The term lymphadenopathy refers to an abnormality in size, consistency or morphological aspect of one or several lymph nodes. Although lymphadenopathies are commonly observed in everyday clinical practice, the difficulty of differentiating benign and malignant disease may delay therapeutic approaches. The present review aims to update diagnostic algorithms in different clinical situations based on the currently available literature. A literature review was performed to assess current knowledge of and to update the diagnostic approach. A short clinical vignette was used as an example of a typical clinical presentation. This case of metastatic lymphadenopathy with incomplete patient history demonstrates how misleading such lymphadenopathy may be, leading to a delayed diagnosis and even a fatal outcome. Any lymphadenopathy persisting for more than 2 weeks should be considered suspicious and deserves further investigation. Precise clinical examination, meticulous history-taking and a search for associated symptomatology are still cornerstones for diagnosing the origin of the condition. The next diagnostic step depends on the anatomical region and the specific patient's situation. Imaging starts with ultrasound, while computed tomography (CT) and magnetic resonance imaging (MRI) allow assessment of the surrounding structures. If the diagnosis remains uncertain, tissue sampling and histological analyses should be performed. Except for head and neck loco-regional lymphadenopathy, there are no methodical guidelines for persistent lymphadenopathy. The present review clarifies several confusing and complex situations. The accuracy of fine needle aspiration cytology could be increased by using core needle biopsy with immunocytologic and flow cytometric methods. Notably, except in the head and neck area, open biopsy remains the best option when lymphoma is suspected or when inconclusive results of previous fine needle aspiration cytology or core needle biopsy are obtained. The incidence of malignant lymphadenopathy varies with its location and the various diagnostic strategies. In metastatic lymphadenopathy of unknown primary origin, European Society for Medical Oncology (ESMO) guidelines and modern methods like next-generation sequencing (NGS) may help to manage such complex cases.

According to the seventh edition of tumour-node-metastasis (TNM) classification, pN3a status in breast cancer patients consists of presence of an infraclavicular lymph node metastasis (LNM) and/or presence of ≥10 axillary LNMs. The aim of this study was to determine whether prognosis of pN3a based on at least an infraclavicular LNM differs from ≥10 axillary LNMs.

Data were obtained from the Netherlands Cancer Registry. All patients were diagnosed between 2005 and 2008 with primary invasive epithelial breast cancer and pN2a or pN3a status as pathologic result. Patients with pN3a were subdivided in pN3a based on at least an infraclavicular LNM or ≥10 axillary LNMs. Disease-free survival (DFS) included any local, regional or contralateral recurrence, distant metastasis or death within 5 years. Kaplan-Meier curves provided information on 5-year DFS and 8-year overall survival (OS). In addition, Cox proportional hazards model was used to measure the effect of relevant clinicopathological variables on DFS and OS.

A total of 3400 patients with pN2a and 1788 patients with pN3a were included. In 83 patients, pN3a was based on at least an infraclavicular LNM (4.6%) and in 1705 patients because of ≥10 axillary LNMs (95.4%). After multivariable analyses, DFS and OS were inferior in patients with pN3a based on ≥10 axillary LNMs compared to infraclavicular LNM (DFS 48.8% versus 63.8%, hazard ratio [HR] 1.59, p = 0.036; OS 46.6% versus 63.9%, HR 1.46, p = 0.042). Furthermore, pN2a and pN3a based on infraclavicular LNM had comparable DFS and OS.

PN3a status based on an at least an infraclavicular LNM is rare, yet its prognosis is superior to ≥10 axillary LNMs. Reclassification of infraclavicular LNM in the next TNM should therefore be considered into pN2a.

The definition of locally advanced breast cancer (LABC) includes patients with large tumors, extensive regional lymph node involvement, or direct involvement of the skin or underlying chest wall. Neoadjuvant chemotherapy followed by surgery has become the standard of care and a valuable strategy in the multimodality management of LABC. Variations in practice exist and the purpose of this article is to explore the surgical considerations in the management of LABC.

There exist various diagnostic and treatment considerations in LABC patients that help guiding clinicians in the optimal management of LABC. The evolving concepts of breast conservation, immediate breast reconstruction and optimal management of the axilla are addressed.

