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Detection of nodal micrometastasis (tumor size: 0.2–2.0 mm) is challenging for pathologists due to the small size of metastatic foci. Since lymph nodes with micrometastasis are counted as positive nodes, detecting micrometastasis is crucial for accurate pathologic staging of colorectal cancer. Previously, deep learning algorithms developed with manually annotated images performed well in identifying micrometastasis of breast cancer in sentinel lymph nodes. However, the process of manual annotation is labor intensive and time consuming. Multiple instance learning was later used to identify metastatic breast cancer without manual annotation, but its performance appears worse in detecting micrometastasis. Here, we developed a deep learning model using whole-slide images of regional lymph nodes of colorectal cancer with only a slide-level label (either a positive or negative slide). The training, validation, and testing sets included 1963, 219, and 1000 slides, respectively. A supercomputer TAIWANIA 2 was used to train a deep learning model to identify metastasis. At slide level, our algorithm performed well in identifying both macrometastasis (tumor size > 2.0 mm) and micrometastasis with an area under the receiver operating characteristics curve (AUC) of 0.9993 and 0.9956, respectively. Since most of our slides had more than one lymph node, we then tested the performance of our algorithm on 538 single-lymph node images randomly cropped from the testing set. At single-lymph node level, our algorithm maintained good performance in identifying macrometastasis and micrometastasis with an AUC of 0.9944 and 0.9476, respectively. Visualization using class activation mapping confirmed that our model identified nodal metastasis based on areas of tumor cells. Our results demonstrate for the first time that micrometastasis could be detected by deep learning on whole-slide images without manual annotation.

BACKGROUND Axillary sentinel lymph node biopsy (SLNB) is standard treatment for patients with clinically and pathological negative lymph nodes. However, the role of completion axillary lymph node dissection (cALND) following positive sentinel lymph node biopsy (SLNB) is debated. AIM To identify a subgroup of women with high axillary tumor burden undergoing SLNB in whom cALND can be safely omitted in order to reduce the risk of long-term complications and create a Preoperative Clinical Risk Index (PCRI) that helps us in our clinical practice to optimize the selection of these patients. METHODS Patients with positive SLNB who underwent a cALND were included in this study. Univariate and multivariate analysis of prognostic and predictive factors were used to create a PCRI for safely omitting cALND. RESULTS From May 2007 to April 2014, we performed 1140 SLN biopsies, of which 125 were positive for tumor and justified to practice a posterior cALND. Pathologic findings at SLNB were micrometastases (mic) in 29 cases (23.4%) and macrometastasis (MAC) in 95 cases (76.6%). On univariate analysis of the 95 patients with MAC, statistically significant factors included: age, grade, phenotype, histology, lymphovascular invasion, lymph-node tumor size, and number of positive SLN. On multivariate analysis, only lymph-node tumor size (≤ 20 mm) and number of positive SLN (> 1) retained significance. A numerical tool was created giving each of the parameters a value to predict preoperatively which patients would not benefit from cALND. Patients with a PCRI ≤ 15 has low probability (< 10%) of having additional lymph node involvement, a PRCI between 15-17.6 has a probability of 43%, and the probability increases to 69% in patients with a PCRI > 17.6. CONCLUSION The PCRI seems to be a useful tool to prospectively estimate the risk of nodal involvement after positive SLN and to identify those patients who could omit cALND. Further prospective studies are necessary to validate PCRI clinical generalization.

En cáncer de mama, el ganglio centinela (GC) es el primer ganglio que recibe el drenaje linfático del área de la mama que contiene el tumor, siendo capaz de predecir el estado de los demás ganglios axilares. En los últimos años, múltiples estudios han demostrado el poco impacto que tiene el vaciamiento axilar (VA) en términos de la supervivencia libre de enfermedad (SLE) y la supervivencia global (SG), lo que a su vez ha permitido establecer algunos criterios para omitir la linfadenectomía axilar en pacientes con cáncer de mama en estadios tempranos. Las mujeres con cáncer de mama infiltrante y tumores T1 y T2, con axila clínicamente negativa, son candidatas a la realización del GC. Si el GC es positivo, puede omitirse el VA sólo si se cumplen los siguientes requisitos: 1) manejo quirúrgico del tumor primario con cirugía conservadora o mastectomía, 2) bordes de resección quirúrgicos negativos para malignidad y 3) reporte de patología del GC que muestre hasta dos GC positivos para micro o macrometástasis, sin extensión extracapsular, o con una dimensión de la extensión extracapsular

