Prognostic significance of a positive axillary lymph node fine-needle aspirate in patients with invasive breast carcinoma
Martin C. Chang MD, PhD,
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
Corresponding author: Martin C. Chang, MD, PhD, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, 6-500, Toronto, ON M5G 1X5, Canada; Fax: (416) 586-8628; email@example.com
This study was presented in abstract form at the 18th International Congress of Cytology held in Paris, France, in May 2013.
Image-guided axillary lymph node fine-needle aspirates (FNAs) correlate well with pathologic lymph node staging in cases of invasive breast carcinoma. The objective of this study was to determine the prognostic significance of a positive lymph node.
Consecutive cases of nonmetastatic (M0) invasive breast carcinoma evaluated by image-guided FNA were identified (4-year period, median follow-up of 51 months). “Positive” and “nonpositive” groups were compared using Kaplan-Meier survival analysis. Multivariate Cox regression was used to correct for clinicopathologic and treatment factors. A total of 142 cases was included, 70 with positive axillary FNA and 72 with a nonpositive result.
FNA-positive and nonpositive cases did not differ in patient age, tumor subtype, or hormone receptor status. Positive FNA was significantly associated with advanced T and N pathologic stage, and with HER2 (human epidermal growth factor receptor 2) positivity. FNA-positive patients were more likely to undergo mastectomy and to receive chemotherapy. Kaplan-Meier analysis showed that positive FNA is associated with poor prognosis, both with respect to disease-free survival (89% nonpositive versus 73% positive at 5 years, P < .001) and overall survival (94% versus 81%, respectively, at 5 years, P = .01). Multivariate analysis showed that when correcting for other variables, FNA positivity was not independently significant.
Preoperative evaluation of the axillary lymph nodes has become standard in the management of patients with carcinoma of the breast.[1-7] It is playing an increasing role in the planning of further management, including surgical approach[7-10] and neoadjuvant systemic therapy.[11, 12] Definitive nodal staging is based on surgical pathologic evaluation of sentinel lymph node(s) or axillary dissection specimens.[13, 14] However, axillary imaging combined with image-guided fine-needle aspiration (FNA) of selected lymph nodes has proven successful in detecting lymph node metastases prior to surgical management.[15-19] Studies correlating axillary FNA with final pathologic staging have demonstrated the excellent positive predictive value of axillary lymph node FNA.[20-23] However, there is a lack of data correlating patient outcome with axillary FNA status.
Neoadjuvant treatment is being used increasingly, not only for cases considered inoperable, but for any case in which preoperative evaluation demonstrates a potential benefit for cytotoxic chemotherapy.[24-26] This depends not only on size, estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 oncoprotein (HER2) status, but also on the result of diagnostic axillary FNA.[11, 12] In a significant subset of neoadjuvant cases, subsequent surgical staging is challenging because of complete or near-complete treatment response of the tumor. Axillary lymph node FNA is therefore increasing in importance as the first, and sometimes only, opportunity to obtain a tissue-based diagnosis of nodal spread. Although the sensitivity and specificity of axillary lymph node FNA is well established,[12, 21, 23] its independent significance as a prognostic marker of tumor stage is unclear.
The purpose of this study was to determine the prognostic significance of a positive axillary FNA in cases of invasive breast carcinoma, rather than simply its positive predictive value relative to a subsequent resection specimen. Clinical follow-up data was analyzed, and clinicopathologic features of disease were compared between FNA-positive and FNA-nonpositive cases to assess the value of FNA positivity in preoperative staging.
MATERIALS AND METHODS
A case search was performed, in accordance with the protocol approved by our institutional research ethics board. Consecutive cases (during the period January 1, 2005, to December 31, 2008) were identified based on the availability of an image-guided axillary lymph node FNA sample, obtained during the work-up of a primary biopsy-proven invasive breast carcinoma. Cases were excluded if only ductal carcinoma in situ was present or if the invasive carcinoma was considered to be a recurrence of a prior incident carcinoma. Cases were also excluded if the patient had distant metastases at presentation. In all included cases, the carcinoma was surgically excised (either by breast-conserving surgery with radiation or by total mastectomy). The resulting cohort overlapped with, but was not identical to, our previous study of clinicoradiologic correlation.
The clinical and pathologic reports were reviewed to determine the patient age, tumor stage (T classification and N classification), tumor characteristics (histologic type, histologic grade, ER, PgR, HER2 status), surgical treatment (breast-conserving surgery or mastectomy), and whether cytotoxic chemotherapy was given (either adjuvant or neoadjuvant). In our cohort, treatment with hormonal agents depended primarily on ER/PgR status and treatment with trastuzumab on HER2 status. To distinguish between pN0 and pN1 nodal stages, a positive lymph node was defined as having a micrometastasis or a macrometastasis (ie, having a largest deposit of >0.2 mm).
