Axillary Lymph Node Dissection Extension in Breast Cancer Between Under and Overtreatment Analysis of a series of cases and literature review

DANIEL ION1,2, ALEXANDRA BOLOCAN1,2*, BOGDAN SOCEA2,3, OCTAVIAN ANDRONIC1,2, GEORGIANA RADU2, DAN NICOLAE PADURARU1,2 1University Emergency Hospital Bucharest, 3rd General Surgery Clinic, 169 Splaiul Independentei, 050098, Bucharest, Romania 2Carol Davila University of Medicine and Pharmacy, 37 Dionisie Lupu Str., 020021, Bucharest, Romania 3Sf. Pantelimon Emergency Clinical Hospital, 340-342 Pantelimon Road, 021659, Bucharest, Romania

Along with the size of the tumor, the status of the axillary lymph nodes is a basic element in the staging and prognosis of breast cancer. If the first parameter can be evaluated relatively simply both clinically and imagistically, when talking about the axilla the evaluation is more complex even after the introduction of the sentinel ganglion technique. The simple equation Positive Sentinel Ganglion = Complete ALND has been discussed by numerous studies with multiple adjustments and nuances to center the surgical indication as accurately as possible without ever reaching a universally accepted algorithm [1][2][3].
Hormonal contraception increases the risk of breast cancer [4] and coexistence with ovarian cancer can be present [5].
Our retrospective study aims to analyze the accuracy of full ALND (Axillary Lymph Node Dissection) indication in early breast cancer patients in order to avoid the two extremes: under and over surgical treatment of the axilla.

Materials and methods
We present a retrospective, descriptive, unicentric study carried out between the 1 st of January 2017 and the 31 st of December 2017 in the 3rd General and Emergency Surgical Section from the Emergency University Hospital Bucharest, Romania which comprises 53 cases.
The main objective was to confront the histological examination of the ALND with the preoperative evaluation of the lymph node and their degree of overlapping.
Inclusion criteria: -Patients with breast cancer for whom mastectomy and partial / total ALND were practiced -Stage IIA (T2N0M0 / T1N1M0), IIB (T2N1M0 / T3N0M0), IIIA (T3N1M0) and IIIB (T4N1M0) -The presence of all necessary information in the HP (histopathology) result papers Exclusion criteria: -Stage IV -Conservative surgical management of the breast The consultation of available literature was conducted using the PubMed, Scopus and WoS platforms using the following keywords: santinel node biopsy and axillary lymph node dissection, with filtering of the results according to the year of publication (more recent than 2000) and the availability of in extenso articles in English.

Results and discussions
The evaluation of the studied group of patients revealed an age distribution between 28-87 years with an average of 59.01 years ( fig. 1).
Out of 53 patients in the whole lot, 25 had partial ALND (47.2%) with a 44% rate of positivity and the other 28 had complete ALND (52.8%) with a 53.76% rate of positivity (table 1).
The distribution of neoplastic disease based on TNM staging relative to the ALND positivity (detailed in table 2 and fig. 2) revealed a downward overtreatment rate from 80% in Stage IIA to 37.5% in Stage IIIB. At the same time, the degree of differentiation was a parameter correlated with the rate of positivity growing from 30% in the G1 stage to 73.3% in G3 ( fig. 3).
For patients in whom an axillary node invasion has been proven, an average number of 4.6 invaded ganglions were identified. The number of invaded nodes in relation to the stage (table 3) has highlighted a smaller average value in patients with a IIIB stage when compared to patients with a IIIA stage.
In what concerns the immunohistochemical profile, the highest positivity rate in the studied lot was identified in the group of patients with ER+PR+HER (table 4).
Most patients with positive SLN in early-stage breast cancer have no additional metastasis in non-SLN, as proven by the ALND [3,6]. These patients are at risk of morbidity from excessive axillary dissection, without any benefit in what concerns the survival rate.
Despite numerous studies on the issue, discussions on the most rigorous selection criteria to reduce unnecessary ALND still persist [7].
Even in the case of SLN, the non-SLN positive frequency does not exceed 1/3 in some studies [8][9][10]. The rest, i.e. almost 2/3, the ganglia located beyond the sentinel group are not invaded, so they should not be removed. The question arises whether there is a factor or a group of quantifiable factors that could help nuance the indication of ALND so as to minimize axilla overtreatment [11][12][13].
The first of these factors was the positive SLN aspect: the presence of two macrometastases in patients programmed for breast conservative surgery, in which the entire breast irradiation and systemic adjuvant treatment were mandatory, requires ALND [14].
A second factor is the differentiation between micro and macrometastases [15][16][17][18]. A cancer cell depot must contain more than 200 cells or a size of at least 0.2 mm to modify stage N. Otherwise, even if it does not alter the N stage, it also attracts the addition of an abbreviation (i + <isolated tumor cell>for a small number of immunohistochemically identified cells, mol + when cells cannot be visualized but are identified by RT-PCR) to identify how the invasion is highlighted. The scattering range of cancer cells ranging from 0.2mm to 2mm defines the micrometastasis. Any area greater than 2 mm defines macrometastasis and changes the N stage [19][20][21].
The third factor is the use of the S classification of SLN and microanatomic location of SLN metastases. The S classification uses the maximum depth of metastatic invasion measured from the inner layer of the capsule to the tumor cell mass. Based on this distance, 3 stages are     Patients with only subcapsular SLN metastasis (SI) have the lowest risk of metastasis in nonSLNs, being therefore included in the category where ALND is not indicated. This reduces the batch of overtreatment according to classical criteria [9]. The fourth factor is the microanatomic location (MAL) of the tumor deposit in the sentinel ganglion. Tumor deposits are mapped inside the SLN having a prognostic value relative to location. From the combination of the possible mapping variants into the ganglion, 5 categories are shown: only subcapsular, parenchymal, subcapsular and parenchymal, multifocal metastatic disease and extended metastatic disease, including extracapsular invasion [22].
Furthermore, studies have shown that the apparition of lymph nodes recurrences is not related to the occurrence of distant metastases, and that they can be identified previously, simultaneously or afterwards [23][24][25][26][27][28]. The evolution in terms of survival and the occurrence of local recurrences in breast cancer patients who were treated with ALND did not show any significant differences from those with SNB alone, regardless of their positivity [29][30][31]. The associated comorbidities may play a role in the final prognosis [32][33][34][35][36].
Breast tumors can be divided according to their histological forms into favorable (tubular, mucinous and papillary), and aggressive (comedo, inflammatory), as well as according to the G1, G2 and G3 grading. Framing the tumor through a biopsy into these categories can weight in the decision regarding the ALND indication and extension -partial or complete.

Conclusions
To conclude, we have drawn the following final ideas from the study and literature review: Surgery of the axilla in breast cancer is of value in both staging and the therapeutic management. Establishing the degree of extension of nerve courage has been made over the last decades on the basis of questionable criteria in which positive SLN occupied the central site but led to an unacceptable percentage of cases of overtreatment.
Partial ALND and qualitative extemporaneous HP outcome by adopting the S Classification and MAL requires time and cooperation, but can reduce the number of completely abusive ALNDs.
A periodic review of HP results after ALND and the reassessment of the opportunity for ALND for each case helps improving the indication [37].
The temptation of the extension of the surgical gesture exists and follows a certain routine and even a general resistance to the paradigm changes.