The ACOSOG Z0011 study, heralded as a "practice changing" trial, suggested that women with T1-2 breast cancer with 1-2 SLN+, undergoing breast conservation therapy, need not be offered further ALND. However, whether these results are applicable to all women in the Indian setting, it remains debatable. A retrospective audit of all cN0 operated from 2013 to 2018 was conducted. We analyzed the percentage of additional LN positive (LN+) in the ALND group and compared it to the ACOZOG Z11 trial. Of the 2350 cN0 with EBC who underwent LAS, 687 (29%) had positive lymph nodes on final histopathology. Five hundred ninety-seven (86.9%) patients had 1-2 LN+, 40 (5.8%) patients had 3 LN+, and 50 (7.3%) had 4 or more nodes positive. Demographic features in the ACOSOG Z11 are different from those in our study, looking at ACOZOG Z11 versus our cohort-median pT 1.7 cm versus 3 cm, 45% micrometastasis versus 99.16% macrometastasis, and 28-30% grade 3 tumors versus 73.7%. In our cohort 31.82% of the 1-2 LN positive had additional LN+ on ALND. Keeping in mind the difference in clinicopathological features between our cohort and that of ACOZOG Z0011 and that 31.82% of women had additional LN+ on ALND, it may not be appropriate to apply the results of the ACOSOG Z0011 trial directly to our general population. Possibly, only a select subset of patients who match the trial population of the ACOSOG Z11 could be offered observation of the axilla and validated nomograms can be used to identify high-risk patients.

Background. Methylene blue is the most commonly used tracer for sentinel lymph node (SLN) biopsy (SLNB) in China. This study aimed to investigate the feasibility of clinical application of SLNB using methylene blue dye (MBD) for early breast cancer and the prognosis of patients with different SLN and non-SLN statuses. Methods. We retrospectively analyzed the clinicopathological data of patients with early breast cancer treated at the Peking University First Hospital between 2013 and 2018. We calculated the SLN identification rate (IR) in SLNB with MBD and the false-negative rate (FNR), and analyzed the prognosis of patients with different SLN and non-SLN statuses using Kaplan-Meier curves. Results. Between January 2013 and December 2018, 1603 patients with early breast cancer underwent SLNB with MBD. The SLN IR was 95.8% (1536/1603). Two SLNs (median) were detected per patient. There were significant differences in FNR between patients with SLN micrometastasis and macrometastasis (19.0% vs. 4.5%, χ2 = 12.771, P

Background and Objectives: This study investigated predictive risk factors for cervical nodal recurrence or metastasis in papillary thyroid carcinoma (PTC). Materials and Methods: From September 2014 to February 2015, a total of 321 PTC patients were enrolled retrospectively. Except for 154 N0 patients, the remaining 167 patients were divided into two groups as follows: Group I (n=140), central lymph node (LN) metastasis (pN1a); Group II (n=27), lateral LN metastasis (pN1b, n=23) or LN recurrence (n=4). The patients who had LN metastasis or recurrence underwent selective LN dissection or recurrent LN excision. Results: Central LN metastases were found in 44.0% (142/321) of patients. Two hundred thirty patients (71.7%) were classified as being at low-risk for LN disease, as evidenced by N0 or fewer than five micrometastases. The mean size of central metastatic LNs was 0.37±0.34 cm. A total of 76 patients (46.6%) presented with micrometastasis, and ten (3.1%) presented with extranodal extension (ENE). The multiple/bilateral cancer, Extrathyroidal extension, size of metastatic LN, ENE, high risk LN disease (＞5, macrometastasis, ＞3.0 cm) and high thyroglobulin were significant risk factors in predicting LN recurrence or lateral LN metastasis (p＜0.05) in univariate analysis. Patients with ENE were 10.3 times more at risk for recurrence or metastasis than patients without ENE. Conclusion: We consider the ENE was the most potent risk factors for LN recurrence or lateral LN metastasis in PTC.