LABC represents a heterogenous cohort of patients for whom a multidisciplinary care team is critical. A more detailed understanding of the surgical considerations will facilitate the optimal diagnostic evaluation and management of these patients.

At The University of Texas MD Anderson Cancer Center, we have used sonography (US) extensively for more than 2 decades to refine the local and regional staging of invasive breast cancer. Although magnetic resonance imaging is superior to all other imaging modalities in the measurement of the primary tumor and detection of additional foci of malignancy, in our experience US has shown sufficient accuracy in clinical practice to stage most invasive breast cancers. The exceptions are ill-defined tumors such as invasive lobular cancers and tumors in breasts containing extensive diffuse benign disease. An advantage of US is that multifocality or multicentricity can be confirmed via US-guided fine-needle aspiration within 15 minutes and the information shared immediately with the patient and the breast surgeon or medical oncologist. US has also proved indispensable in the evaluation of lymphatic spread because it can evaluate more nodal basins (e.g., the supraclavicular fossa and low neck) than magnetic resonance imaging can and because it can guide needle biopsy to confirm the status of any indeterminate node (including internal mammary nodes) within minutes.

Assessment of the regional lymphatics is important for accurate staging and treatment of breast cancer patients. We sought to determine the role of regional ultrasound in providing clinically relevant information. We retrospectively analyzed data from patients who were treated curatively in 1996-2006 at The University of Texas MD Anderson Cancer Center for clinical stage III breast cancer. We compared differences in regional lymph node staging based on ultrasound versus mammography and physical examination in the 865 of 1,200 patients who had external-beam radiation as part of their treatment and regional ultrasound studies as part of their initial evaluation. Ultrasound uniquely identified additional lymph node involvement beyond the level I or II axilla in 37% of the patients (325 of 865), leading to a change in clinical nodal stage. Ninety-one percent of these abnormalities that could be biopsied (266 or 293) were confirmed to contain disease. The sites of additional regional nodal disease were: infraclavicular disease, 32% (275 of 865); supraclavicular disease, 16% (140 of 865); and internal mammary disease, 11% (98 of 865). All patients with involvement in the extra-axillary regional nodal basins received a radiation boost to the involved areas ≥ 10 Gy. Thus, over one third of patients with advanced breast cancer had their radiation plan altered by the ultrasound findings. Regional ultrasound evaluation in patients with advanced breast cancer commonly revealed abnormalities within and beyond the axilla, which changed the clinical stage of disease and the radiation treatment strategy. Therefore, regional ultrasound is beneficial in the initial staging evaluation for such patients.

The optimal method for locoregional staging in patients treated with neoadjuvant chemotherapy (NAC), usually ultrasound (US) and pre- or post-chemotherapy sentinel lymph node biopsy (SLNB), remains subject of debate. The aim of this study was to assess the value of 18F-FDG PET/CT for detecting locoregional lymph node metastases in primary breast cancer patients scheduled for NAC. 311 breast cancer patients, scheduled for NAC, underwent PET/CT of the thorax in prone position with hanging breasts. A panel of four experienced reviewers examined PET/CT images, blinded for other diagnostic procedures. FDG uptake in locoregional nodes was determined qualitatively using a 4-point scale (0 = negative, 1 = questionable, 2 = moderately intense, and 3 = very intense). Results were compared with pathology obtained by US-guided fine needle aspiration or SLNB prior to NAC. All FDG-avid extra-axillary nodes were considered metastatic, based on the previously reported high positive predictive value of the technique. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FDG-avid nodes for the detection of axillary metastases (score 2 or 3) were 82, 92, 98, 53, and 84 %, respectively. Of 28 patients with questionable axillary FDG uptake (score 1), 23 (82 %) were node-positive. Occult lymph node metastases in the internal mammary chain and periclavicular area were detected in 26 (8 %) and 32 (10 %) patients, respectively, resulting in changed regional radiotherapy planning in 50 (16 %) patients. In breast cancer patients scheduled for NAC, PET/CT renders pre-chemotherapy SLNB unnecessary in case of an FDG-avid axillary node, enables axillary response monitoring during or after NAC, and leads to changes in radiotherapy for a substantial number of patients because of detection of occult N3-disease. Based on these results, we recommend a PET/CT as a standard staging procedure in breast cancer patients scheduled for NAC.

