Rotter’s Lymph Nodes—Do We Really Need to Remove During Axillary Clearance?

Abstract

Surgical management of node positive breast cancer requires axillary dissection. Interpectoral nodes (IPNs) or Rotter’s nodes removal is controversial as there is hardly any tissue in this region. IPNs involvement is rarely seen among breast cancer patients. Developing an effective protocol for surgical management of axilla is necessary for uniformity, to reduce the risk of regional recurrence and to avoid the morbidity of interpectoral lymphatic tissue clearance. This study aimed to evaluate the detection of lymph nodes in Rotter’s region and positive metastasis rate of IPNs in patients with node positive breast cancer for analyzing the prognostic and therapeutic value of IPN excision during axillary clearance. Fifty-six patients undergoing axillary clearance, aged ≥ 18 years, were studied. Patients with recurrence or those who underwent neoadjuvant chemotherapy were excluded. Baseline investigations were done pre-operatively along with core needle biopsy, estrogen receptor (ER), progesterone receptor (PR), and Ki-67 status. Association between IPN status, age, and clinicopathological parameters were assessed by Kruskal Wallis and Chi-square test using R v 3.6.0. P value of ≤ 0.05 was considered statistically significant. Majority of patients had upper outer quadrant tumor location (22/56), and the most common histopathological type was invasive ductal carcinoma (46/56). IPNs were identified in 35.71% (20/56) of 56 patients, with metastasis prevalence of 27.27% (9/33 node positive patients). Patients having IPN metastasis had larger tumor size, later TNM classification, lower ER/PR, and higher Ki-67 positivity. Dissection of IPNs can be practiced routinely during axillary clearance and should be subjected to histopathological examination separately.

Introduction

Breast cancer impacts 2.1 million females annually and is among the most frequent cancer types, responsible for nearly 15% of cancer deaths [1]. Around 1.7 million new breast cancer cases will arise in the year 2020 in the developing countries [2]. Early breast cancer is treated by surgery which includes a lumpectomy or mastectomy, with axillary clearance or sentinel lymph node biopsy, with or without post-operative radiotherapy and chemotherapy [3]. The current recommendation by Asian Society of Mastology is to offer Breast conservation surgery which includes oncoplasty and sentinel lymph node biopsy in all cases of clinically node negative (cN0) breast cancer if facilities are available. SLNB may be performed by any of the multiple techniques that are available. There are centers available to get trained in oncoplasty and SLNB and thereafter offer the same to the patient. However, due to lack of infrastructure and awareness, most places in developing countries perform axillary dissection in cN0 status. The second and relevant controversy with regard to this study is the presence of lymph nodes in the interpectoral region (between the pectoralis major and minor muscles) [4] also called as Rotter’s nodal basin. The reason for the controversy are lack of visible or palpable lymph node tissue in a majority of cases in this region and the morbidity of damage to the pectoral nerves and blood vessels, which are closely associated with the interpectoral fat and lymphatic tissue, leading to atrophy and weakness of pectoral muscles along with symptoms of pain and shoulder morbidity [5]. There is an ongoing debate on whether routine removal of the interpectoral nodes (IPNs), also known as Rotter’s nodes, has any potential prognostic or therapeutic benefits despite the recommendation from National Comprehensive Cancer Network (NCCN) in their guidelines [6]. The metastasis rate of IPNs in breast cancer is only 4–9.9% in many studies [7]. Therefore, this study was attempted to facilitate the pathological examination of IPNs by dissecting and labeling them separately during axillary clearance in breast cancer patients. In addition, we aimed to estimate the metastasis rate in IPNs and to analyze the prognostic or therapeutic value of IPN excision during surgical management of breast cancer patients.

Materials and Methods

A prospective study was conducted in the department of surgical oncology from October 2016 to September 2018 and comprised 56 patients who underwent axillary clearance (AC) with lumpectomy or mastectomy. Prior ethical approval was taken from the institutional ethical committee, and written informed consent was taken from all the patients. Exclusion criteria included patients with recurrence and who had undergone neoadjuvant chemotherapy (NACT) earlier. Baseline investigations such as clinical (site, size of primary tumor, details of axillary nodes) as well as TNM (tumor node metastasis), radiological, and pathological staging were assessed preoperatively and recorded. Core needle biopsy was performed for all patients as per the protocol of Rikabi and Hussain [8]. All patients underwent surgery as per the procedure of Vrdoljak et al. [9]. The dissected tissue samples from each patient were sent for pathological examination and correlated with the histopathological report. This was done to evaluate the potential benefit of IPN removal during surgery and to confirm or disprove the dictum of IPN dissection in case of only palpable node.

