Abstract
Management of breast cancer has gradually shifted from era of radical surgery to present days of multimodality management and conservatism. Management of carcinoma breast is primarily multimodality of which surgery is one of the important roles to play. Our study is a prospective observational study to determine the involvement of level III axillary lymph nodes in clinically involved axilla with grossly involved lower-level axillary nodes. Underestimation of a number of involved nodes at level III shall result in inaccuracy of subset risk stratification leading to substandard prognostication. The enigma of not addressing presumably involved nodes thereby altering the staging vs acquired morbidity has always been a contentious issue. Mean lymph node harvest at the lower level (I and II) was 17.9 ± 6.3 (range: 6–32) while positive lower-level axillary lymph node involvement was 6.5 ± 6.5 (range: 1–27). The mean ± SD for level III positive lymph node involvement was 1.46 ± 1.69 (range: 0–8). Our prospective observational study though limited by the number and years of follow-up has demonstrated that the presence of more than three positive LN at a lower level increases the risk for higher nodal involvement substantially. It is also evident in our study that PNI, ECE, and LVI increased the probability of stage up-gradation. LVI was found to be a significant prognostic factor for apical LN involvement in multivariate analysis. On multivariate logistic regression > 3 pathological positive lymph nodes at the level I and II and LVI involvement elevated the risk of involvement at level III by 11 and 46 times, respectively. It is recommended that patients who have a positive pathological surrogate marker of aggressiveness should be evaluated perioperatively for level III involvement, especially in the setting of visible grossly involved nodes. The patient should be counseled and informed decision to perform complete axillary lymph node dissection with the added risk of morbidity should be contemplated.
Keywords: Axillary Lymph Nodes, Level III Lymph Node Dissection, Pathological Markers
Introduction
Breast cancer is one of the most common cancers worldwide in females with a variable rate of incidences across countries and regions. It impacts more than 2.1 million women each year and causes the greatest number of cancer-related deaths among women. Worldwide, it accounts for one of the leading causes of cancer-related death, accounting for 25% of cancer cases and 15% of cancer death [1]. The incidence of breast cancer has been steadily increasing in developing countries and it is expected that the majority of new cases would be reported from developing nations [2].
Management of carcinoma breast is primarily multimodality of which surgery is one of the important roles to play. Treatment of breast cancer also includes the management of the axilla. The axillary lymph nodes are the main group for breast lymphatic drainage and are the main location for metastasis. Hence, axillary lymph nodal status forms an important component of invasive non-metastatic breast cancer management. The management of axilla has changed from complete axillary lymph nodes dissection to the present era of sentinel node biopsy. Axillary lymph node dissection includes level I and II lymph nodes removal while level III nodes are not addressed routinely as it leads to increased surgical morbidity [3].
At present, there is no consensus as to what level of axillary nodes should be dissected for N1 or node-positive breast cancer. It has been observed that in cases with grossly nodal disease, positive nodes are found beyond the domain of normal axillary lymph node dissection, thereby leading to the persistence of disease in the lymph node basin [4]. The proponents of complete axillary LN dissection advocate its advantage in better prognostication and superior local control with a possible role in long-time survival.
Level III lymph node involvement represents an important part in the NCCN tumor staging of a patient with breast cancer, leading directly to pathologically stage IIIC. NCCN guidelines version 1.2022 for invasive breast carcinoma recommends that level III dissection should be performed where gross disease in level I and II and/or level III is present [5].
Aim and Objectives
We conducted a prospective observational study with an aim to determine the incidence of level III lymph nodes positivity and predictive factors if any in patients of carcinoma breast with clinically positive level II nodes.
Statistical Methods
For estimation of sample size, the following formula has been used: n = [Zα 2 P Q]/d2, where Zα is the value of standard normal variate corresponding to α level of significance, P is likely the value of the parameter, Q = 1 − P, and d is margin of errors.
