Proliferative epithelial disease identified in nipple aspirate fluid and risk of developing breast cancer: a systematic review

Figures & data

Table 1. Search terms.

No.	Search terms^a	Category	Hits
1	breast OR mammary OR nipple	Site/Specimen	376,482
2	aspirate* OR (aspirate fluid) OR (aspirate specimen)		23,002
3	1 AND 2		1716
4	cytolog* OR cytopatholog*	Method	863,772
5	epitheli* OR exfoliat*		375,257
6	4 OR 5		1,154,066
7	risk factor* OR epidemiolog*	Outcomes	1,695,774
8	hyperplasia OR ductal OR patholog* OR disease* OR cancer OR neoplasms OR precancerous		6,269,714
9	mortality OR death OR die		1,204,252
10	8 OR 9		6,817,466
11	inciden* OR prevalen* OR rate OR risk		3,385,485
12	10 AND 11		1,620,320
13	7 OR 12		2,634,741
14	3 AND 6 AND 13	Results	262
	Limitations: Humans, English, published by October 2013		241

^aAsterisks represent truncation in PubMed search. For example, a search with “aspirate*” will capture all terms that have the root “aspirate”.

Figure 1. Flow diagram of the systematic search and screening. Updating reports or subgroup analyses were excluded from analysis but discussed along with the results from the representative publication of the corresponding populations. The 7 articles identified by citation search and reference review included Buehring38, Filassi20, King (Part II)22, Krishnamurthy23, Papanicolaou12, Petrakis (Environ Health Perspect)36, and Proctor25. FNA, fine-needle aspiration.

Table 2. Association of cytological finding and carcinoma outcomes.

Study	Study description	Cytological Subgroup	Number of subjects (% of total)	% with breast carcinoma	Association measure^a and 95% CI	p Value
King classification
Wrensch et al.30	Long-term follow-up of subjects free of cancer at study entry and within 6 months of study entry (Group 1 from breast screening center, variety of clinics and health fairs; Group 2 from breast and other clinic patients and UCSF employees)	No NAF	2775 (40.2)	3.7	RR^b (referent)
		Scant cells	453 (6.6)	7.5	1.2 (0.8–1.7)	–
		Normal cells	2627 (38.1)	6.6	1.3 (1.0–1.7)	–
		Hyperplasia	940 (13.6)	8.2	2.0 (1.5–2.8)	–
		Atypia	109 (1.6)	11.0	2.1 (1.1–3.9)	–
Baltzell et al.17		Long-term follow-up of cohort seen by Sartorius at SB breast clinic (free of cancer at initial visit and within 6 months of initial visit)	No NAF	714 (75)	9	OR^c (referent)
	Scant cells		19 (2)	11	1.4 (0.32–6.4)	0.64
	Normal cells		89 (9)	12	1.7 (0.87–3.5)	0.12
			Hyperplasia or atypia	124 (13)	14	2.0^d (1.1–3.6)	0.02
Sauter et al.32^e	Cross-sectional comparison of NAF from mastectomy against histological results (breasts having undergone excisional biopsy demonstrating DCIS or IBC; mastectomy performed after excisional biopsy)	Scant cells or no atypia	57 (79.2)	43.9	–	<0.001
		Atypia or malignant	15 (20.8)	93.3	–
Papanicolaou classification
Buehring et al.18	Long-term follow-up of subjects that were mostly asymptomatic, self-selected by responding to appeals through newspapers and television, posted announcements, and oral presentations	No NAF	517 (53.2)	11.6	RR^f (referent)	≤0.005
		No cells	316 (32.5)	11.0	1.05 (0.71–4.57)
		Any cells	139 (14.3)	18.3	1.92 (1.22–3.01)
Papanicolaou et al.12		Cross-sectional comparison of NAF and clinical & pathological findings. Three groups: (1) secretion smears from women without breast complaints; (2) secretion smears obtained at the breast clinics from patients with symptoms of breast disease; (3) secretion smears from one breast in patients who either had carcinoma present in the other breast or had had unilateral mastectomy for carcinoma	No NAF	1703 (55.0)	0.4	–	–
	Class I		534 (17.3)	0.6	–	–
	Class I–II		506 (16.4)	1.8	–	–
	Class II		278 (9.0)	2.9	–	–
	Class CD		39 (1.3)	10.3	–	–
	Class III		15 (0.5)	66.7	–	–
	Class IV		4 (0.1)	100.0	–	–
	Class V		15 (0.5)	100.0	–	–
The NCI FNA criteria
Krishnamurthy et al.23	Cross-sectional comparison of NAF from affected breasts and histopathologic findings in women with biopsy confirmed intraductal or invasive carcinoma with or without a history of preoperative neoadjuvant chemotherapy	Scant cells	30 (40.5)	0.0	–	–
		Normal cells	34 (45.9)	85.2	–	–
		Mild atypia	5 (6.8)	20.0	–	–
		Marked atypia	1 (1.4)	100.0	–	–
		Malignancy	4 (5.4)	100.0	–	–
Other cytological classification system
Zimmerman et al.31	Cross-sectional comparison of NAF and histological diagnosis	No epithelial groups	1552 (41.2)	0.5	–	–
		Epithelial groups	2218 (58.8)	1.2	–	–
Cytological classification system not reported
Sauter et al.29	Cross-sectional comparison of NAF and histopathologic results in women with a suspicious breast lesion identified on an imaging study and/or a solid palpable breast mass, prior to scheduled excisional breast biopsy	Scant cells	107 (70.4)	31.8	–	–
		No atypia	39 (25.7)	48.7	–	–
		Atypia	4 (2.6)	50.0	–	–
		Malignant	2 (1.3)	100.0	–	–

