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ScienceDirect EJSO xx (2014) 1e6
www.ejso.com
A prospective validation study of sentinel lymph node biopsy in multicentric breast cancer: SMMaC trial R.F.D. van la Parra a,*, W.K. de Roos b, C.M.E. Contant c, C.D.L. Bavelaar-Croon d, P.C. Barneveld e, K. Bosscha f a
Department of Surgery, Netherlands Cancer Institute e Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands b Department of Surgery, Gelderse Vallei Hospital, Ede, The Netherlands c Department of Surgery, Maasstad Hospital, Rotterdam, The Netherlands d Department of Nuclear Medicine, Gelderse Vallei Hospital, Ede, The Netherlands e Department of Nuclear Medicine, Jeroen Bosch Hospital, ’s-Hertogenbosch, The Netherlands f Department of Surgery, Jeroen Bosch Hospital, ’s-Hertogenbosch, The Netherlands Accepted 4 November 2013 Available online - - -
Abstract Background: Multicentric breast cancer is often considered a contra-indication for sentinel lymph node (SLN) biopsy due to concerns with sensitivity and false negative rate. To assess SLN feasibility and accuracy in multicentric breast cancer, the multi-institutional SMMaC trial was conducted. Methods: In this study 30 patients with multicentric breast cancer and a clinically negative axilla were prospectively included. Periareolar injection of radioisotope and blue dye was administered. In all patients SLN biopsy was validated by back-up completion axillary lymph node dissection. Results: the SLN was successfully identified in 30 of 30 patients (identification rate 100%). The incidence of axillary metastases was 66.7% (20/30). The false negative rate was 0% (0/20) and the sensitivity was 100% (20/20). The negative predictive value was 100% (10/10). Conclusion: SLN biopsy in multicentric breast cancer seems feasible and accurate and should therefore be considered in patients with multicentric breast cancer and clinically negative axilla. Ó 2014 Elsevier Ltd. All rights reserved. Keywords: Sentinel lymph node biopsy; Multicentric breast cancer; False negative rate; Axillary lymph node dissection
Introduction Sentinel lymph node (SLN) biopsy has replaced routine axillary lymph node dissection (ALND) as the standard of care to assess axillary lymph node status in clinically node negative early stage breast cancers. The procedure is minimally invasive, associated with a low false negative rate and a high accuracy that allows more than 50% of patients to be spared the morbidity of ALND. The concept of SLN biopsy has been validated for unifocal breast cancer, whereas multifocal (MF) or multicentric (MC) breast cancers are considered a (relative) contra-indication for SLN biopsy.
* Corresponding author. Department of Surgery, Netherlands Cancer Institute e Antoni van Leeuwenhoek Ziekenhuis, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. Tel.: þ31 647006347. E-mail address: [email protected] (R.F.D. van la Parra).
Multicentric breast cancer is defined as the presence of at least two invasive primary tumours in two different quadrants of the breast or in the same quadrant but at least 5 cm apart. Multifocal breast cancer is defined as multiple invasive foci located in the same quadrant of the breast. The reported incidence of multifocal and multicentric breast cancer ranges between 11% and 16%.1 Surgical therapy for patients with multifocal/multicentric invasive breast cancer traditionally included a modified radical mastectomy. Most of the sentinel lymph node biopsy studies available in literature have excluded patients with multifocal and multicentric tumours due to concern that tumours located in different quadrants of the breast might drain to different lymph node sites, which could result in inaccurate lymph node staging and higher false negative rates.2e4
0748-7983/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.11.004 Please cite this article in press as: van la Parra RFD, et al., A prospective validation study of sentinel lymph node biopsy in multicentric breast cancer: SMMaC trial, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2013.11.004
2
R.F.D. van la Parra et al. / EJSO xx (2014) 1e6
However, early5,6 and even more recent studies7e9 reported the existence of a deep and a superficial lymphatic system with a subareolar plexus that drains towards the axillary lymph nodes via one or two main lymphatic vessels thereby supporting the theory that all quadrants of the breast drain via a constant set of lymphatic pathways into to the same lymph node(s). Thus, these studies show that all quadrants of the breast drain via common afferent lymphatic channels and indicate that multiple tumours do not affect lymphatic drainage. Hence, we speculated that SLN biopsy through periareolar injection of the tracer should be accurate in multicentric breast cancers. The current Dutch guideline10 states that SLN biopsy in multicentric breast cancer is considered a relative contraindication due to concerns with accuracy and false negative rate. Large randomized trials on this topic are lacking. Furthermore, multicentric breast cancer is associated with a higher risk of sentinel node involvement compared with unifocal lesions of the same size.11 The role of SLN biopsy in multicentric breast cancer is therefore still unclear. The purpose of this validation study was to assess the feasibility of SLN biopsy in multicentric breast cancer using the periareolar injection technique.