Assumptions were made as per reference articles and available literature; P = positivity rate of lymph node metastases in level I + II = 70% (reference article) [6–10]; Zα = 2.576 (corresponding to 99% confidence interval) with precision (d) of ± 15.0%.
With these assumptions, the sample size was calculated as 63 with lost to follow-up patients as 10%, and a minimum sample size of 70 was decided.
Descriptive analysis of quantitative parameters was expressed as means and standard deviation. Categorical data were expressed as absolute numbers and percentages. The independent Student t-test was used for testing of mean value between independent groups. Cross tables were generated, and Pearson chi-square or Fisher’s exact test was used for testing associations between level III axillary lymph nodes (ALN) metastases and other categorical variables.
Univariate and multivariate logistic regression was used to identify independent predictors of level III ALN involvement. The diagnostic accuracy to identify the number of ALNs in level I and II to predict level III pathological involvement was assessed by receiver operating characteristic (ROC) curve analysis and the optimal cutoff value was calculated using the formula, minimum {(1 – Sn)2 + (1 – Sp)2} with the best combination of sensitivity and specificity.
p-value < 0.05 was considered statistically significant. All analyses were done using SPSS software, version 24.0.
Study Methodology
This study was conducted on patients with carcinoma breast treated at surgical oncology department over a period of 1 year who were then followed up 3 monthly for 1 year. Seventy consecutive cases satisfying inclusion and exclusion criteria were selected for study and allocated to the clinical study after obtaining the patient’s written informed consent. Patients with clinically positive bulky, grossly involved axillary nodes (confirmed with preoperative FNAC) were included. Patients with clinically negative axilla were not part of the study. All patients underwent axillary lymph node dissection and those with clinically involved lymph nodes I and lymph nodes II (bulky, grossly involved) had level III lymph node dissection. Level III lymph nodes were marked and sent separately for histopathological study along with the regular specimen. Grossly pathological nodes are those nodes that are more than 1 cm, firm to hard in consistency, and appear to be involved in the final histopathological examination. The report determined the number of harvested and pathologically positive level III lymph nodes.
Results
The mean ± SD (standard deviation) age of the patients was 50.3 ± 12.9 years and the median age was 48 years. Approximately 70% of our patients belonged to the age group of 40–70 years. In our study, more than 60% of patients reported tumors in left the breast, and in 47% of patients, it was located in the upper outer quadrant (Table 1). Mean lymph node harvest at the lower level (I and II) was 18 (15–22) 17.9 ± 6.3 (range: 6–32) while positive lower-level axillary lymph node involvement III was 4 (IQR: 2–8) 6.5 ± 6.5 (range: 1–27). The mean ± SD for level III positive lymph node involvement was 1 (0–2) 1.46 ± 1.69 (range: 0–8).
Table 1.
Summary of clinical and social demographics (n = 70)
| Characteristics | Statistics | |
|---|---|---|
| Age (years), median (IQR) | 48 (39–62) | |
| Laterality, n (%) | Right | 27 (38.6%) |
| Left | 43 (62.0%) | |
| Birth history, n (%) | First birth | 17.9 ± 1.5 (16–24) |
| Last birth | 24.4 ± 2.4 (19–30) | |
| Duration of breast feeding (months), n (%) | < 3 | 12 (17.1%) |
| 3–6 | 46 (65.7%) | |
| 6–9 | 10 (14.3%) | |
| > 9 | 2 (2.9%) | |
| Menstrual history, mean ± SD (range) | Menarchy (years) | 14.3 ± 0.9 (12–16) |
| Menopause (years) | 49.4 ± 2 (42–52) | |
| Family history, n (%) | 7 (10.0%) | |
A receiver operating characteristic curve (ROC) was plotted to identify the number of positive levels I and II that would predict level III axillary lymph node involvement (Fig. 1) A significant, 0.765 (95% C.I.: 0.627–0.904), area under the curve was obtained. An optimal cutoff of 2.5 LNs was obtained with 80.9% sensitivity, 68.2% specificity, 83.8% positive predictive value (PPV), 63.6% negative predictive value (NPV), and 76.7% accuracy. For practical purposes, an optimal cutoff of lymph nodes was taken as 3 for the statistical analysis.
