Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Abstract

incidence and epidemiologyIn 2008, the estimated age-adjusted annual incidence of breast cancer in Europe (40 countries) was 88.4/100 000 and the mortality 24.3/100 000. The incidence increased after the introduction of mammography screening and continues to do so with the aging of the population. The most important risk factors include genetic predisposition, exposure to estrogens (endogenous and exogenous) and ionising radiation, low parity and history of atypical hyperplasia. The Western-style diet, obesity and consumption of alcohol also contribute to the rising incidence of breast cancer [2.McTiernan A. Behavioral risk factors in breast cancer: can risk be modified?.Oncologist. 2003; 8: 326-334Crossref PubMed Scopus (104) Google Scholar]. There is a steep age gradient, with about a quarter of breast cancers occurring before age 50, and <5% before age 35. The estimated prevalence of breast cancer in Europe in 2010 was 3 763 070 cases [3.Gatta G. Mallone S. van der Zwan J.M. et al.Cancer prevalence estimates in Europe at the beginning of 2000.Ann Oncol. 2013; 24: 1660-1666Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar] and is increasing, both as a consequence of increased incidence and of improvements in treatment outcomes. In most Western countries, the mortality rate has decreased in recent years, especially in younger age groups because of improved treatment and earlier detection [4.Autier P. Boniol M. La Vecchia C. et al.Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database.BMJ. 2010; 341: c3620Crossref PubMed Scopus (265) Google Scholar]. However, breast cancer is still the leading cause of cancer-related deaths in European women.Breast cancer in males is rare, contributing ∼1% of cases. The major risk factors include clinical disorders carrying hormonal imbalances, radiation exposure and, in particular, a positive family history and genetic predisposition [5.Ottini L. Palli D. Rizzo S. et al.Male breast cancer.Crit Rev Oncol Hematol. 2010; 73: 141-155Crossref PubMed Scopus (96) Google Scholar].diagnosis and pathology/molecular biologyEighteen European countries have established national or regional population-based mammography screening programmes with the purpose of detecting breast cancers at a pre-clinical stage, in order to improve the chance of survival [6.Giordano L. von Karsa L. Tomatis M. et al.Mammographic screening programmes in Europe: organization, coverage and participation.J Med Screen. 2012; 19: 72-82Crossref PubMed Scopus (103) Google Scholar]. The European Guidelines for quality assurance in breast cancer screening and diagnosis recommend standards and describe performance parameters and indicators that should be monitored in any screening programme [7.Perry N. Broeders M. deWolf C. et al.European guidelines for quality assurance in breast cancer screening and diagnosis.4th edition. European Commission Office for Official Publications of the European Communities, Luxembourg2006Google Scholar]. Biannual mammography screening has been shown to have the greatest effect on breast cancer mortality reduction in the age group of 50–69 years and mammography screening in this age group is recommended by the European Union and numerous countries [8.Association of European Cancer LeaguesEuropean Union Council Recommendation on Cancer Screening http://www.europeancancerleagues.org/cancer-in-europe/resources-on-cancer-in-europe/82-eu-council-recommendation-on-cancer-screening.html (2 July 2013, date last accessed).Google Scholar], while the effect in women aged 40–49 years is disputed [9.Gøtzsche P.C. Nielsen M. Screening for breast cancer with mammography.Cochrane Database Syst Rev. 2011; 1: CD001877Crossref PubMed Google Scholar]. There is no consensus about the exact effect of mammography screening on breast cancer mortality reduction, and the estimates reported vary. In a recent UK review of the randomised, controlled mammography trials, a 20% relative breast cancer mortality reduction was estimated in women invited to screening in the age group of 50–70 years [10.Independent UK Panel on Breast Cancer Screening The benefits and harms of breast cancer screening: an independent review.Lancet. 2012; 380: 1778-1786Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar], although the review stresses the importance of taking into account the risk of overdiagnosis and overtreatment as well as false-positive screening when balancing the benefits and harms of screening. Additionally, screening programmes carry the risk of false-negative results and consequently a false feeling of security among patients and doctors.In women with familial breast cancer with or without proven BRCA mutations, annual screening with magnetic resonance imaging (MRI) of the breast in combination with mammography can detect the disease at a more favourable stage compared with mammography screening alone (70% lower risk to be diagnosed with breast cancer stage II or higher). It is not known, however, whether breast cancer mortality is lowered [11.Warner E. Messersmith H. Causer P. et al.Systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer.Ann