Background This study evaluated the usefulness of judgment of central lymph node (LN) metastasis by surgeon's palpation in papillary thyroid cancer. Methods This study included 127 patients who underwent thyroidectomy and central compartment node dissection between October 2014 and February 2015. The criterion for suspicious LNs was hardness. Results Of the 20.5% (28/127) of suspicious for metastatic LNs according to surgeon determination, 92.8% (26/28) were confirmed to be metastatic in the final pathological examinations. Metastatic LNs were found in 38 (38.3%) of 99 patients without suspicious LNs, 29 of whom (76.3%) had micrometastases. The sensitivity, specificity, and positive and negative predictive values for the determination of LN metastasis by a surgeon were 40.6%, 96.8%, 92.9%, and 61.6%, respectively. Conclusion Determination of central LN metastasis by a surgeon's palpation may be useful to evaluate LNs owing to the high specificity and positive predictive values, especially in macrometastasis or high-risk LN disease.

Introduction: Breast cancer represents the most common type of cancer among women in the world. The presence and extent of axillary lymph node involvement represent an important prognostic factor. Sentinel lymph node biopsy (SLNB) is currently accepted for T1 and T2 with negative axillae (N0); however, many patients with T3-T4b tumors with N0 are often submitted to unnecessarily axillary lymph node dissection. Materials and Methods: This is a retrospective, observational study of patients treated for breast cancer between 2008 and 2015, with T3/T4b tumors and N0, who underwent SLNB. A systematic review of the literature was also carried out in 5 bases. Results: We analyzed 73 patients, and SLNB was negative for macrometastasis in 60.3% of the cases. With a mean follow-up of 45 months, no ipsilateral axillary local recurrence was observed. In the systematic review, only 7 articles presented data for analysis. Grouping these studies with the present series, the rate of N0 was 32.1% for T3 and 61.0% for T4b; grouping all studies (T3 and T4b n = 431) the rate was 32.5%. Conclusions: SLNB in T3/T4b tumors is a feasible and safe procedure from the oncological point of view, as it has not been associated with ipsilateral axillary relapse.

Introduction/Background* The objective of the present study is to determine the role of sentinel lymph node (SLN) ultrastaging in apparent early-stage ovarian cancer. Methodology We previously demonstrated the feasibility of SLN in early-stage ovarian cancer in a pilot study and in a clinical trial (NCT03452982). The SLN of the 30 patients involved in both were processed following an ultrastaging protocol. The cost of ultrastaging processing was also reported. Result(s)* A SLN was detected in up to 91.3% and 90% in the pelvic and para-aortic region, respectively. In all cases, a SLN was detected at least in one field, pelvic or para-aortic. The mean time from injection to SLN resection was 53.3 ± 20.3 min. Two of 30 (6.6%) patients had a contralateral SLN in the para-aortic field, but no patients had contralateral SLN within the pelvic field after injection. The mean number of harvested SLN was 2.1 ± 1.4 (range: 0-5) and 2.7 ± 1.5 (range: 0-7) in the pelvic and para-aortic region, respectively. Two patients were upgraded to stage IIIA1 because of lymph node metastasis. In the first case, based on single sections and haematoxylin and eosin (H&E) examination, a pelvic SLN micrometastasis (1 mm) was found on the first H&E section. By using the ultrastaging protocol, the size of the metastasis was increased to 2.1 mm (macrometastasis). In the same patient, the ultrastaging study of the inframesenteric para-cava SLNs found isolated tumour cells in the subcapsular and interfollicular lymph nodes sinus in one of the two SLN harvested (in one of the sections at the fourth and fifth ultrastage levels). The other upstaged case was a para-aortic macrometastasis in a patient in whom the SLN was not identified in the para-aortic field because of the absence of migration from the infundibulo-pelvic stump injection. The cost of ultrastaging in on average 96.8 € (range: 0-230.5) and 124.5 € (range: 0-322.7€) for pelvic and para-aortic SLN, respectively. Conclusion* A uniform protocol for ultrastaging is essential for lower-volume metastasis detection and to provide reproducible information between upcoming studies, as evidence about SLN in ovarian cancer is growing.