The aim of this prospective study was to assess the incidence of extra-axillary lymph node involvement on baseline FDG PET/CT in patients with stage II-III breast cancer scheduled for neo-adjuvant chemotherapy.

Patients with invasive breast cancer of >3 cm and/or proven axillary lymph node metastasis were included for before neo-adjuvant chemotherapy. Baseline ultrasound of the infra- and supraclavicular regions was performed with fine-needle biopsy as needed. Subsequently FDG PET/CT was performed. All visually FDG-positive nodes were regarded as metastatic based on the previously reported high specificity of the technique.

Sixty patients were included. In 17 patients (28%) extra-axillary lymph nodes were detected by FDG PET/CT, localised in an intra-mammary node (1 lymph node in 1 patient), mediastinal (2 lymph nodes in 2 patients), internal mammary chain (9 lymph nodes in 8 patients), intra- and interpectoral (6 lymph nodes in 4 patients), infraclavicular (5 lymph nodes in 4 patients) and in the contralateral axilla (3 lymph nodes in 2 patients). Ultrasound-guided cytology had detected extra-axillary lymph node involvement in seven of these patients, but was unable to detect extra-axillary nodes in the other 10 patients with positive extra-axillary lymph nodes on FDG PET/CT. Radiotherapy treatment was altered in 7 patients with extra-axillary involvement (12% of the total group).

FDG PET/CT detected extra-axillary lymph node involvement in almost one-third of the patients with stage II-III breast cancer, including regions not evaluable with ultrasound. FDG PET/CT may be useful as an additional imaging tool to assess extra-axillary lymph node metastasis, with an impact on the adjuvant radiotherapy management.

Staging of disease is routine in the evaluation of patients newly diagnosed with breast cancer. Assessment of palpable and/or nonpalpable locoregional lymph nodes is an important component of the initial staging. Ultrasound (US) is the favored imaging modality for the initial investigation of lymph nodes and results in a significant increase in the specificity of the overall evaluation when used in conjunction with fine-needle aspiration (FNA). This review provides a concise summary, based on published literature, of the current applications and future prospects of FNA biopsy of locoregional lymph nodes in the initial staging and subsequent surgical management of patients with breast cancer. Patients undergo either sentinel lymph node (SLN) biopsy or complete axillary lymph node dissection, based on whether the axillary lymph node status is determined to be negative or positive in the initial staging process. The status of lymph nodes in the supraclavicular, infraclavicular, and internal mammary regions provides more accurate staging information and also impacts subsequent surgical management. The identification and evaluation of intramammary lymph nodes can add value in the overall assessment of patients with breast cancer. The feasibility of noninvasive imaging modalities for SLN mapping in animal models has indicated a good potential for FNA biopsy in the subsequent investigation of SLNs identified noninvasively in humans.

The indications and benefits of postmastectomy radiation therapy (PMRT) continue to evolve. Advances in systemic adjuvant therapy and targeted therapy for breast cancer are likely to play an increasingly important role in control of locoregional as well as distant disease. Ongoing scrutiny of patterns of chest wall failure will be required to define the net benefit derived from PMRT. This article discusses the 2001 American Society of Clinical Oncology guidelines for PMRT and current practices using PMRT in selected groups of patients who have breast cancer.

We examined the relationship between different expressions of positive axillary lymph nodes (PN) and the outcomes of node-positive breast carcinoma patients to determine the best predictor(s) among these expressions and to assess whether anatomic high level involvement is an independent prognostic factor.

In this retrospective study, the primary endpoints were distant recurrence (DR), locoregional recurrences (LRR), and disease-free survival (DFS). Univariate and multivariate prognostic factor analyses were carried out using survival and regression methods in the data of 704 patients with PN.

