title: Extra-nodal extension of sentinel lymph node metastasis is a marker of poor prognosis in breast cancer patients: A systematic review and an exploratory meta-analysis.
abstract: Invasive breast cancer is the most common malignancy in women. Its most common site of metastasis is represented by the lymph nodes of axilla, and the sentinel lymph node (SLN) is the first station of nodal metastasis. Axillary SLN biopsy accurately predicts axillary lymph node status and has been accepted as standard of care for nodal staging in breast cancer. To date, the morphologic aspects of SLN metastasis have not been considered by the oncologic staging system. Extranodal extension (ENE) of nodal metastasis, defined as extension of neoplastic cells through the nodal capsule into the peri-nodal adipose tissue, has recently emerged as an important prognostic factor in several types of malignancies. It has also been considered as a possible predictor of non-sentinel node tumor burden in SLN-positive breast cancer patients. We sought out to clarify the prognostic role of ENE in SLN-positive breast cancer patients in terms of overall and disease-free survival by conducting a systematic review and meta-analysis. Among 172 screened articles, 5 were eligible for the meta-analysis; they globally include 624 patients (163 ENE+ and 461 ENE-) with a median follow-up of 58 months. ENE was associated with a higher risk of both mortality (RR = 2.51; 95% CI: 1.66-3.79, p < 0.0001, I(2) = 0%) and recurrence of disease (RR = 2.07, 95% CI: 1.38-3.10, p < 0.0001, I(2) = 0%). These findings recommend the consideration of ENE from the gross sampling to the histopathological evaluation, in perspectives to be validated and included in the oncologic staging.
authors.affiliation: Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Nottegar
authors.affiliation: Department of Medicine, DIMED, University of Padua, Padua, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Veronese
authors.affiliation: Department of Surgery, Loma Linda University, Loma Linda, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Senthil
authors.affiliation: Department of Medical Oncology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: R M
authors.initials: RM
authors.lastname: Roumen
authors.affiliation: Health Service and Population Research Department, King's College London, De Crespigny Park, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Stubbs
authors.affiliation: Department of Surgery, Loma Linda University, Loma Linda, CA, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Choi
authors.affiliation: Department of Surgery, Máxima Medical Center, Veldhoven, The Netherlands.
authors.forename: N C
authors.initials: NC
authors.lastname: Verheuvel
authors.affiliation: Department of Neuroscience, University of Padua, Padua, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Solmi
authors.affiliation: Department of Surgery, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pea
authors.affiliation: Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Capelli
authors.affiliation: Department of Medicine, DIMED, University of Padua, Padua, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Department of Medicine, DIMED, University of Padua, Padua, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sergi
authors.affiliation: Department of Medicine, DIMED, University of Padua, Padua, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Manzato
authors.affiliation: Medical Oncology Unit, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Maruzzo
authors.affiliation: Department of Surgery, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Bagante
authors.affiliation: Necmettin Erbakan University, Meram Medical School Department of Radiation Oncology, Konya, Turkey.
authors.forename: M
authors.initials: M
authors.lastname: Koç
authors.affiliation: Health Science University, Konya Training and Educational Hospital, Department of General Surgery, Konya, Turkey.
authors.forename: M A
authors.initials: MA
authors.lastname: Eryilmaz
authors.affiliation: Medical Oncology, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bria
authors.affiliation: Medical Oncology, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Carbognin
authors.affiliation: Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Bonetti
authors.affiliation: Department of Pathology, Santa Chiara Hospital, Trento, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Barbareschi
authors.affiliation: Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology, Santa Chiara Hospital, Trento, Italy; ARC-NET Research Center, University and Hospital Trust of Verona, Verona, Italy. Electronic address: claudio.luchini@katamail.com.
authors.forename: C
authors.initials: C
authors.lastname: Luchini
mesh_terms: D001943:Breast Neoplasms / Q000401:mortality* / Q000473:pathology* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008197:Lymph Node Excision; D008207:Lymphatic Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D000071036:Sentinel Lymph Node / Q000473:pathology* / Q000601:surgery*; D021701:Sentinel Lymph Node Biopsy; D016019:Survival Analysis
keywords: Breast cancer; ENE; Extra-nodal; Extracapsular; Extranodal; Sentinel