Intern Med. 2008; 148: 671-679Crossref PubMed Google Scholar].The diagnosis of breast cancer is based on clinical examination in combination with imaging, and confirmed by pathological assessment (Table 1). Clinical examination includes bimanual palpation of the breasts and locoregional lymph nodes and assessment for distant metastases (bones, liver, lungs and neurological examination in the case of symptoms). Imaging includes bilateral mammography and ultrasound of the breast and regional lymph nodes. The added value of ultrasound is well proven. An MRI of the breast is not routinely recommended, but may be considered in cases of familial breast cancer associated with BRCA mutations, breast implants, for lobular cancers, before neoadjuvant chemotherapy or when the findings of conventional imaging are inconclusive such as positive axillary lymph node status with occult primary tumour in the breast, suspicion of multifocality/multicentricity (in particular in lobular breast cancer) and for evaluating response to primary systemic therapy [12.Sardanelli F. Boetes C. Borisch B. et al.Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group.Eur J Cancer. 2010; 46: 1296-1316Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar]. Several new techniques are being tested for screening and diagnostic imaging, such as 3D mammography (breast tomosynthesis), 3D ultrasound, shear wave elastography, and contrast-enhanced mammography/spectral mammography. None of them is routinely implemented as yet, but all show promising preliminary results and could increase diagnostic accuracy, especially in women with dense breasts [13.Rafferty E.A. Park J.M. Philpotts L.E. et al.Assessing radiologist performance using combined digital mammography and breast tomosynthesis compared with digital mammography alone: results of a multicenter, multireader trial.Radiology. 2013; 266: 104-113Crossref PubMed Scopus (281) Google Scholar].Table 1Diagnostic work-up for early breast cancerAssessment of general health statusHistoryMenopausal statusPhysical examinationFull blood countLiver and renal function tests, alkaline phosphatase and calciumAssessment of primary tumourPhysical examinationMammographyBreast ultrasoundBreast MRIaNot routinely recommended, but may be considered in cases of familial breast cancer associated with BRCA mutations, breast implants, for lobular cancers, before neoadjuvant chemotherapy or when the findings of conventional imaging are inconclusive (see the text).BiopsyAssessment of regional lymph nodesPhysical examinationUltrasoundUltrasound-guided biopsy if suspiciousAssessment of metastatic diseasePhysical examinationOther tests are not routinely recommended, unless locally advanced or when symptoms suggestive of metastases are presenta Not routinely recommended, but may be considered in cases of familial breast cancer associated with BRCA mutations, breast implants, for lobular cancers, before neoadjuvant chemotherapy or when the findings of conventional imaging are inconclusive (see the text). Open table in a new tab Apart from imaging, pretreatment disease evaluation includes pathological examination of the primary tumour and cytology/histology of axillary nodes if involvement is suspected. Other assessments include complete personal medical history, family history relating to breast/ovarian and other cancers, physical examination, full blood count, liver and renal function tests, alkaline phosphatase and calcium. Assessing the menopausal status is imperative, if in doubt by measuring serum estradiol and follicle-stimulating hormone levels.Pathological diagnosis should be based on a core needle biopsy obtained manually or, preferably, by ultrasound or stereotactic guidance. A core needle biopsy (or, if that is not possible, at least a fine needle aspiration indicating carcinoma) must be obtained before any type of treatment. If preoperative systemic therapy is planned, a core needle biopsy is mandatory to ensure a diagnosis of invasive disease and assess biomarkers, and a marker (e.g. surgical clip, carbon) should be placed into the tumour at biopsy to facilitate evaluation of tumour response during treatment and to ensure surgical resection of the correct site [V, A]. As a minimum, ultrasound-guided fine needle aspiration or core biopsy of suspicious lymph nodes should be carried out. In patients with clinically and imaging negative axilla, the best timing to carry out sentinel lymph node biopsy (SLNB), before or after preoperative systemic therapy, remains controversial.Final pathological diagnosis should be made according to the World Health Organization (WHO) classification [14.Lakhani S.R. Ellis I.O. Schnitt S.J. et al.WHO Classification of Tumours.4th edition. IARC WHO Classification of Tumours, IARC Press, Lyon2012Google Scholar] and the tumour–node–metastases (TNM) staging system analysing all tissue removed. The pathological report should include the histological type, grade, immunohistochemical (IHC) evaluation of estrogen receptor (ER) status using a standardised assessment methodology (e.g. Allred or H-score), and, for invasive cancer, IHC evaluation of PgR and HER2 receptor expression. HER2 gene amplification status may be determined directly from all tumours using in situ hybridisation (fluorescent or chromogenic or silver in situ hybridisation), replacing IHC or only for tumours with an ambiguous (2+) IHC score [II, B] [15.Hammond M.E. American Society of Clinical Oncology-College of American Pathologists guidelines for breast predictive factor testing: an update.Appl Immunohistochem Mol Morphol. 