In multivariate analysis, the number of PN, ratio of PN, log odds of PN, and level III (L-III) involvement, separately, were significant factors for DR in addition to age, tumor size, and lymphovascular invasion (LVI). In the final model including all expressions of nodal involvement, age (continuous P = 0.001; hazard ratio [HR]: 0.98; 95% confidence Interval [95% CI]: 0.96-0.99), tumor size (continuous: P < 0.0001; HR: 1.3; 95% CI, 1.2-1.5), LVI (yes vs. no: P = 0.005; HR: 1.6; 95% CI, 1.2-2.2), and ratio of PN (continuous: P = 0.02; HR: 1.03; 95% CI, 1.01-1.06) were the independent prognostic factors for DR. For LRR, ratio of PN (continuous: P = 0.001; HR: 1.02; 95% CI, 1.01-1.03) was the most important factor in addition to age (continuous: P = 0.02; HR: 0.98; 95% CI, 0.97-0.99) and tumor size (continuous: P = 0.04; HR: 1.3; 95% CI, 1.1-1.6). When patients were stratified by number categories of PN (1-3 vs. 4-9 vs. >/= 10), there was no difference between DFSs of patients with and without L-III involvement. In contrast, when patients were stratified by L-III involvement, DFSs according to the number categories were statistically different.

Ratio of PN was more valuable than number of PN for predicting outcome in node-positive breast carcinoma patients. Level III involvement was not an independent prognostic indicator either for locoregional or for distant recurrences.

US is a powerful tool for characterization of superficial lymph nodes. Unlike other imaging techniques like CT and MRI, which mainly depend on size for differential diagnosis, US can evaluate important parameters such as shape, margins, internal structure and abnormal vascularization. It has the advantage of showing early subtle findings of neoplastic involvement like asymmetric thickening and focal lobulations in the cortex, as well as late findings such as diffuse cortical thickening and absence of hilum. It is possible to evaluate the heterogeneous inner structure due to necrosis, unsharp or irregular borders due to extracapsular spread and abnormal vascularization with multiple subcapsular feeding vessels due to tumor angiogenesis. The advances in US technology like high-resolution transducers, power Doppler function and contrast agents have all contributed to the well established role of US in the evaluation of lymph nodes. This article mainly focuses on the sonographic criteria for differential diagnosis of normal, reactive, inflammatous and neoplastic lymph nodes as well as examination techniques in the neck, axilla, internal mammary and inguinal regions and indications in various clinical settings.

As infraclavicular lymph node metastases is one of the parameters of stage III-C, the diagnostic techniques aiming to identify the metastases of this region have gained importance recently. In this study, we investigated the presence of axillary and infraclavicular lymph node metastases with ultrasonography.

Axillary and infraclavicular lymph nodes were evaluated by preoperative ultrasonography in 100 consecutive breast cancer patients. Median age was 47 (23-76) years.

Ultrasonography identified lymph nodes correlating with metastases in the infraclavicular region in 20 patients. In 19 of these patients, metastases were verified in the lymph nodes with histopathologic examination (false positivity rate 5%). Of the 80 patients who were not considered as having metastases by ultrasonography, 59 had no metastatic lymph nodes on histological examination. The specificity of ultrasonography in the identification of metastatic lymph nodes in the infraclavicular region was 98.3%, with a sensitivity of 47.5%, positive predictive value of 95%, negative predictive value of 73.7%, and overall accuracy of 78%.

Patients who were identified to have infraclavicular lymph node metastases by preoperative ultrasonographic examination should have a relevant treatment plan as they are classified as locally advanced, stage III-C disease.

A Breast Task Force comprised of nationally known experts in the field of breast cancer treatment was charged with recommending additions and changes for the 6th edition of the TNM Classification that were based on published evidence and/or were consistent with widespread clinical consensus. Additions made to the staging system were designed to facilitate the uniform collection of clinically relevant information about new techniques for the detection of metastatic cells. These additions include quantitative criteria to distinguish micrometastases from isolated tumor cells, and specific identifiers to record the use of sentinel lymph node biopsy, immunohistochemical (IHC) staining, and molecular biology techniques. Revisions of the previous staging system are related to the number of affected axillary lymph nodes and to the classification of level III axillary lymph nodes and lymph nodes outside of the axilla.