Fig. 1.
Area under the curve (AUC) of axillary lymph nodes involved in level I and II for best predicting of pathologically positive level III lymph nodes. *p-value < 0.05, statistically significant
When more than three lower-level lymph nodes were pathologically involved, level III involvement was observed in 87.0% of patients among the subset whereas only 13.0% of patients had positive level III if fewer than three lower-level axillary lymph nodes were pathologically positive. This difference was statistically significant (p = 0.001). Thirty-four patients had tumor sizes more than 3 cm while 36 patients had tumor sizes smaller than 3 cm. Among 34 patients with tumor size more than 3 cm, 27 patients (82%) were found to have pathological positive axillary lymph nodes while 19 patients (52%) had involved level III lymph nodes (Table 2, 3, 4, and 5).
Table 2.
Total number of level I/II lymph nodes harvested
| Level I/II + lymph node harvested | Mean ± SD (range) | Median (IQR) |
|---|---|---|
| Total harvested | 18 ± 6 (6–32) | 18 (14–23) |
| Harvested—positive | 6.7 ± 6.2 (1–27) | 4 (2–8) |
Table 3.
Total number of harvested and pathologically positive level III lymph node
| Level III + lymph node harvested | Mean ± SD (range) | Median (IQR) |
|---|---|---|
| Total harvested | 4.9 ± 2.7 (1–11) | 5 (3–7) |
| Pathologically positive | 2.2 ± 1.6 (1–8) | 2 (1–3) |
Table 4.
Number of positive level I & II LN and pathological positive level III axillary lymph nodes
| No. of + ve LN I and II | Level III ALN | ||
|---|---|---|---|
| Total | Positive | Negative | |
| ≥ 3 | 46 | 38 (82.6%) | 8 (17.4%) |
| < 3 | 24 | 9 (37.5%) | 15 (62.5%) |
Table 5.
Tumor size and pathological positive level III axillary lymph nodes
| Tumor Size (cm) | Level III ALN | ||
|---|---|---|---|
| Total | Positive | Negative | |
| ≥ 3 | 34 | 28 (82.4%) | 6 (17.6%) |
| < 3 | 36 | 19 (52.8%) | 17 (47.2%) |
There was no association observed between age, duration of symptoms, family history, and ER and PR positivity with Level III ALN involvement (p = 0.555, 0.553, 0.873, 0.946, 0.808, respectively). A higher grade has been a marker of poor prognosis and depicts a higher risk of early relapse post-treatment. There was a statistically significant association observed in Level III axillary lymph-nodal pathological positivity rate with higher grade, HER2 positivity, LVI (lymphovascular invasion), ECE (extra capsular extension), and PNI (peri nodal involvement) (Table 6).
Table 6.
