Description:
Nipple aspiration and/or ductal lavage are non-invasive techniques to obtain epithelial cells for cytological examination to aid in the evaluation of nipple discharge for breast cancer risk.

Regulatory Status
A search for “ductal lavage” and “nipple aspirate” on the FDA website on May 30, 2019 yielded no results. Additionally, many labs have developed specific tests that they must validate and perform in house.  These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88).  As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use. 

Policy:
Cytologic analysis of epithelial cells from nipple aspirations as a technique to assess breast cancer risk and manage patients at high risk of breast cancer is investigational and/or unproven and therefore is NOT MEDICALLY NECESSARY. Techniques of collecting nipple aspiration fluid, include, but are not limited to, ductal lavage and suction. 

Table of Terminology

Rationale
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women in the United States. Approximately 1 in 8 women will develop breast cancer in their lifetime and breast cancer alone makes up 30% of female cancers (Siegel et al., 2021; Siegel et al., 2019). Nipple discharge is a common breast complaint. Most nipple discharge is of benign origin; however, it is necessary to differentiate patients with benign nipple discharge from those who have an underlying pathology. In approximately 5-15 percent of pathologic nipple discharge cases, cancer is identified (Golshan, 2020).

Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. Cytological evaluation of epithelial cells in nipple discharge has been used as a diagnostic aid. Due to the scant cellularity of specimens obtained by expression or aspiration of nipple discharge, ductal lavage was developed to enhance the ease and efficiency of collecting breast epithelial cells for cytologic analysis. The analysis of breast-specific liquid biopsies, such as nipple aspirate fluid, has potential to be used as a biomarker profiling technique for monitoring breast health (Shaheed et al., 2018). Researchers report that the measurement of nipple aspirate fluid, including miRNA, pathological nipple discharge, and breast ductal fluids, may help to improve early detection and management of breast cancer (Moelans et al., 2019).

Analytic Validity
In a retrospective study of 618 patients with nipple discharge over a 14-year period, the sensitivity and specificity of cytology were 17 and 66 percent, respectively; the authors concluded that “nipple discharge cytology has little complementary diagnostic value” (Kooistra et al., 2009).

Clinical Utility and Validity
Hornberger et al. (2015) performed a meta-analysis on the use of nipple aspirate fluid (NAF) in identifying breast cancer based on proliferative epithelial disease (PED). The authors reviewed 16 articles, 20808 unique aspirations, and 17378 subjects. Among cancer-free patients, 51.5% aspirations contained fluid, of which 27.7% showed a PED on cytology. Of the two prospective studies of 7850 women, patients with abnormal cytology showed a 2.1-fold higher risk of developing breast cancer compared to those without fluid (Hornberger et al., 2015).

Chatterton et al. (2016) measured sex steroid levels in nipple aspirate fluid; hormones were measured in samples from 160 breast cancer cases and 157 controls. Results showed a significantly higher concentration of dehydroepiandrosterone (DHEA) in the nipple aspirate fluid of patients with breast cancer compared to controls; further, DHEA levels were highly correlated with estradiol levels, indicating “a potentially important role of this steroid in breast cancer risk” (Chatterton et al., 2016).

American Society of Breast Surgeons (ASBS) 
The Official Statement by the American Society of Breast Surgeons (ASBS, 2019) regarding Screening Mammography does not mention ductal lavage at all in their statement. 

In 2016, the ASBS published a consensus guideline on the concordance assessment of image-guided breast biopsies and the management of borderline or high-risk lesions. These guideline state that “The decision to excise a papillary lesion without atypia needs to be individualized based on risk, including such criteria as size; symptomatology, including palpability and presence of nipple discharge; and breast cancer risk factors” (ASBS, 2016). This is the only mention of nipple discharge in the document.

National Comprehensive Cancer Network (NCCN) 
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, breast cancer screening and diagnosis guidelines (NCCN, 2021) state that “current evidence does not support the routine use of ductal lavage as a screening procedure,” and that “ductal lavage is not recommended by the NCCN for breast cancer screening or diagnosis.”

Food and Drug Administration (FDA)
In 2017 the FDA issued a safety warning (FDA, 2017) stating that “the FDA is unaware of any valid scientific data to show that a nipple aspirate test, when used on its own, is an effective screening tool for any medical condition, including the detection of breast cancer or other breast disease.” 