2011; 19: 499-500Crossref PubMed Scopus (0) Google Scholar]. Proliferation markers such as the Ki67 labelling index may supply additional useful information, particularly if the assay can be standardised [V, A] [16.Dowsett M. Nielsen T.O. A'Hern R. et al.Assessment of Ki67 in breast cancer: recommendations from the International Ki-67 Breast Cancer Working Group.J Natl Cancer Inst. 2011; 103: 1656-1664Crossref PubMed Scopus (0) Google Scholar, 17.Guiu S. Michiels S. André F. et al.Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 working group statement.Ann Oncol. 2012; 23: 2997-3006Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar]. Alternatively, these biological markers can be assessed in the definitive surgical specimen if primary systemic therapy is not planned, although fixation is better controlled for core biopsies, allowing safer antigen preservation for IHC [18.Mann G.B. Fahey V.D. Feleppa F. Buchanan M.R. Reliance on hormone receptor assays of surgical specimens may compromise outcome in patients with breast cancer.J Clin Oncol. 2005; 23: 5148-5154Crossref PubMed Scopus (106) Google Scholar]. In case of negativity of ER/PgR and HER2 in the biopsy specimen, it is advisable to retest them in the surgical specimen, to account for the putative tumour heterogeneity [19.Chen X. Yuan Y. Gu Z. Shen K. Accuracy of estrogen receptor, progesterone receptor, and HER2 status between core needle and open excision biopsy in breast cancer: a meta-analysis.Breast Cancer Res Treat. 2012; 134: 957-967Crossref PubMed Scopus (62) Google Scholar].For the purpose of prognostication and treatment decision-making, tumours are grouped into surrogate intrinsic subtypes defined by routine histology and IHC data (Table 2) [20.Goldhirsch A. Winer E.P. Coates A.S. et al.Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.Ann Oncol. 2013; 24: 2206-2223Abstract Full Text Full Text PDF PubMed Scopus (1554) Google Scholar].Table 2Surrogate definitions of intrinsic subtypes of breast cancer according to the 2013 St Gallen Consensus Conference and also recommended by the ESMO Clinical Practice Guidelines [20.Goldhirsch A. Winer E.P. Coates A.S. et al.Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.Ann Oncol. 2013; 24: 2206-2223Abstract Full Text Full Text PDF PubMed Scopus (1554) Google Scholar]Intrinsic subtypeClinicopathologic surrogate definitionNotesLuminal A‘Luminal A-like’•ER-positive•HER2-negative•Ki67 low*•PgR high***The cut-off point between high and low values for Ki67 varies between laboratories.**Suggested values are 20% for both PgR and Ki67, but laboratory specific cut-off points can be used to distinguish between low and high values for Ki67 and PgR; quality assurance programmes are essential for laboratories reporting these results.Luminal B‘Luminal B-like (HER2-negative)’•ER-positive•HER2-negative•and either•Ki67 high or•PgR low‘Luminal B-like (HER2-positive)’•ER-positive•HER2-positive•any Ki67•any PgRHER2 overexpression‘HER2-positive (non-luminal)’•HER2-positive•ER and PgR absent‘Basal-like’‘Triple-negative (ductal)’•ER and PgR absent•HER2-negativeThere is ∼80% overlap between ‘triple-negative’ and intrinsic ‘basal-like’ subtype, but ‘triple-negative’ also includes some special histological types such as (typical) medullary and adenoid cystic carcinoma with low risks of distant recurrence. Open table in a new tab staging and risk assessmentDisease stage should be assessed according to the TNM system (Tables 3 and 4). In early breast cancer, routine staging evaluations are directed at locoregional disease, as asymptomatic distant metastases are very rare and patients do not benefit from comprehensive laboratory (including tumour markers [21.Harris L. Fritsche H. Mennel R. et al.American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer.J Clin Oncol. 2007; 25: 5287-5312Crossref PubMed Scopus (1692) Google Scholar]) and radiological staging [III, D]. Additional investigations such as chest computed tomography (CT), abdominal ultrasound or CT scan and bone scan should be considered for patients with clinically positive axillary nodes, large tumours (e.g. ≥5 cm) or clinical signs, symptoms or laboratory values suggesting the presence of metastases [III, B]. Dual imaging methods combining functional and anatomical information such as fluorodeoxyglucose positron emission tomography (FDG-PET)/CT may be useful when conventional methods are inconclusive. Current evidence does not support the use of FDG-PET/CT in the staging procedure of local/regional disease, due to limited specificity compared with the gold standard methods for axillary staging —SLNB and axillary lymph node dissection [22.Robertson I.J. Hand F. Kell M.R. FDG-PET/CT in the staging of local/regional metastases in breast cancer.Breast. 