Accuracy for Cytological Evaluation in the Detection of Breast Cancer Among Patients with Pathologic Nipple Discharge: A PRISMA-Compliant Meta-Analysis
Nipple discharge refers to the passage of liquid material through the nipple of the breast and is a common complaint among patients with breast disease. It is often indicative of a possible intraductal lesion and requires further evaluation. While nipple discharge is most commonly caused by benign conditions such as intraductal papilloma or duct ectasia, it can also be associated with malignancies like ductal carcinoma in situ and invasive ductal carcinoma. Diagnostic imaging methods, including mammography and high-frequency ultrasound, are often used to evaluate patients with pathological nipple discharge. However, these methods may not always detect abnormalities, particularly in cases of non-palpable breast cancer. Magnetic resonance imaging (MRI) has been suggested as an alternative, but its value is limited in patients with unilateral bloody nipple discharge and no detectable masses. Given the limitations of these imaging techniques, nipple discharge cytology has emerged as a simple, non-invasive, and cost-effective method for detecting underlying malignancies.
Nipple discharge cytology involves the microscopic examination of cells obtained from the nipple discharge. This method has been studied extensively, but the results have been highly variable. To address this variability, the present study conducted a systematic review and meta-analysis of published studies to evaluate the diagnostic accuracy of nipple discharge cytology in detecting breast cancer among patients with pathological nipple discharge.
The study began with a systematic literature search of databases, including Medline/PubMed, Embase, the Cochrane Library, and Google Scholar. The search focused on studies published between January 2000 and October 2018 that investigated the diagnostic capacity of nipple discharge cytology in patients with pathological nipple discharge. The inclusion criteria required that studies provide histopathological confirmation of breast cancer diagnoses, include patients with nipple discharge, and provide sufficient data to calculate sensitivity and specificity. Studies were excluded if they were case reports, review articles, or lacked sufficient data. Ultimately, 12 studies involving 1,476 patients were included in the meta-analysis.
The quality of the included studies was assessed using the Methodological Index for Non-randomized Studies (MINORS) and the Quality Assessment of Diagnostic Accuracy Study 2 (QUADAS-2) tools. These tools evaluate the risk of bias and the applicability of the studies. Heterogeneity among the studies was tested using the Cochran Q test and the I² statistic. A random-effects model was used to perform the meta-analysis, and the results were summarized using pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio. The area under the summary receiver operating characteristic (SROC) curve was also calculated to assess diagnostic accuracy.
The meta-analysis revealed that nipple discharge cytology had a pooled sensitivity of 63% (95% confidence interval [CI]: 53%–72%) and a specificity of 95% (95% CI: 87%–98%). The positive likelihood ratio was 12.35 (95% CI: 4.87–31.34), indicating that patients with breast cancer were nearly 12 times more likely to have a positive cytology result than those without breast cancer. The negative likelihood ratio was 0.39 (95% CI: 0.30–0.50), suggesting that a negative cytology result reduced the likelihood of breast cancer. The diagnostic odds ratio was 31.88 (95% CI: 11.30–89.98), further supporting the diagnostic value of nipple discharge cytology. The area under the SROC curve was 0.79 (95% CI: 0.75–0.82), indicating good diagnostic accuracy.
The studies included in the meta-analysis were conducted in various countries, including China, the United States, Japan, and Bulgaria. The sample sizes ranged from 27 to 434 patients. Nipple discharge was obtained using two primary methods: squeezing the nipple and ductal lavage. The latter method, which includes the ThinPrep cytology test (TCT), was associated with lower heterogeneity and higher reliability in the diagnosis of breast cancer. Squeezing the nipple, while simpler, was associated with greater heterogeneity, possibly due to variations in the amount and quality of cells obtained.
Heterogeneity among the studies was significant, particularly for specificity (I² = 91.77%). However, meta-regression analysis suggested that the heterogeneity was not due to differences in the regions of the study populations, methods of obtaining nipple discharge, or sample sizes. Subgroup analysis revealed that the method of obtaining nipple discharge was a major source of heterogeneity, with ductal lavage showing lower heterogeneity compared to squeezing the nipple.
The study also assessed publication bias using Deeks’ funnel regression method, which indicated no significant publication bias (P = 0.169). Sensitivity analysis, in which each study was sequentially eliminated and the results were reanalyzed, confirmed the stability of the findings.
The diagnostic value of nipple discharge cytology was further supported by comparisons with other diagnostic methods. Galactography, for example, has a reported sensitivity of 56.3% to 83.0% and a specificity of 26.7% to 62.4%. Fiberoptic ductoscopy (FDS) has a sensitivity of 55.2% to 94.2% and a specificity of 61.5% to 100%. While these methods have their strengths, they are often invasive and may not provide consistent results. Nipple discharge cytology, on the other hand, is non-invasive and can be performed repeatedly, making it a valuable complementary tool in the diagnosis of breast cancer.
Despite its strengths, the study has several limitations. Nine of the twelve included studies were conducted in Asian countries, which may limit the generalizability of the findings to other populations. Additionally, the heterogeneity in specificity suggests that further research is needed to standardize the diagnostic criteria for nipple discharge cytology. The inclusion of studies with different thresholds for positive cytology results may also have contributed to the variability in the findings.
In conclusion, the meta-analysis demonstrates that nipple discharge cytology is a useful diagnostic modality for detecting breast cancer in patients with pathological nipple discharge. It offers moderate sensitivity and high specificity, making it a valuable tool in the diagnostic process. The method of obtaining nipple discharge, particularly ductal lavage, plays a significant role in the accuracy and reliability of the results. Future multicenter studies with larger sample sizes are needed to further validate these findings and to establish standardized diagnostic criteria.
doi.org/10.1097/CM9.0000000000000643
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