Exclusion criteria were: ductal or lobular in situ carcinomas, clinical and/or ultrasound evidence of positive axilla, previous neo-adjuvant chemotherapy, previous breast or axillary surgery or radiotherapy and distant metastasis. If the preoperative multicentric breast cancer diagnosis was not confirmed on the surgical specimen examination, patients were excluded from the study. Lymphatic mapping technique Lymphatic mapping with SLN biopsy was performed via a 1- or 2-day protocol by periareolar intradermal injection of 25 MBq Tc-99m nanocolloid in a volume of 0.1e0.2 ml in 4 (clockwise) quadrants of the breast. Patent blue dye was injected in a volume of 1e2 ml at the same injection sites just before surgery. Static lymphoscintigraphy was performed to visualize and localize sentinel lymph nodes (SLNs) and a hand-held gamma probe (Europrobe CE 0459 system, PI Medical Diagnostic Equipment B.V., Tijnje, The Netherlands) was used to identify the sentinel lymph nodes intraoperatively. All blue and/or radioactive nodes counting 10-fold ex vivo relative to the background were regarded as sentinel lymph nodes. All patients underwent standard axillary lymph node dissection, regardless of the SLN status, in the same operation.
Patients and methods Histopathological examination Patients and data From January 2008 until January 2013 patients with a preoperative diagnosis of multicentric invasive breast cancer were prospectively included in the SMMaC (Sentinel node in Multicentric Mamma Carcinoma) trial validating the sentinel lymph node biopsy procedure in these patients. The SMMaC trial is a multicenter, national registration study with 7 participating Dutch hospitals. Approval of the Medisch Ethische Toetsing Onderzoek Pati€enten en Proefpersonen (METOPP) and the local Ethical Committee from the participating centres was obtained and all patients gave written informed consent. Multifocality was defined as multiple invasive foci located in the same quadrant of the breast at a distance less than 5 cm apart. Multicentricity was defined as the presence of at least two invasive primary tumours in two or more different breast quadrants of the breast or in the same quadrant but at least 5 cm apart. Cases of suspicious multicentric tumours identified after clinical, mammographic, ultrasound and magnetic resonance imaging (MRI) assessment had to be confirmed by positive fine needle aspiration cytology (FNAC) or core biopsy histology in at least 2 different nodules. Cases with one positive lesion associated with other suspicious nodules with atypical cells on FNAC were also included in this study. Patients were only included if they had a clinically node negative (cN0) breast carcinoma. Patients with T2 and T3 tumours were also included.