2011; 20: 491-494Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar].Table 3Tumour–node–metastases (TNM) staging system for carcinoma of the breast [27.National Cancer Institute PDQ® Breast Cancer Treatment. National Cancer Institute, Bethesda, MD2013www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessionalGoogle Scholar]Primary tumour (T)aDCIS, ductal carcinoma in situ; LCIS, called lobular carcinoma in situ. Post-treatment ypT: The use of neoadjuvant therapy does not change the clinical (pre-treatment) stage. Clinical (pre-treatment) T will be defined by clinical and radiographic findings, while y pathological (post-treatment) T will be determined by pathological size and extension. The ypT will be measured as the largest single focus of invasive tumour, with the modifier ‘m’ indicating multiple foci. The measurement of the largest tumour focus should not include areas of fibrosis within the tumour bed.,bThe T classification of the primary tumour is the same regardless of whether it is based on clinical or pathological criteria, or both. Designation should be made with the subscript ‘c’ or ‘p’ modifier to indicate whether the T classification was determined by clinical (physical examination or radiological) or pathological measurements, respectively. In general, pathological determination should take precedence over clinical determination of T size.,cSize should be measured to the nearest millimetre.,dMultiple simultaneous ipsilateral primary carcinomas are defined as infiltrating carcinomas in the same breast, which are grossly or macroscopically distinct and measurable. T stage is based only on the largest tumour. The presence and sizes of the smaller tumour(s) should be recorded using the ‘(m)’ modifier. TXPrimary tumour cannot be assessed T0No evidence of primary tumour TisCarcinoma in situ Tis (DCIS)Ductal carcinoma in situ Tis (LCIS)Lobular carcinoma in situ Tis (Paget's)Paget's disease (Paget disease) of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget's disease are categorised based on the size and characteristics of the parenchymal disease, although the presence of Paget's disease should still be noted. T1Tumour ≤20 mm in greatest dimension T1miTumour ≤1 mm in greatest dimension T1aTumour >1 mm but ≤5 mm in greatest dimension T1bTumour >5 mm but ≤10 mm in greatest dimension T1cTumour >10 mm but ≤20 mm in greatest dimension T2Tumour >20 mm but ≤50 mm in greatest dimension T3Tumour >50 mm in greatest dimension T4Tumour of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)eInvasion of the dermis alone does not qualify as T4; dimpling of the skin, nipple retraction or any other skin change except those described under T4b and T4d may occur in T1, T2 or T3 without changing the classification. The chest wall includes ribs, intercostal muscles and serratus anterior muscle, but not the pectoralis muscles. T4aExtension to the chest wall, not including only pectoralis muscle adherence/invasion T4bUlceration and/or ipsilateral satellite nodules and/or oedema (including peau d'orange) of the skin, which do not meet the criteria for inflammatory carcinoma T4cBoth T4a and T4b T4dInflammatory carcinomafInflammatory carcinoma is a clinical–pathological entity characterised by diffuse erythema and oedema (peau d'orange) involving a third or more of the skin of the breast. These skin changes are due to lymphoedema caused by tumour emboli within dermal lymphatics. Although dermal lymphatic involvement supports the diagnosis of inflammatory breast cancer, it is neither necessary nor sufficient, in the absence of classical clinical findings, for the diagnosis of inflammatory breast cancer.Regional lymph nodes (N) Clinical (cN)gClassification is based on axillary lymph node dissection with or without SLNB. Classification based solely on SLNB without subsequent axillary lymph node dissection is designated (sn) for ‘sentinel node’, e.g. pN0(sn)., hIsolated tumour cell clusters (ITCs) are defined as small clusters of cells not >0.2mm, or single tumour cells, or a cluster of <200 cells in a single histological cross-section. ITCs may be detected by routine histology or by immunohistochemical (IHC) methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated., iPost-treatment yp ‘N’ should be evaluated as for pre-treatment ‘N’. The modifier ‘sn’ is used if a sentinel node evaluation was carried out. If no subscript is attached, it is assumed that the axillary nodal evaluation was by axillary node dissection., jypN categories are the same as those for pN., kClinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathological macrometastasis based on fine needle aspiration biopsy with cytological examination. Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, e.g. cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, e.g. cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine needle aspiration, core biopsy or sentinel lymph node biopsy. Pathological classification (pN) is used for excision or SLNB only in conjunction with a pathological T assignment.NXRegional lymph nodes cannot be assessed (e.g. previously removed)N0No regional lymph node metastasesN1Metastases to movable ipsilateral level I, II axillary lymph node(s)N2Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in clinically detectedkClinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathological macrometastasis based on fine needle aspiration biopsy with cytological examination. Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, e.g. cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, e.g. cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine needle aspiration, core biopsy or sentinel lymph node biopsy. Pathological classification (pN) is used for excision or SLNB only in conjunction with a pathological T assignment. ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasesN2aMetastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structuresN2bMetastases only in clinically detectedkClinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathological macrometastasis based on fine needle aspiration biopsy with cytological examination. Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, e.g. cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, e.g. cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine needle aspiration, core biopsy or sentinel lymph node biopsy. Pathological classification (pN) is used for excision or SLNB only in conjunction with a pathological T assignment. ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastasesN3Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement; or in clinically detectedkClinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathological macrometastasis based on fine needle aspiration biopsy with cytological examination. Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, e.g. cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, e.g. cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine needle aspiration, core biopsy or sentinel lymph node biopsy. Pathological classification (pN) is used for excision or SLNB only in conjunction with a pathological T assignment. ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvementN3aMetastases in ipsilateral infraclavicular lymph node(s)N3bMetastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)N3cMetastases in ipsilateral supraclavicular lymph node(s)Regional lymph nodes (N) Pathological (pN)hIsolated tumour cell clusters (ITCs) are defined as small clusters of cells not >0.2mm, or single tumour cells, or a cluster of <200 cells in a single histological cross-section. ITCs may be detected by routine histology or by immunohistochemical (IHC) methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated., iPost-treatment yp ‘N’ should be evaluated as for pre-treatment ‘N’. The modifier ‘sn’ is used if a sentinel node evaluation was carried out. If no subscript is attached, it is assumed that the axillary nodal evaluation was by axillary node dissection., jypN categories are the same as those for pN., kClinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathological macrometastasis based on fine needle aspiration biopsy with cytological examination. Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, e.g. cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, e.g. cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine needle aspiration, core biopsy or sentinel lymph node biopsy. Pathological classification (pN) is used for excision or SLNB only in conjunction with a pathological T assignment.pNXRegional lymph nodes cannot be assessed (e.g. previously removed or not removed for pathological study)pN0No regional lymph node metastasis identified histologicallypN0(i–)No regional lymph node metastases histologically, negative immunohistochemistry (IHC)pN0(i+)Malignant cells in regional lymph node(s) not >0.2 mm [detected by haematoxylin and eosin (H&E) staining or IHC including isolated tumour cell clusters (ITCs)]pN0(mol–)No regional lymph node metastases histologically, negative molecular findings (RT–PCR)lRT–PCR: reverse transcription–polymerase chain reaction.pN0(mol+)Positive molecular findings (RT–PCR)lRT–PCR: reverse transcription–polymerase chain reaction., but no regional lymph node metastases detected by histology or IHCpN1Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by SLNB but not clinically detectedm‘Not clinically detected’ is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.pN1miMicrometastases (>0.2 mm and/or >200 cells, but none >2.0 mm)pN1aMetastases in 1–3 axillary lymph nodes, at least one metastasis >2.0 mmpN1bMetastases in internal mammary nodes with micrometastases or macrometastases detected by SLNB but not clinically detectedm‘Not clinically detected’ is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.pN1cMetastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by SLNB but not clinically detectedm‘Not clinically detected’ is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.pN2Metastases in 4–9 axillary lymph nodes; or in clinically detectedkClinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathological macrometastasis based on fine needle aspiration biopsy with cytological examination. Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, e.g. cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, e.g. cN1. Information regarding the confirmation of the nodal s