American College of Radiology (ACR) 
In 2017, the ACR published appropriateness criteria for the evaluation of nipple discharge. These criteria state that “Cytologic examination of nipple discharge has not proven to be effective in differentiating benign from malignant lesions” (Lee et al., 2017).
 

References:  

1. ASBS. (2016). Consensus Guideline on Concordance Assessment of Image-Guided Breast Biopsies and Management of Borderline or High-Risk Lesions. Retrieved from https://www.breastsurgeons.org/docs/statements/Consensus-Guideline-on-Concordance-Assessment-of-Image-Guided-Breast-Biopsies.pdf
2. ASBS. (2019). Screening Mammography. Retrieved from https://www.breastsurgeons.org/docs/statements/Position-Statement-on-Screening-Mammography.pdf
3. Chatterton, R. T., Heinz, R. E., Fought, A. J., Ivancic, D., Shappell, C., Allu, S., . . . Khan, S. A. (2016). Nipple Aspirate Fluid Hormone Concentrations and Breast Cancer Risk. Horm Cancer, 7(2), 127-136. doi:10.1007/s12672-016-0252-7
4. FDA. (2017). Nipple Aspirate Test Is No Substitute for Mammogram. Retrieved from https://www.fda.gov/consumers/consumer-updates/nipple-aspirate-test-no-substitute-mammogram
5. Golshan, M. (2018). Nipple discharge - UpToDate. In W. Chen (Ed.), UpToDate. Retrieved from https://www.uptodate.com/contents/nipple-discharge?source=search_result&search=nipple%20lavage&selectedTitle=1~150#H27
6. Golshan, M. (2020). Nipple discharge - UpToDate. In W. Chen (Ed.), UpToDate. Retrieved from https://www.uptodate.com/contents/nipple-discharge?source=search_result&search=nipple%20lavage&selectedTitle=1~150#H27
7. Hornberger, J., Chen, S. C., Li, Q., Kakad, P., & Quay, S. C. (2015). Proliferative epithelial disease identified in nipple aspirate fluid and risk of developing breast cancer: a systematic review. Curr Med Res Opin, 31(2), 253-262. doi:10.1185/03007995.2014.988209
8. Kooistra, B. W., Wauters, C., van de Ven, S., & Strobbe, L. (2009). The diagnostic value of nipple discharge cytology in 618 consecutive patients. Eur J Surg Oncol, 35(6), 573-577. doi:10.1016/j.ejso.2008.09.009
9. Lee, S. J., Trikha, S., Moy, L., Baron, P., diFlorio, R. M., Green, E. D., . . . Newell, M. S. (2017). ACR Appropriateness Criteria(®) Evaluation of Nipple Discharge. J Am Coll Radiol, 14(5s), S138-s153. doi:10.1016/j.jacr.2017.01.030
10. Moelans, C. B., Patuleia, S. I. S., van Gils, C. H., van der Wall, E., & van Diest, P. J. (2019). Application of Nipple Aspirate Fluid miRNA Profiles for Early Breast Cancer Detection and Management. Int J Mol Sci, 20(22). doi:10.3390/ijms20225814
11. NCCN. (2019). NCCN Clinical Practice Guidelines in Oncology; Breast Cancer Screening and Diagnosis v1.2019. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf. from National Comprehensive Cancer Network https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf
12. NCCN. (2021). NCCN Clinical Practice Guidelines in Oncology; Breast Cancer Screening and Diagnosis V1.2021. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf. from National Comprehensive Cancer Network https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf
13. Shaheed, S. U., Tait, C., Kyriacou, K., Linforth, R., Salhab, M., & Sutton, C. (2018). Evaluation of nipple aspirate fluid as a diagnostic tool for early detection of breast cancer. Clin Proteomics, 15, 3. doi:10.1186/s12014-017-9179-4
14. Siegel, R. L., Miller, K. D., Fuchs, H. E., & Jemal, A. (2021). Cancer Statistics, 2021. CA Cancer J Clin, 71(1), 7-33. doi:10.3322/caac.21654
15. Siegel, R. L., Miller, K. D., & Jemal, A. (2019). Cancer statistics, 2019. CA Cancer J Clin, 69(1), 7-34. doi:10.3322/caac.21551

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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