Level III lymph node involvement and various pathological markers with tumor grade
| PNI | Level III ALN | ||
| Total | Positive | Negative | |
| Positive | 25 | 23 (92%) | 2 (8%) |
| Negative | 45 | 24 (53.3%) | 21 (46.7%) |
| LVI | Level III ALN | ||
| Total | Positive | Negative | |
| Positive | 45 | 40 (88.9%) | 5 (11.1%) |
| Negative | 25 | 7 (28%) | 18 (72%) |
| ECE | Level III ALN | ||
| Total | Positive | Negative | |
| Positive | 24 | 21 (87.5%) | 3 (12.5%) |
| Negative | 46 | 26 (56.5%) | 20 (43.5%) |
| HER2 | Level III ALN | ||
| Total | Positive | Total | |
| Positive | 25 | Positive | 25 |
| Negative | 45 | Negative | 45 |
| ER | Level III ALN | ||
| Total | Positive | Negative | |
| Positive | 43 | 29 (67.4%) | 14 (32.6%) |
| Negative | 27 | 18 (66.7%) | 9 (33.3%) |
| PR | Level III ALN | ||
| Total | Positive | Negative | |
| Positive | 25 | 21 (84%) | 4 (16%) |
| Negative | 45 | 26 (57.8%) | 19 (42.2%) |
| Tumor grade | Level III ALN | ||
| Total | Positive | Total | |
| Grade 1 or 2 | 45 | Grade 1 or 2 | 45 |
| Grade 3 | 25 | Grade 3 | 25 |
Univariate evaluation patients who had tumor size ≥ 3 cm were at 3.3 times more risk for level III lymph nodal involvement as compared to those patients who had tumor size < 3 cm, Similarly, those who had a number of positive axillary lymph nodes ≥ 3 at the level I and II had 9 times increased risk for level III pathological positivity. Also, positive HER2 neu were found to be at 3.8 times higher risk while positive LVI and ECE increased risk by 9 times (Table 7). On multivariate logistic regression > 3, pathological positive lymph nodes at the level I and II and LVI involvement elevated the risk of involvement at level III by 11 and 46 times, respectively (Table 8).
Table 7.
Univariate logistic regression for predicting ability for pathological positive level III axillary lymph nodes
| Beta coefficient (β) | Std. error | Odds ratio (OR) | 95% C.I. for OR | p-value | ||
|---|---|---|---|---|---|---|
| Lower | Upper | |||||
| Age > 50 years (RC: age ≤ 50 years) | − 0.30 | 0.51 | 0.74 | 0.27 | 2.01 | 0.556 |
| Inner | 1.01 | 1.04 | 2.75 | 0.35 | 21.30 | 0.333 |
| Outer | 1.19 | 0.82 | 3.30 | 0.656 | 16.61 | 0.148 |
| Tumor size ≥ 3 cm (RC: < 3 cm) | 1.20 | 0.57 | 3.32 | 1.08 | 10.18 | 0.036* |
| Tumor grade—3 (RC: grade 1 or 2) | 1.34 | 0.62 | 3.84 | 1.13 | 13.02 | 0.031* |
| No. of positive ALN ≥ 3 (RC: < 3) | 2.20 | 0.59 | 9.05 | 2.85 | 28.70 | 0.0001* |
| ER—positive (RC: negative) | 0.04 | 0.52 | 1.04 | 0.37 | 2.88 | 0.946 |
| PR—positive (RC: negative) | 0.13 | 0.52 | 1.13 | 0.41 | 3.11 | 0.808 |
| HER2—positive (RC: negative) | 1.34 | 0.62 | 3.84 | 1.13 | 13.02 | 0.031* |
| LVI—positive (RC: negative) | 3.02 | 0.65 | 20.57 | 5.75 | 73.64 | 0.0001* |
| PNI—positive (RC: negative) | 2.31 | 0.80 | 10.06 | 2.12 | 47.84 | 0.004* |
| ECE—positive (RC: negative) | 1.68 | 0.69 | 5.38 | 1.41 | 20.62 | 0.014* |
Table 8.
