Sentinel lymph-node biopsy in breast cancer
Biopsia del linfonodo sentinella nel tumore della mammella
Dott. Walter Antonelli
Divisione di Chirurgia, Ospedale di Macerata
La biopsia del linfonodo sentinella (SLNB) e una metodica innovativa di stadi azione del coinvolgimento linfonodale ascellare nelle pazienti affette da carcinoma mammario; tale metodica si basa sul concetto che attraverso l’identificazione e l’esame istologico del linfonodo sentinella si può stabilire il drenaggio linfatico linfatico dal sito tumorale. Scopo del lavoro e stato quello di valutare l’impatto della biopsia del linfonodo sentinella nel trattamento delle pazienti con carcinoma mammario in fase precoce.
Trecentoquarantuno pazienti con carcinoma mammario in fase iniziale, con diametro < 2 cm (< 3 cm a partire da gennaio 2012) e con linfonodi ascellari clinicamente indenni sono state arruolate per lo studio. Nelle fasi iniziali dello studio è stata impiegata la tecnica radioguidata.
Il linfonodo sentinella e risultato positivo in 108 pazienti (81.7%); in 22 pazienti sono state riscontrate micrometastasi e in un solo caso cellule tumorali isolate. Il numero medio di linfonodi sentinella rimossi e stato di 1.8. In 57 casi su 108 il linfonodo sentinella è risultato essere l’unico positivo (52.8%). La percentuale di recidive ascellari nelle pazienti linfonodo sentinella-negativo è stata dello 0%.
L’accuratezza diagnostica del SLNB nella stadiazione dello stato linfonodale ascellare è stata ormai confermata in numerosi studi. Il tasso di recidiva ascellare è stimato dello O-1.6% in diverse casistiche, mentre varia dallo O al 3% dopo linfoadenectomia ascellare. Nella nostra esperienza non abbiamo osservato recidive ascellari nelle 233 pazienti linfonodo sentinella-negativo (follow-up mediano 33 mesi), a conferma dell’accuratezza della metodica.
Sentinel lymph-node biopsy is an innovative method for axillary staging in breast
cancer patients, based on the concept that information about the status of the entire lymphatic drainage from a tumour site could be obtained by identiﬁcation and sampling of a “sentinel node”.
The aim of the study was to evaluate the impact of sentinel lymph-node biopsy in the management of patients with early invasive breast carcinoma.
Three hundred and forty-one patients with primary invasive breast carcinoma
measuring less than 2 cm (less than 3 cm from January 2012) and clinically negative axillary nodes were recruited into the study.
Sentinel lymph-nodes were positive for metastases in 108/841 cases (31.7%). Micrometastases were found in 22 patients and isolated tumour cells in 1 case. The mean number of sentinel lymph-nodes removed was 1.8 per patient. The sentinel lymph-node was the only positive node in 57 of 108 patients (52.8%). The percentage of axillary recurrence in sentinel lymph-node-negative patients was 0%. The accuracy of sentinel lymph-node biopsy for axillary staging has been confirmed in many studies. Axillary recurrences after sentinel lymph-node biopsy range from O to 1.6% in many series, while axil|ary recurrence after axillary lymph-node dissection is about O-3%. In our experience we observed no axillary recurrences in
283 patients with sentinel lymph-node biopsy alone, with a median follow-up of 33 months, confirming the accuracy of the procedure, and sentinel lymph-node negative patients with sentinel lymph-node biopsy alone are no more at risk for axillary recurrences than those undergoing axillary lymph-node dissection.
Axillary lymph-node dissection(ALND) has been the surgical standard treatment of the axilla for breast cancer patients for decades.
It provides staging information as well as reducing axillary recurrence.The mammographic screening programs led to an increase in the number of women diagnosed with small primary breast cancer with axillary lymph-nodes free of metastases(l).
Sentinel lymph-node biopsy(SLNB) is an innovative method for axillary staging in breast cancer patients,based on the concept that information about the status of theentire lymphatic drainage from a
tumor site could be obtained by identification and sampling of a
“sentinel node”(2). The technique of SLNB is simple and concerns the
identification and subsequent removal of the initial lymph-nodes upon which primary tumour drains. Histopathological evaluation of these nodes identify patients who are likely to be node negative, avoiding ALND and associated major problems such as pain,restriction of arm motion,neurovascular injury or chronic lymphoedemam (1-3). In the present study, we report our prospective experience from a community-based Breast Cancer Unit.We adopted SLNB as standard procedure for all patients presenting with early invasive breast cancer.