The cytopathologic findings for each case were reviewed to confirm the diagnosis. For our analysis, a “positive” case was defined as being fully diagnostic for malignancy. A “nonpositive” case could be either “suspicious,” “atypical,” “nondiagnostic,” or “negative.” The performance of axillary FNA was compared to the final surgical pathologic finding in the axillary nodes (“gold standard”) for calculation of sensitivity, specificity, positive predictive value, and negative predictive value. Statistical differences between groups were determined either by the chi-square test (multiple categories) or the Fisher exact test (2 categories).
The survival curves for FNA-positive and FNA-nonpositive groups were estimated using the Kaplan-Meier method, both with respect to disease-free survival (survival without recurrence or metastasis) and overall survival. For the latter, an event was defined as death by any cause. Comparison of survival between groups was performed using the log-rank test. Multivariate analysis correcting for clinicopathologic variables was performed using the Cox proportional hazards model. Clinicopathologic variables (n = 10) were chosen on the basis of their importance in breast cancer management. Patient age was represented as a continuous variable in years. Other variables were considered in categories as follows: FNA result (positive versus nonpositive), T stage (pT1, pT2, pT3), tumor grade (Nottingham 1, 2, 3), N stage (pN0, pN1, pN2, pN3), chemotherapy treatment (treated versus untreated), histologic type (ductal/metaplastic, lobular, mucinous/tubular), surgical management (breast-conserving versus mastectomy), ER/PgR (positive versus negative), and HER2 status (positive versus negative). Because the order in which chemotherapy is provided (neoadjuvant versus postsurgical adjuvant) is not expected to result in a prognostic difference,[25, 26] either approach was classified as “treated” with respect to chemotherapy.
Hazard ratios were calculated and P values determined by comparison of the cumulative hazard functions. For both log-rank and proportional hazards analyses, the assumption is made that the hazard ratio does not depend on time. This assumption was checked by inspection of the logarithm of the cumulative hazard function for both groups.
A total of 142 breast cancer cases was included in our series, including 70 with an axillary FNA positive for metastatic carcinoma and 72 with a nonpositive (negative, atypical/indeterminate, suspicious) result. The median and mean follow-up times were 51 and 50 months, respectively. The characteristics of these cases are summarized in Table 1. Axillary FNA-positive and nonpositive cases did not differ with respect to patient age (means ± standard deviation), tumor subtype, or hormone receptor status. In all (70 of 70) FNA-positive cases and in 70 of 72 FNA-nonpositive cases, axillary lymph node sampling was performed at surgical excision.
Cases with a positive axillary FNA were significantly associated with more advanced stage, both with respect to local tumor size and the nodal classification (based on surgical pathology). Tumors with positive HER2 status were more likely to have a positive axillary FNA. Treatment was also more aggressive in FNA-positive cases; these patients were more likely to undergo mastectomy compared with breast-conserving surgery, and were more likely to receive chemotherapy.
In the current series, there were 3 cases in which positive axillary FNA was correlated with N stage = 0 at surgical resection. All of these cases demonstrated nodal treatment effect, and therefore represented a complete pathologic response to neoadjuvant treatment. Because of uncertainty with respect to the final pathologic staging, these cases were excluded in calculating the specificity (100%) and positive predictive value (100%) of a positive FNA. In the survival analyses, these cases were retained within the FNA-positive category.
There were 22 cases in which a nonpositive axillary FNA was correlated with at least 1 lymph node being positive at surgical resection. This includes 6 cases reported as “suspicious” and 8 cases considered indeterminate (“atypical” or “nondiagnostic”). Excluding these cases from analysis, and excluding 2 of 72 cases without surgical lymph node sampling, axillary FNA had a negative predictive value of 75%, with a sensitivity of 89%. None (0 of 8) of the patients with an indeterminate FNA had a subsequent event (recurrence/metastasis or death). Among the suspicious cases, 1 of 6 (16%) had a subsequent event (death). The event rate among FNA-positive cases was 21 of 71 (30%). For a detailed discussion of FNA performance in this cohort with respect to micrometastases/macrometastases and other clinicoradiologic parameters, one may refer to our prior study.
Prognostic Significance of a Positive Axillary FNA
Kaplan-Meier survival analysis showed that a positive FNA is associated with poor prognosis, both with respect to disease-free survival (Fig. 1A) and overall survival (Fig. 1B). The 5-year disease-free survival in our series was 89% for nonpositive axillary FNA cases and 73% for positive axillary FNA cases. Based on log-rank analysis, this difference was statistically significant (P = .00002). Similarly, the 5-year overall survival was 94% for cases with a nonpositive FNA result and 81% for positive FNA cases (also statistically significant, P = .01).
Multivariate analysis using the Cox regression model is summarized in Table 2. The model represented in Table 2 includes 10 clinicopathologic parameters considered to be prognostically important in the management of breast carcinoma. Based on our series, the variables of independent prognostic significance with respect to disease-free survival were tumor grade (adverse with higher grade), overall nodal status (adverse), and chemotherapy treatment (favorable). Similarly, the variables of independent prognostic significance with respect to overall survival were tumor grade (adverse with higher grade), overall nodal status (adverse), and HER2 status (favorable; see Discussion section). When accounting for the effect of other variables, FNA positivity was not independently significant with respect to disease-free survival or overall survival. Additional analysis in which nonsignificant parameters such as histology, ER/PgR, and T stage were omitted did not result in independent significance for FNA positivity.