^aOdds ratio (OR) or risk ratio/relative risk (RR) reported by the studies. If no direct report, the cell was left with a hyphen.

^bAdjusted by Cox regression for age, age squared, and year of specimen collection.

^cAdjusted for age at the time of the NAF visit.

^dUsing the equation RR = OR/(1 − ACR × (1 − OR)), the corresponding RRs are 1.4 for ‘scant cells’, 1.6 for ‘normal cells’, and 1.8 for ‘hyperplasia or atypia’. ACR, assumed control risk.

^eThis study analyzed residual cancer in mastectomy specimens with histological review.

^fAdjusted for age and length of time in study as continuous variables.

NAF, nipple aspirate fluid; DCIS, ductal carcinoma in situ; IBC, invasive breast cancer; NCI, National Cancer Institute; FNA, fine-needle aspiration.

Table 3. Cytological classification system (King)^a.

Cytological group	Description
No NAF	Nipple aspiration attempted, but fluid not obtained.
NAF/scant cells	Specimen obtained, but unsatisfactory for cytological diagnosis, e.g., less than 10 cells in specimen or unacceptable technical quality.
NAF/benign	Duct epithelial cells within normal limits; foam cells; apocrine metaplastic cells.
NAF/hyperplasia	Minimal changes, slight cell and nuclear enlargement; cell distribution predominantly in groups; papillary grouping – a subcategory; apocrine type – a subcategory.
NAF/atypia	Moderate-to-severe abnormality, distinct nuclear enlargement, increasing N:C alteration and chromatin change; cell distribution in groups and papillary formations; single cells increase in numbers with increasing degree of abnormality; apocrine type – a subcategory.
NAF/malignancy	Single cells and groups of cells with unequivocal nuclear features of cancer.

^aTable adapted from King et al. Nipple aspirate cytology for the study of breast cancer precursors. J Natl Cancer Inst 1983;71:1115-2140, with permission. Content in JNCI published prior to 1997 is in the public domain for reuse.

NAF, nipple aspirate fluid; N:C, nuclear-to-cytoplasmic ratio.

Figure 2. Assessment of risk of bias. Sartorius26 reported two studies, thus there were 17 studies from 16 articles.

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