The aim of the study was to evaluate the impact of SLNB in the management of all women with early invasive breast carcinoma.
Materials and methods
Between March 2006 and October 2013, 34l patients presenting at our
Institution with primary invasive breast carcinoma measuring less
than 2 cm,(less than 3 cm from January 2012) and clinically negative
axillary nodes were entered into the study Patients who had previous excision of the primary tumor or multicentric lesions were excluded. All patients were informed of the aims of the procedure and signed a consent form at the time of admission. The diagnosis of invasive breast carcinoma was performed by fine needle or core needle biopsy prior to surgery in all cases. The median follow-up was 53 months with a maximum time of 94 months and a minimum follow-up time of 23 months.
Patients characteristics are summarized in Table1. The combined technique using radioactive tracerwas performed to identify SLNB.
A detailed report of both methods used to identify the SLN is entirely
described in a previous trial performed by the Authors (4).In short, on the day before surgery the radioactive tracer was injected peritumour by nuclear medicine physician if cancer was palpable.
Ultrasound or mammographic localization was used for not palpable lesions. Colloidal particles of human albumin (Nanocoll,Sorin Biomedica,Saluggia,Italy) labeled with 300 mCi of 99″‘Technetium
were used as radioactive tracer.A two projection lymphoscintigram
was used to identify any “hot spot” in the draining basin and skin
marks were placed to facilitate axillary incision. Following removal of each node, the gamma probe was placed back into the wound to identify additional sentinel nodes. Suspicious palpable nodes detected during the procedure were excised also. All removed nodes were submitted for definitive histologic evaluation. Complete axillary dissection was performed whereas sentinel nodes contained metastases.
Histological examination of sentinel node was made on a few sections of the specimen such as lymph-nodes of a typical axillary dissection. The number of sectionswas increased, so that it was possible a complete examination of the whole sentinel node to detect micrometastases.
Here is described the techniqueused at our lnstitution. First,the SLN
is sliced at 2 mm intervals perpendicular to long axis. One routine haematoxylin-eosin (H&E) stained section is examined; if negative, serial level slices are performed through each block (two sections for each level,with aspacing of 50 micro between the following levels).One segment for each level is stained with H&E and one is for an additional immuno-histochemical analysis with keratins to compare cluster of histologically suspected cells. This approach offers a good sensitivity for detection of micrometastases and isolated tumoral cells with reasonable costs.
Recently there is a trend toward examining the entire lymph-node at
0.25 mm intervals with keratin,to be sure to detect ITC (isolated tumoral cells).This procedure has the highest rate of specificity(100%),but some controversy exists to accept it as standard protocol because the clinical significance of these occult metastases will be determined by long-term follow-up.For this reason the above mentioned method is not usually employed by the Authors.
The SLNB was identified in 331 of 341 cases,calculating an identification rate of 97% with a false negative rate of 0%. More frequent histotype was ductal cancer (260 cases) ; a lymphovascular invasion was found in 128 patients,while neural invasion in 61.Positiveness for ER was frequent,288 on 332 tested histological specimen; a similar report was recorded for PgR (283 positive cases). HER2/neu overexpression showed the following profile: 180 patients were negative, 30 patients had a 1+ positivity,23 expressed a 2+ positivity and 35 patients had an intense and complete expression (3+).More histological findings are enlisted in Table ll.
SLNs were positive for metastases in 108 of 341 cases (31.7); micrometastases were found in 22 patients and isolated tumoral cells in 1 case.The mean number of SLNs removed was 1.8 per patients. See
Table2 for further nodes characteristics.
The SLN was the only positive node in 57 of 108 patients (52.8%).