R software v 3.6.0 was used to analyze data. Clinicopathological variables were analyzed using Chi-square test and presented as frequency and percentages. An association between IPN status and age was assessed using Kruskal-Wallis test. Non-categorical data were presented as mean ± standard deviation (SD). A P value ≤ 0.05 was considered statistically significant.

Results

Among the 56 female patients who underwent axillary dissection, the mean age of patients was 52.68 ± 11.42 years, and the majority belonged to the 36–45 years age group. IPNs were detected anatomically in 35.71% (20/56) patients, out of which 45% (9/20) were metastasized.

The association between status of IPN and different clinicopathological variables were also tested using Chi-square test. However, only TNM stage, along with status of axillary apical node metastasis and perinodal spread, was found to be significantly associated with IPN status (P value ≤ 0.05), as shown in Table 1. On comparing TNM stage with IPN metastasis, majority of the stage II disease had no lymph nodes in interpectoral region, or the lymph nodes here had no metastasis. However, in most cases where IPN showed metastasis, they had later TNM staging, i.e., stage III and tumor grading (grade 3), which was noted to be 8 (88.89%).

Table 1.

Clinicopathological characteristics of the patients based on IPN

Variables	Category	IPN undetected (n = 36)	IPN detected		P value
			Metastasis (n = 9)	Non-metastasis (n = 11)
		n (%)	n (%)	n (%)
TNM staging	Stage I	4 (11.11)	0 (0)	1 (9.09)	0.02*
	Stage II	22 (61.11)	1 (11.11)	7 (63.64)
	Stage III	10 (27.78)	8 (88.89)	3 (27.27)
Tumor grading	Grade 1	4 (11.11)	1 (11.11)	3 (27.27)	0.63
	Grade 2	21 (58.33)	4 (44.44)	5 (45.45)
	Grade 3	11 (30.56)	4 (44.44)	3 (27.27)
Histological type	Medullary CA	2 (5.56)	1 (11.11)	2 (18.18)	0.74
	Papillary CA	1 (2.78)	0 (0)	0 (0)
	Inv. ductal CA	30 (83.33)	7 (77.78)	9 (81.82)
	Inv. lobular CA	1 (2.78)	1 (11.71)	0 (0)
	Mucinous CA	2 (5.56)	0 (0)	0 (0)
Location	UOQ	13 (36.11)	4 (44.44)	5 (45.45)	0.75
	UIQ	6 (16.67)	0 (0)	0 (0)
	LIQ	2 (5.56)	0 (0)	0 (0)
	LOQ	6 (16.67)	1 (11.11)	2 (18.18)
	CQ	4 (11.11)	1 (11.11)	2 (18.18)
	> 1Q	5 (13.89)	3 (33.33)	2 (18.18)
Axillary apical nodes	Metastasis	18 (50.00)	9 (100)	4 (36.36)	0.01**
	Non-metastasis	18 (50.00)	0 (0)	7 (63.66)
Estrogen receptor	Present	19 (52.78)	3 (33.33)	7 (63.64)	0.38
	Absent	16 (44.44)	6 (66.67)	4 (36.36)
Progesterone receptor	Present	19 (52.78)	3 (33.33)	7 (63.64)	0.38
	Absent	16 (44.44)	6 (66.67)	4 (36.36)
Her 2/neu	Present	6 (16.67)	3 (33.33)	2 (18.18)	0.64
	Absent	26 (72.22)	5 (55.56)	9 (81.82)
	Equivocal	3 (8.33)	1 (11.11)	0 (0.00)
Ki-67	Positive	21 (58.33)	6 (66.67)	6 (54.55)	0.85
	Negative	15 (41.67)	3 (33.33)	5 (45.45)
Lymphovascular invasion	Present	16 (44.44)	7 (77.78)	4 (36.36)	0.13
	Absent	20 (55.56)	2 (22.22)	7 (63.64)
Perineural invasion	Present	7 (19.44)	3 (33.33)	3 (27.27)	0.64
	Absent	29 (80.56)	6 (66.67)	9 (72.73)
Perinodal spread	Present	9 (25.00)	8 (88.89)	2 (18.18)	0.001**
	Absent	27 (75.00)	1 (11.11)	9 (81.82)

Note: CA carcinoma, CQ central quadrant, Her 2/neu human epidermal growth factor/proto-oncogene, Inv invasive, IPN interpectoral node, LIQ lower inner quadrant, LOQ lower outer quadrant, 1Q one quadrant, TNM tumor node metastasis, UIQ upper inner quadrant, UOQ upper outer quadrant

* and ** indicate statistically significant values of ≤ 0.05 and ≤ 0.01

Most patients had the tumor in the upper outer quadrant–tumor location (22/56), and the most common histopathological type was invasive ductal carcinoma (46/56). Most important of all, all the patients showing metastasis in IPNs had associated metastasis in other non-IPN axillary nodes as well (9; 100%). Isolated IPN metastasis was not seen in this study. A higher incidence of perinodal spread (8; 88.89%) and lymphovascular invasion (7; 77.78%) were also noted whenever IPNs were involved by tumor. No significant association was noted between the IPN metastasis and estrogen receptor (ER), progesterone receptor (PR), Her 2/neu, as well as Ki-67 presence.