The American Joint Committee on Cancer staging system for breast carcinomas has been revised. According to this revised staging system, metastasis to infraclavicular lymph nodes and number of positive axillary nodes have prognostic significance and a new stage, stage IIIC, has been introduced. The aim of this study is to investigate the association of positive axillary nodes by level and number with survival and stage migration between the old and the new stages in a large series of mastectomy patients.

Data from 1277 consecutive breast cancer patients treated by mastectomy were studied, retrospectively. Prognostic value of number of positive axillary nodes and entirely invasion of apex axillary nodes were analysed. Survival curves were generated by Kaplan-Meier method, and multivariate analysis was performed by Cox proportional hazard model.

Five-year survival rates for metastasis to axillary level III and for stage IIIC breast cancer were 35.4 and 38.2%, respectively. Metastases to apex axillary nodes, 4-9 and 10 or more positive lymph nodes were found to be adverse and independent prognostic factors for survival in lymph node positive patients.

Invasion of infraclavicular nodes and 4-9 and > or =10 positive axillary lymph nodes were independent predictors for survival in node positive breast carcinomas in this series. Patients with the new stage IIIC had the worst survival among breast cancer patients.

Increased breast health awareness has led to earlier stage distribution among breast cancer patients in the United States; however, locally advanced tumors remain a major source of morbidity and mortality. Early attempts to control this high-risk pattern of disease with surgery or radiation alone were met with disappointingly high rates of treatment failure in locoregional and distant sites. Multimodality strategies represent a major advance in management of these difficult cancers. The current standard of care is neoadjuvant chemotherapy to improve operability, followed by breast and axillary surgery (including lumpectomy for appropriately selected patients). Following surgery, decisions regarding the need for additional chemotherapy with or without locoregional irradiation are made based on stage at presentation, response to systemic therapy, and surgical-pathology findings. Recommendations for adjuvant endocrine therapy are based on hormone receptor status. Studies of these tumors have confirmed that primary response to induction therapy is an excellent surrogate marker of success in eradicating micrometastases, as patients experiencing a complete pathologic response have a statistically significant survival advantage. Ongoing investigations of locally advanced breast cancer include studies of systemic chemotherapy with or without neoadjuvant endocrine regimens that increase the complete pathologic response rate, and correlation with outcome; integration of lymphatic mapping and sentinel lymph node biopsy into clinical trials; and defining the optimal extent of locoregional irradiation in patients who experience a strong response to neoadjuvant treatment.

Since its inception, the AJCC staging system for breast cancer has been in an almost constant state of evolution, striving with each revision to reflect the most up-to-date clinical research as well as the widespread consensus among physicians about appropriate diagnostic and treatment standards. To date, these revisions have essentially represented a "fine-tuning" of the initial judgment that tumor size, lymph node status, and presence of distant metastases are the most significant prognostic factors for breast cancer. With the problems of standardization and reproducibility being resolved, it is likely that histologic grade will join this group of independent markers and be incorporated into the AJCC staging system in the near future. Over the last 15 years. considerable attention has been focused on the discovery of new markers visualized with immunohistochemistry and RT-PCR that may be validated as independent prognostic indicators (reviewed by Mirza et al). To date, the usefulness of many of these markers has been limited by lack of standardization in measurement techniques, but several show great promise for the future. By increasing the number of prognostic markers that can give independent information about patient outcome, physicians will be better able to determine optimal treatment approaches for individual patients.

To revise the American Joint Committee on Cancer staging system for breast carcinoma.

A Breast Task Force submitted recommended changes and additions to the existing staging system that were (1) evidence-based and/or consistent with widespread clinical consensus about appropriate diagnostic and treatment standards and (2) useful for the uniform accrual of outcome information in national databases.

Major changes included the following: size-based discrimination between micrometastases and isolated tumor cells; identifiers to indicate usage of innovative technical approaches; classification of lymph node status by number of involved axillary lymph nodes; and new classifications for metastasis to the infraclavicular, internal mammary, and supraclavicular lymph nodes.

This revised staging system will be officially adopted for use in tumor registries in January 2003.