Table 1. Clinicopathologic Characteristics of the Patient Cohort (N = 142)
No. of Cases
P (FNA-Positive vs Not Positive)
Axillary FNA Not Positive
Includes high-grade metaplastic carcinomas (n = 3)
Includes 11 cases where neoadjuvant chemotherapy was given.
Abbreviations: BCS, breast-conserving surgery; ER, estrogen receptor; FNA, fine-needle aspirate; NOS, not otherwise specified; PgR, progesterone receptor.
Importance of Axillary FNA in Breast Carcinoma Management
Our results show that patients with breast carcinoma who present with a positive preoperative axillary lymph node FNA are in a high-risk group both with respect to clinicopathologic features and to prognosis. Multivariate analysis shows that the prognostic significance of a positive FNA is not independent when correcting for clinicopathologic parameters, including overall nodal status. Our series excluded those patients with distant metastases at presentation, which is a finding with adverse prognosis independent of nodal status. Although previous studies have shown that axillary FNA predicts for pathologic nodal status,[20-23] this series is the first to our knowledge that addresses the question of prognostic significance using survival analysis.
Nodal status was an independently significant predictor of both disease-free survival and overall survival, even when correcting for other significant factors such as chemotherapy treatment and tumor grade. It is likely that a positive axillary FNA, although not independently significant on multivariate analysis, derives its significance on univariate analysis from its close association with overall nodal status.
Notwithstanding the loss of independence on multivariate analysis of the axillary FNA result, the univariate significance is far from trivial in the era of neoadjuvant treatment. Although not associated with a survival benefit, neoadjuvant treatment has 2 principal advantages over postsurgical adjuvant chemotherapy: the conversion of surgically inoperable cases to operable ones and the in vivo measurement of treatment response in all cases in which adjuvant treatment may be considered.[24-26] The significance of the latter point is that any patient who would reasonably be considered for adjuvant treatment may be considered for neoadjuvant treatment, a decision that depends both on tumor characteristics (grade, ER/PgR/HER2) and nodal assessment. In our series, 11 of 101 (11%) chemotherapy-treated cases were treated with a neoadjuvant approach; however, in actual practice, this proportion is rapidly increasing in major centers. Complete response rates after neoadjuvant treatment differ mainly with ER, PgR, and HER2 status and ranges from 12% to 44%. Therefore, a positive FNA result ultimately may be the most definitive evidence of nodal involvement in a significant subset of cases.
Other Findings on Clinicopathologic/Survival Analysis
It was surprising that a significant minority of FNA-positive cases (13 of 49, 27%) were associated with tumors classified as T1 (not exceeding 2 cm). In another study, axillary FNA positivity was typically associated with more locally advanced tumors. This may reflect differences in case selection for axillary FNA. In our series, not all patients with accessible axillary lymph nodes underwent FNA; rather, FNA was performed on the basis of radiologic features.
As expected, tumor grade remained a strong independent prognostic factor, as a reflection of underlying tumor biology that remains independent of tumor burden and treatment efforts. Similarly, chemotherapy was prognostically beneficial (reaching statistical significance with respect to disease-free survival, but not overall survival) reflecting the overall efficacy of cytotoxic agents. Although ER/PgR positivity has favorable hazard ratios as expected, this did not reach statistical significance in our series. By contrast, HER2 positivity is considered a poor prognostic marker. In our series, HER2 positivity was associated with favorable hazard ratios (not reaching statistical significance), likely reflecting the effectiveness of targeted therapy in this subpopulation. During the period of our study, all patients with HER2-positive tumors exceeding 1 cm in size were eligible for treatment by chemotherapy and trastuzumab.
Not all clinicopathologic parameters considered to be important in breast cancer management had independent significance on multivariate survival analysis (Table 2). In particular, T stage is considered a major prognostic factor; however, our data would suggest that it may lose its significance when considering N stage. Another possibility is that T stage is more predictive of recurrence than overall survival; in our series, T stage had a smaller P value with respect to disease-free survival, but did not reach statistical significance. With respect to histologic type, most of the tumors were either ductal (no special type) or lobular, and as such, a prognostic difference was not expected. Surgical approach (breast-conserving surgery versus mastectomy) was also not prognostically significant. In our population, most patients undergoing breast-conserving surgery are given radiation, thereby making their risk of disease progression comparable to that of patients undergoing mastectomy.
A positive axillary lymph node FNA correlates to poorer disease-free survival and overall survival in patients being evaluated for invasive breast carcinoma. Overall nodal status, but not axillary FNA positivity, remained independently significant when correcting for all other variables in multivariate analysis. We conclude that the prognostic significance of axillary FNA likely results from its ability to predict for nodal status, and as such, axillary FNA has utility as a preoperative staging procedure.