Multivariate logistic regression for predicting ability for pathological positive level III axillary lymph nodes
| Beta coefficient (β) | Std. error | Odds ratio (OR) | 95% C.I. for OR | p-value | ||
|---|---|---|---|---|---|---|
| Lower | Upper | |||||
| Age > 50 years (RC: age ≤ 50 years) | 0.92 | 1.12 | 2.52 | 0.28 | 22.61 | 0.409 |
| Inner | 1.80 | 2.00 | 6.05 | 0.12 | 307.36 | 0.369 |
| Outer | 1.98 | 1.50 | 7.28 | 0.38 | 138.32 | 0.187 |
| Tumor size ≥ 3 cm (RC: < 3 cm) | − 1.46 | 1.12 | 0.23 | 0.03 | 2.07 | 0.191 |
| Tumor grade—3 (RC: Grade 1 or 2) | − 1.16 | 1.17 | 0.31 | 0.03 | 3.11 | 0.321 |
| No. of positive ALN ≥ 3 (RC: < 3) | 2.39 | 1.02 | 10.93 | 1.49 | 80.13 | 0.019* |
| ER—positive (RC: negative) | − 2.49 | 2.13 | 0.08 | 0.00 | 5.41 | 0.243 |
| PR—positive (RC: negative) | − 4.49 | 2.37 | 0.01 | 0.00 | 1.17 | 0.058 |
| HER2—positive (RC: negative) | − 0.28 | 1.08 | 0.76 | 0.09 | 6.33 | 0.799 |
| LVI—positive (RC: negative) | 3.84 | 1.45 | 46.45 | 2.72 | 79.62 | 0.008* |
| PNI—positive (RC: negative) | − 1.34 | 1.33 | 0.26 | 0.02 | 3.51 | 0.311 |
| ECE—positive (RC: negative) | 0.66 | 1.17 | 1.94 | 0.19 | 19.28 | 0.572 |
Discussion
This study comprised surgically treated patients at a single tertiary care center with uniform treatment protocols. The objective of this study was to analyze the involvement of level III axillary lymph nodes in cases of grossly nodal axillary lymph nodes undergoing breast cancer surgery. The patient’s clinicopathological profile of the patients with pathologically positive level III nodes was correlated to identify predictors for higher nodal involvement.
According to the revised classification of breast cancer in 2002 by AJCC, infraclavicular (apical) node involvement in breast cancer was categorized as N3. These patients were staged as IIIC because the survival of these patients was similar to those who had supraclavicular lymph node metastases.
The most controversial aspect of axillary dissection has been its impact on survival. In a study of more than a thousand patients, apical metastasis was found to be an independent predictor of survival in node-positive breast cancer and was found to have poor survival rates [11]. Similarly, other studies have also concluded better local control with complete nodal dissection which subsequently compounds to a survival advantage. The two studies Kodama et al. [3] and Tominaga et al. [12] evaluated the impact of level III axillary lymph nodal dissection and concluded that it has no impact on survival. However, the studies were criticized as they included both node-positive and node-negative tumors thereby potentially mitigating the results. There have not been any randomized systematic methodical studies on the impact of level III nodal dissection in carcinoma breast.
The mean tumor size was 3.0 ± 0.8 cm (1–5). In our study among 34 patients who had a tumor size of more than 3 cm, approximately 80% of patients had involved level III lymph nodes whereas it was 57.6% if tumor size was < 3 cm. This difference was statistically significant (p = 0.032). The predictive role of tumor size in breast cancer with axillary lymph node involvement has been studied and published. The authors deduced that there is a 15.3% overall incidence of axillary LN involvement in tumors ≤ 2 cm, while in patients with tumors ≥ 2 cm, it progressed to 84.3%. The study advised that the best management for tumors more than 2 cm should be full ALND [13].
All patients were clinically positive. The inclusion criteria included clinical examination; USG axilla followed by FNAC of the suspected nodes if present. USG axilla was utilized to correctly stage the axilla as clinical examination of the axilla is notoriously incorrect. Studies have shown that clinical accuracy for axillary LN remains around 30% [14]. USG and USG-FNAC have been reported to have high accuracy for staging axillary lymph nodes. Published estimates of USG-FNAC show a sensitivity varying from 25 to 87%, a specificity ranging from 14 to 100%, PV between 54 and 78%, and a PPV ranging from 37 to 100% [15].
For practical purposes, an optimal cutoff of lymph nodes was taken as 3 for the statistical analysis. In a recent study evaluating the merits of level III lymph nodal dissection, authors concluded that level III was found to be positive in 53.2% of patients while only 9.4% when less than four LN were found involved [16].