Pathological analysis consisted of serially sectioning the sentinel lymph node at 4 levels of 250 mm intervals along the longitudinal axis for permanent section. From every section, 2 parallel slides of 4 mm were made. All slides were stained with haematoxylin and eosin (HE) and with anti-cytokeratin 8. Frozen section analysis was not performed. All paraffin blocks of sentinel lymph nodes were step sectioned in 4 mm sections through the entire lymph node. Slides were then studied by immunohistochemical stain for cytokeratin and evaluated by light microscopy. Macrometastases were defined as a tumour size >2 mm and micrometastases as a tumour size between 0.2 and 2 mm. Tumours
ScienceDirect EJSO xx (2014) 1e6
www.ejso.com
A prospective validation study of sentinel lymph node biopsy in multicentric breast cancer: SMMaC trial R.F.D. van la Parra a,*, W.K. de Roos b, C.M.E. Contant c, C.D.L. Bavelaar-Croon d, P.C. Barneveld e, K. Bosscha f a
Department of Surgery, Netherlands Cancer Institute e Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands b Department of Surgery, Gelderse Vallei Hospital, Ede, The Netherlands c Department of Surgery, Maasstad Hospital, Rotterdam, The Netherlands d Department of Nuclear Medicine, Gelderse Vallei Hospital, Ede, The Netherlands e Department of Nuclear Medicine, Jeroen Bosch Hospital, ’s-Hertogenbosch, The Netherlands f Department of Surgery, Jeroen Bosch Hospital, ’s-Hertogenbosch, The Netherlands Accepted 4 November 2013 Available online - - -
Abstract Background: Multicentric breast cancer is often considered a contra-indication for sentinel lymph node (SLN) biopsy due to concerns with sensitivity and false negative rate. To assess SLN feasibility and accuracy in multicentric breast cancer, the multi-institutional SMMaC trial was conducted. Methods: In this study 30 patients with multicentric breast cancer and a clinically negative axilla were prospectively included. Periareolar injection of radioisotope and blue dye was administered. In all patients SLN biopsy was validated by back-up completion axillary lymph node dissection. Results: the SLN was successfully identified in 30 of 30 patients (identification rate 100%). The incidence of axillary metastases was 66.7% (20/30). The false negative rate was 0% (0/20) and the sensitivity was 100% (20/20). The negative predictive value was 100% (10/10). Conclusion: SLN biopsy in multicentric breast cancer seems feasible and accurate and should therefore be considered in patients with multicentric breast cancer and clinically negative axilla. Ó 2014 Elsevier Ltd. All rights reserved. Keywords: Sentinel lymph node biopsy; Multicentric breast cancer; False negative rate; Axillary lymph node dissection
Introduction Sentinel lymph node (SLN) biopsy has replaced routine axillary lymph node dissection (ALND) as the standard of care to assess axillary lymph node status in clinically node negative early stage breast cancers. The procedure is minimally invasive, associated with a low false negative rate and a high accuracy that allows more than 50% of patients to be spared the morbidity of ALND. The concept of SLN biopsy has been validated for unifocal breast cancer, whereas multifocal (MF) or multicentric (MC) breast cancers are considered a (relative) contra-indication for SLN biopsy.
* Corresponding author. Department of Surgery, Netherlands Cancer Institute e Antoni van Leeuwenhoek Ziekenhuis, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. Tel.: þ31 647006347. E-mail address: [email protected] (R.F.D. van la Parra).
Multicentric breast cancer is defined as the presence of at least two invasive primary tumours in two different quadrants of the breast or in the same quadrant but at least 5 cm apart. Multifocal breast cancer is defined as multiple invasive foci located in the same quadrant of the breast. The reported incidence of multifocal and multicentric breast cancer ranges between 11% and 16%.1 Surgical therapy for patients with multifocal/multicentric invasive breast cancer traditionally included a modified radical mastectomy. Most of the sentinel lymph node biopsy studies available in literature have excluded patients with multifocal and multicentric tumours due to concern that tumours located in different quadrants of the breast might drain to different lymph node sites, which could result in inaccurate lymph node staging and higher false negative rates.2e4
0748-7983/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.11.004 Please cite this article in press as: van la Parra RFD, et al., A prospective validation study of sentinel lymph node biopsy in multicentric breast cancer: SMMaC trial, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2013.11.004
2
R.F.D. van la Parra et al. / EJSO xx (2014) 1e6
However, early5,6 and even more recent studies7e9 reported the existence of a deep and a superficial lymphatic system with a subareolar plexus that drains towards the axillary lymph nodes via one or two main lymphatic vessels thereby supporting the theory that all quadrants of the breast drain via a constant set of lymphatic pathways into to the same lymph node(s). Thus, these studies show that all quadrants of the breast drain via common afferent lymphatic channels and indicate that multiple tumours do not affect lymphatic drainage. Hence, we speculated that SLN biopsy through periareolar injection of the tracer should be accurate in multicentric breast cancers. The current Dutch guideline10 states that SLN biopsy in multicentric breast cancer is considered a relative contraindication due to concerns with accuracy and false negative rate. Large randomized trials on this topic are lacking. Furthermore, multicentric breast cancer is associated with a higher risk of sentinel node involvement compared with unifocal lesions of the same size.11 The role of SLN biopsy in multicentric breast cancer is therefore still unclear. The purpose of this validation study was to assess the feasibility of SLN biopsy in multicentric breast cancer using the periareolar injection technique.
