follow-up was addressed Case-control study—If applicable, explain how matching of cases and controls was addressed Cross-sectional study—If applicable, describe analytical methods taking account of sampling strategy |
||
| (e) Describe any sensitivity analyses | ||
| Results | ||
| Participants | 13* | (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analyzed |
| (b) Give reasons for non-participation at each stage | ||
| (c) Consider use of a flow diagram | ||
| Descriptive data |
14* | (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders |
| (b) Indicate number of participants with missing data for each variable of interest | ||
| (c) Cohort study—Summaries follow-up time (eg, average and total amount) | ||
| Outcome data | 15* | Cohort study—Report numbers of outcome events or summary measures over time |
| Case-control study—Report numbers in each exposure category, or summary measures of exposure | ||
| Cross-sectional study—Report numbers of outcome events or summary measures | ||
| Main results | 16 | (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included |
| (b) Report category boundaries when continuous variables were categorized | ||
| (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period | ||
| Other analyses | 17 | Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses |
| Discussion | ||
| Key results | 18 | Summaries key results with reference to study objectives |
| Limitations | 19 | Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias |
| Interpretation | 20 | Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence |
| Generalizability | 21 | Discuss the generalizability (external validity) of the study results |
| Other information | ||
| Funding | 22 | Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based |
The articles were evaluated independently by two researchers who evaluated the possible disagreement, and when no agreement was made, a third author (LS) assessed the study. Data extraction was done by two independent matched reviewers based on a uniform Excel sheet. A checklist was applied to extract data, like (1) publication year, (2) author, (3) country (4) type of study, (5) Number sample, (6) age (7), Assessment (N) (8) MG, (9) MRI, (10) CESM and (11) US. Data has been assembled in Table 2.
| N Author Year Country |
Type of study | Number sample | Age (Mean) |
Assessment (N) | % | ||||||||||||||||||||||||||
| MG (multifocal ) | MG(unifocal | CESM(multifocal | CESM(unifocal | MRI(multifocal) | MRI(unifocal) | Mammography | MRI | CESM | Sonography | ||||||||||||||||||||||
| Specificity | Sensitivity | PPV | NPV | AUC | Specificity | Sensitivity | PPV | NPV | AUC | Specificity | Sensitivity | PPV | NPV | AUC | Specificity | Sensitivity | PPV | NPV | AUC | ||||||||||||
| Feng(29) | 2022 | China | retrospective | 54 | 48.7 | - | - | 178 | - | 183 | - | 36.4 | 99.4 | - | - | 95.7 | 63.6 | 98.3 | - | - | 96.3 | ||||||||||
| Ferranti(30) | 2022 | Italy | Prospective | 118 | 48.5 | Multifucal 20 |
47 | 99 | 88 | 90 | - | 50 | 10 | 92 | 100 | - | 76 | 97 | - | - | - | ||||||||||
| Steinhof R- (31) | 2021 | Poland | retrospective | 71 | 65 | 16 | 2 | 32 | 3 | 36 | 2 | 84.2 | 84.2 | 88.8 | 58.5 | - | 93.9 | 94.7 | 94.7 | 93.9 | - | 90.9 | 84.2 | 91.4 | 83.3 | - | |||||
| Steinhof-R (32) | 2021 | Poland | retrospective | 60 | 62 | 17 | 1 | 29 | 1 | 31 | 2 | 95.8 | 50 | 94.4 | 57.5 | - | 92.31 | 91.18 | 93.94 | 88.89 | - | 96.15 | 85.29 | 96.67 | 83.3 | - | |||||
| Walstra (33) |
2020 | Netherland | Cohort | 159 | 62 | 10 | 34 | - | - | 3 | 32 | 97.1 | 23.1 | 25 | 77.3 | 91.4 | 76.9 | 76.9 | 91.4 | - | |||||||||||
| Petrillo 34) |
2019 | Italy | retrospective | 34 | 58 | 3 | 20 | - | - | 1 | 12 | 79.6 | 81.5 | 84.1 | 76.5 | - | 83.7 | 90.8 | 88.1 | 87.2 | - | ||||||||||
For each study, false positive (FP), true positive (TP), false negative (FN), and true negative (TN) values were calculated. The homogeneity of results was evaluated by the results of Cochran’s Q test and the inconsistency index (I2) and random-effects model was applied to determine the overall effect. Forest plots with descriptions of the results were applied to explain the estimates of the accuracy measures (sensitivities, specificities, negative and positive likelihood ratios (LRs) receiver operating characteristic curve (ROC), and diagnostic odds ratios (dOR), describing the relationship between sensitivity and specificity of the test) with 95% confidence intervals (CIs). An area under the curve (AUC) close to 1 indicates the good diagnostic performance of the method. Meta-Disc 1.4 was used for all statistical analyses.
Overall, 6 studies were analyzed and their characteristics are shown in Table 2. All patients in this study underwent imaging examination prior to operation to screen those suspected of having multifocal/multicentric BCs. The final diagnosis was made considering pathology, so all studies had a histopathologic examination and were cross-sectional, originating in China (N = 1), Italy (N = 2), Poland (N = 2), and Nederland (N = 1) .1 of these studies were cohort studies and 4 were retrospective studies and 1 was prospective. The age range from (pooled data) 496 samples was 57.3. Statically designed studies for comparing imaging methods with the histopathologic examination were as fellow: 4 studies MRI and CESM (29-32),4 studies MG and MRI (31-34),1 study MG, MRI, and CESM (29), and 1 study MRI, CESM, and US (30). And finally, Feng’s (29) US results had been excluded from analyses because None of the other studies had investigated this issue.
Measurements of the overall accuracy of MG and contrast-enhanced spectral mammography (CESM) compared with the histopathologic examination in the detection of multifocal and multicentric breast cancer (MMBC):
Using the results of 5 published articles for MG and CESM, the overall specificity and sensitivity were 89% (95% CI: 84-93) and 85% (95% CI: 81-88), respectively (Figure 1). The pooled positive and negative likelihood ratios (LRs) were respectively 5.47 (95% CI: 2.53-11.83) and 0.24 (95% CI: 0.12-0.48) (Figure 2). Pooled diagnostic odds ratios (dOR) were high, at 49.90 (95% CI: 17.76-94.21) (Figure 3). The AUC for MG and CESM was 0.94 (Figure 4).
Measurements of the overall accuracy of MRI compared with a histopathologic examination in the detection of multifocal and multicentric breast cancer (MMBC):
Using the results of 5 published articles for MRI, the overall specificity and sensitivity were 81% (95% CI: 73-87) and 85% (95% CI: 81-88), respectively (Figure 5). The pooled positive and negative likelihood ratios (LRs) were also 4.67 (95% CI: 1.81-12.09) and 0.07 (95% CI: 0.03-0.19), respectively (Figure 6). The pooled diagnostic odds ratios (dOR) were high and were 91.70 (95% CI: 37.59-223.69) (Figure 7). The AUC for MRI was 0.96 (Figure 8).