Discussion

Node positive breast cancer mandates axillary clearance either upfront or post neoadjuvant chemotherapy. As per NCCN guidelines, the region between pectoralis major and minor is called IPN or Rotter’s node and is cleared for histopathological examination. During axillary dissection, there is hardly any tissue noted in this area, and hence there is a controversy regarding the need to clear this area during surgery. The major morbidity of clearing this area is the injury to pectoral nerves and blood vessels causing atrophy of the muscles and shoulder pain and morbidity [5].

Researchers have reported differing IPN metastatic involvement, from 2.6% to 10%, in breast cancer patients [10, 11]. However, increased incidences of metastasis of lymph nodes can be detected using special techniques of clearing [12]. We noticed that in 35.71% (20/56) of our patients, lymph nodes were identifiable in the Rotter’s basin. Metastasis in IPN node(s) were noted in 27.27% (9/33) of node positive breast cancer. The remaining 23 patients were node negative breast cancer. Conversely, Yamasaki and Kodama [13] reported that only 5.9% (10/168) cases were metastasized out of 64% (108/168) IPN positive incidences. We also noticed a positive axillary lymph node metastasis among all our patients with IPN metastasis. In addition, metastases in non-excised IPNs may become an important source of systemic or local treatment failure [14].

We also assessed the association between IPN status and various clinicopathological characteristics, such as TNM staging, tumor grading, location, histological type, and status of axillary apical nodes metastasis along with presence of lymphovascular and perineural invasion and perinodal spread. A significant association was found between IPN status and TNM staging, status of axillary apical nodes metastasis, and perinodal spread (P value < 0.05). Vrdoljak et al. [9] tried to correlate clinicopathological variables such as tumor stage and grade along with axillary apical nodes metastasis, IPN status, and CA 15-3 using multiple regression analysis and reported that tumor location and grading were significantly associated with axillary apical nodes metastasis, IPN status, and CA 15-3 (P value < 0.01).

We found that patients with IPN metastasis had a larger tumor size; later TNM staging (mainly stage III); higher axillary node metastasis rate; high Ki-67 proliferative index; higher rate of perinodal spread; and negative ER, PR, and Her 2/neu receptor status. Other researchers have assessed the prognostic value of ER, PR, and Her 2/neu status with axillary lymph node and found them to be significantly associated with axillary lymph node metastasis [15]. However, to the best of our knowledge, none of the studies until date have evaluated the association of IPN status with ER, PR and Her 2/neu receptor status.

We opine that in node positive breast cancer, IPNs must be cleared routinely and subjected to pathological examination in all axillary dissection cases, which is crucial for designing a treatment plan and estimating prognosis of the patients [13, 16]. In node negative breast cancer, sentinel lymph node biopsy is ideal, but if infrastructure is lacking and axillary dissection needs to be done, IPN need not be dissected as in this study, since Rotter’s nodes are never involved in isolation, in the absence of axillary lymph node metastasis [17]. However, this present study has certain limitations since the numbers are few and due to short duration of post-operative follow-up to assess for regional failure and recurrence. A multicentric study can be planned, where post-operative evaluations can be performed with respect to reoccurrence and assessing the effectivity of IPN removal.

Conclusion

The present study highlights that dissection of IPNs may be proposed as a routine practice during axillary dissection in node positive breast cancer and can be avoided in node negative breast cancer during sentinel lymph node biopsy or axillary dissection. Pathological examination of IPNs separately can also be utilized as routine procedure to devise treatment plan and monitor the prognosis of the patients.

Authors’ Contributions

Study conceptualization and designing have been done by Dr. Arun Gowda Keelara, Dr. Satish C, and Dr. Rudresh H K. Material preparation, data collection, and analysis were performed by Dr. Arun Gowda Keelara and Dr. Satish C. The first draft of the manuscript was written by Dr. Arun Gowda Keelara and reviewed by Dr. Satish C, Dr. Rudresh H K, Dr. Harish K, and Dr. Kapali A S. All authors commented on previous versions of the manuscript, read, and approved the final manuscript.

Declarations

Informed Consent

Written informed consent was obtained from all the patients for surgery.

Conflict of Interest

The authors declare no competing interests.