The percentage of axillary recurrence in SLN negative patients was
0%.ln our experience after the first 3 years in which SLNB was per-
formed with an admission of 2-3days,starting from 2003 sentinel
biopsy is carried out in Day-Surgery regimen.
it has been well accepted that the node that receives drainage directly from the primary tumour “sentinel node” — is the first to be involved when lymphatic dissemination occurs (5). SLNB is a minimally invasive surgical procedure that can be easily carried out by experienced surgeons working in experienced teams, after a learning curve of about 20-30 cases and by maintaining experience by performing at least six procedures a month (6-7). If general recommendations regarding the learning curve and the technique are f0llowed,the procedure can be carried out easily by the sentinel node team that include breast surgeon, nuclear medicine physician and pathologist. The accuracy of SLNB for axillary staging has been confirmed in many studies; a review of 2160 patients with breast cancer showed that the radioactive tracer method was able to detect the sentinel lymph-node in 93.6% of cases (range 88%-100%),with a predicted
negative value of 96.6% (range 88%-100%),an accuracy of 96.8% (range 96%-100%),and a false negative rate of 3.8% (range 0-15%).An important data emerging from the review is that the higher the number of evaluated cases, the higher is the accuracy and the lower is the rate of false negative. The learning curve is about 20-30 patients (4). A review of 1219 patients operated for breast carcinoma in the same period proved that blue dyeing was successful to localize sentinel lymph-nodes in 83% of cases (range 66-97%). Predicted negative value was 95% (range of 81-100%),while the accuracy was 93% (ranging from 81% to 100%) and the false negative ratewas7.5% (range of 5-12%)(4).In a previous study performed on 102 patients comparing both methods, the Authors reported that the lymphoscintigraphy had a higher rate of identification of lymphnodes than the patent blue method (97% us 73%); the false negativerates were respectively 0 and 8%; the predicted negative values were 100% and 92% and the accuracy was 100% and 92% (4).
About 30-40% of patients with early breast cancer have positive axillary lymph-nodes, the remaining 60-70% of patients are lymph-node negative and may therefore be overtreated with ALND,with the disadvantage of early and late complications as seroma, pain, limited arm motion, numbness or lymphoedema of the arms (8). Axillary recurrences after SLNB range between 0 and 1.6% in many series (see Table3),while axillary recurrence after ALND is about 0-3%(18). In our experience we observed no axillary recurrence in 233 patients with SLNB alone with a median follow-up of 53 months confirming the accuracy of SLNB and SLN negative patients with SLNB alone are not at risk for axillary recurrences more than ALND.
Anyway the complete knowledge of long-term outcomes of SLNB without ALND must be evaluated with prospective randomised studies. To date there are many trials that are evaluating the recurrence and the survival after SLNB: the European ALMANAC (Axillary Lymphatic Mapping Against Nodal Axillary Clearance)(19), the American NSABP-32 (National Surgical Adjuvant Bowel and Breast Project)(20) and the trial of European Institute
of Oncology (EIO).The latter, per- formed by Veronesi et al,showed
that there are no differences in term of axillary recurrence between patients undergoing SLNB and ALND (14).The other two studies are in the recruitment phase. What has not confidently been determined is the real benefit of further ALND in case of positive SLN. Other studies are currently investigating the need of completion ALND in patients with positive SLNs. The EORTC 10981 AMAROS (After Mapping of Axilla Radiotherapy or Surgery) trial is comparing axillary radiotherapy versus completion ALND in patients with a tumourpositive SLN and hopes to find comparable loco-regional control with less morbidity in the patients treated with axillary radiotherapy (21). The ACSOG Z0011 (American College of Surgeons Oncology Group) trial is randomizing patients with a tumour positive SLNB to ALND and noALND;both groups of patients receive systemic therapy and breast irradiation. Objective of this study is to look for differences in survival, local control and morbidity between two groups (22).
Nevertheless the results of prospective randomised trials in terms of
some technical aspects and long term results are not available, we believe that in the hands of an experienced team of professionals (Nuclear Medicine, Surgery and Pathology),SLNB without ALND in negative SLN breast cancer appears to be a safe and reliable procedure to determine nodal status and ensure loco-regional control of the neoplastic disease, as now well reported in the Annual S.Antonio Breast Cancer Symposium 2011 (23).
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Tabella 1. Characteristics of the 341 study patients
| T (clinical)
Tabella 2. Tumor characteristics in 341 patients undergoing
| Ductal and lobular
|Lynphovascular Invasion (LVI)
| Not specified
| Not Specified
| Not Tested
| Not Tested
| Not Tested
Tabella 3. Nodes characteristics in 341 patiente undergoing sentinel
|Average number of sentinel node per patient
|Number of sections of sentinel node analysed
|Isolated tumour cells