Exclusion criteria were: ductal or lobular in situ carcinomas, clinical and/or ultrasound evidence of positive axilla, previous neo-adjuvant chemotherapy, previous breast or axillary surgery or radiotherapy and distant metastasis. If the preoperative multicentric breast cancer diagnosis was not confirmed on the surgical specimen examination, patients were excluded from the study. Lymphatic mapping technique Lymphatic mapping with SLN biopsy was performed via a 1- or 2-day protocol by periareolar intradermal injection of 25 MBq Tc-99m nanocolloid in a volume of 0.1e0.2 ml in 4 (clockwise) quadrants of the breast. Patent blue dye was injected in a volume of 1e2 ml at the same injection sites just before surgery. Static lymphoscintigraphy was performed to visualize and localize sentinel lymph nodes (SLNs) and a hand-held gamma probe (Europrobe CE 0459 system, PI Medical Diagnostic Equipment B.V., Tijnje, The Netherlands) was used to identify the sentinel lymph nodes intraoperatively. All blue and/or radioactive nodes counting 10-fold ex vivo relative to the background were regarded as sentinel lymph nodes. All patients underwent standard axillary lymph node dissection, regardless of the SLN status, in the same operation.
Patients and methods Histopathological examination Patients and data From January 2008 until January 2013 patients with a preoperative diagnosis of multicentric invasive breast cancer were prospectively included in the SMMaC (Sentinel node in Multicentric Mamma Carcinoma) trial validating the sentinel lymph node biopsy procedure in these patients. The SMMaC trial is a multicenter, national registration study with 7 participating Dutch hospitals. Approval of the Medisch Ethische Toetsing Onderzoek Pati€enten en Proefpersonen (METOPP) and the local Ethical Committee from the participating centres was obtained and all patients gave written informed consent. Multifocality was defined as multiple invasive foci located in the same quadrant of the breast at a distance less than 5 cm apart. Multicentricity was defined as the presence of at least two invasive primary tumours in two or more different breast quadrants of the breast or in the same quadrant but at least 5 cm apart. Cases of suspicious multicentric tumours identified after clinical, mammographic, ultrasound and magnetic resonance imaging (MRI) assessment had to be confirmed by positive fine needle aspiration cytology (FNAC) or core biopsy histology in at least 2 different nodules. Cases with one positive lesion associated with other suspicious nodules with atypical cells on FNAC were also included in this study. Patients were only included if they had a clinically node negative (cN0) breast carcinoma. Patients with T2 and T3 tumours were also included.
Pathological analysis consisted of serially sectioning the sentinel lymph node at 4 levels of 250 mm intervals along the longitudinal axis for permanent section. From every section, 2 parallel slides of 4 mm were made. All slides were stained with haematoxylin and eosin (HE) and with anti-cytokeratin 8. Frozen section analysis was not performed. All paraffin blocks of sentinel lymph nodes were step sectioned in 4 mm sections through the entire lymph node. Slides were then studied by immunohistochemical stain for cytokeratin and evaluated by light microscopy. Macrometastases were defined as a tumour size >2 mm and micrometastases as a tumour size between 0.2 and 2 mm. Tumours