In our study, higher grade was found to be associated with level III involvement. It is similar to a single-center study that predicted a high risk of axillary lymph nodal involvement with grade III tumors [17]. In our study ER, PR was not found to have any significant relationship with level III positivity. It is similar to the results published in a recent study at an apex center and other studies [18].
There was a significant association observed in Level III lymph nodal pathological positivity rate with HER2 test findings (p-value = 0.025). In a clinicopathological profile study of early breast cancer at a tertiary care center in south India, the authors concluded that besides young age, premenopausal status, and lobular pathology, HER2 positivity is a significant risk factor for axillary LN positivity [19]. There was a significant association observed in level III ALN positivity rate with positive LVI findings and ECE. Our results are in coherence with the other studies which have identified LVI as the major determinant for apical LN (level III) involvement [20]. Similarly, a retrospective study of more than 1200 patients concluded that the presence of ECE in breast cancer is positively related to tumor size and the number of positive lymph nodes. It is also a risk factor for locoregional recurrence and distant metastasis. ECE positive group has a much shorter metastasis-free survival, locoregional recurrence-free survival, and overall survival [21].
Conclusion
Indian patients as compared to the western subset mostly report late and are at a higher stage. Nodal involvement itself leads to a poorer prognosis. The pattern of nodal involvement has been different across various studies irrespective of tumor and demographic pattern. Though NCCN recommends apical LN dissection in presence of heavy nodal burden, there has not been much-published literature on the merits of level III LN dissection as the role of axillary dissection in the present era remains prognostic. None of the preoperative non-invasive axillary stagings have been found to be accurate. The role of SNLB has been evolving progressively though limited by logistical constraints in developing countries.
One of the most controversial issues of axillary nodal dissection has been its impact on survival. The available literature results vary across different subsets and it is highly mitigated by the facts of inclusion criteria, follow-up, and role of other modalities of treatment. The ways in which it could affect survival would be because of its being a potential source of metastasis due to accentuated risk of reseeding. Underestimation of the number of involved nodes at level III shall result in the inaccuracy of subset risk stratification leading to substandard prognostication. The enigma of not addressing presumably involved nodes thereby altering the staging vs acquired morbidity has always been a contentious issue. However, our data has a limitation of not addressing its impact on overall survival. More studies with a targeted approach towards its impact on overall survival are required.
Our prospective observational study though limited by the number and years of follow-up has demonstrated that the presence of more than three positive LN at a lower level increases the risk for higher nodal involvement substantially. It is also evident in our study that PNI, ECE, and LVI increased the probability of stage up-gradation. LVI was found to be a significant prognostic factor for apical LN involvement on multivariate analysis with the highest accuracy.
We recommend that patients of clinically positive axilla with gross nodal burden per operative evaluation for the presence of level III must be contemplated and if found palpable and visually involved should be dissected with an additional risk of morbidity in consensus with preoperative counseling with the patient.
Author Contribution
Conceptualization: Dr R Shankaran and Dr D Mukherjee. Design: Dr Surjeet Kumar dwivedi and Dr Varun Agarwal. Definition of intellectual content: Dr R Shankaran and Dr Naresh Saidha. Literature search: Dr Surjeet Kumar Dwivedi and Dr Rohit Sharma. Clinical studies: Dr Surjeet Kumar Dwivedi and Dr Amiy Arnav. Experimental studies: Dr R Shankaran. Data acquisition, data analysis, and statistical analysis: Dr Surjeet Kumar Dwivedi and Dr Rajhans. Manuscript preparation: Dr Surjeet Kumar Dwivedi and Dr Amiy Arnav. Manuscript editing and manuscript review: Dr Surjeet Kumar Dwivedi and Dr Sabita Dwivedi.
Declarations
Consent for Publication
The manuscript has been read and approved by all the authors.
Conflict of Interest
The authors declare no competing interests.
Footnotes
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