Bone metastasis is present in a high percentage of breast cancer (BCa) patients with distant disease, especially in those with the estrogen receptor‐positive (ER+) subtype. Most cells that escape primary tumors are unable to establish metastatic lesions, which suggests that target organ microenvironments are hostile for tumor cells. This implies that BCa cells must achieve a process of speciation to adapt to the new conditions imposed in the new organ. Bone has unique characteristics that can be exploited by cancer cells: it undergoes constant remodeling and comprises diverse environments (including osteogenic, perivascular, and hematopoietic stem cell niches). This allows colonizing cells to take advantage of numerous adhesion molecules, matrix proteins, and soluble factors that facilitate homing, survival, and, eventually, metastatic outgrowth. However, in most cases, metastatic lesions enter into a latency state that can last months, years, or even decades, before forming a clinically detectable macrometastasis. This dormant state challenges the effectiveness of adjuvant chemotherapy. Detecting which tumors are more prone to metastasize to bone and developing new specific therapies that target bone metastasis represent urgent clinical needs. Here, we review the biological mechanisms of BCa bone metastasis and provide the latest options of treatments and predictive markers that are currently in clinical use or are being tested in clinical assays. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

For residual N1 nodal disease following neoadjuvant chemotherapy (NAC) for patients with breast cancer, the optimal local therapy for axilla is an evolving area. We analyzed the long-term results of these patients according to axillary surgical methods using propensity score matching (PSM) to clarify whether omission of axillary lymph node dissection (ALND) is oncologically safe. This was a single institution retrospective study of patients with ypN1 from Asan Medical Center (AMC). We included 324 patients who had undergone axillary surgery with either sentinel lymph node biopsy (SLNB) only or ALND. The patients received NAC at AMC between 2008 and 2013. General indications for ALND included prominent nodes detected clinically before NAC, evident macrometastasis on multiple nodes during SLNB. Patients who had either micrometastasis or macrometastasis in 1 or 2 node(s) were included. SLNB was performed for patients with good responders to NAC with limited nodal burden. Patients were matched for baseline characteristics. After matching, we included 98 patients in each SLNB only group and ALND group respectively. We compared axillary recurrence-free survival (ARFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-free survival (BCSS) according to the surgical method. The median follow-up period was 71 months. Univariate and multivariate analyses revealed no statistically significant differences between the two groups for ARFS, DMFS, OS, and BCSS. After the propensity score matching, no significant statistical differences were observed in 5-year ARFS, DMFS, OS, and BCSS between the SLNB only group and ALND group. SLNB might be a possible option for ALND in patients with breast cancer who have limited axillary node metastasis after NAC without compromising survival outcomes.

PurposeSentinel-lymph-node (SLN) biopsy (SLB) is an efficient and safe axillary surgical approach with decreased morbidity than total axillary lymph node dissection (ALND) in initial patients (T1–T2). Current guidelines strongly suggest avoiding completion of ALND in patients with one or two positive SLNs that will be submitted to whole-breast radiation therapy, but must be done when three SLNs are affected.MethodsWe performed a SEER-based study with breast invasive ductal carcinoma patients treated between 2010 and 2015. Optimal cutoffs of positive LNs predictive of survival were obtained with ROC curves and survival as a continuous variable. Bias was reduced through propensity score matching. Cox regression was employed to estimate prognosis. Nomograms were constructed to analyze the predictive value of clinicopathological factors for axillary burden.ResultsOf 43,239 initial patients that had one to three analyzed LNs, only 425 had two positive LNs and matched analysis demonstrated no survival difference versus pN2 patients [HR: 0.960 (0.635–1.452), p = 0.846]. The positive-to-analyzed LN proportion demonstrated a strong prognostic factor for a low rate (1 positive to ≤1.5 analyzed) [HR = 1.567 (1.156–2.126), p = 0.004], and analysis derived from the results demonstrated that a “negative LN margin” improves survival. Nomograms shows that tumor size is the main factor of axillary burden.ConclusionMacrometastasis of two LNs is a poor prognostic factor, similar to pN2, in SLNB (-like) patients; more extensive studies including preconized therapies must be done in order to corroborate or refute the resistance of this prognostic difference in patients with two macrometastatic lymph nodes within few resected.

Introduction The intraoperative frozen section is a recommended method to detect breast cancer metastasis to axillary sentinel lymph nodes (SLNs); however, frozen section is not widely available and requires an experienced staff. Alternatively, touch imprint cytology (TIC) is a simple and cost-effective technique to detect metastasis. Therefore, in this study, we assessed the diagnostic accuracy of TIC for detecting SLN metastasis and compared it with intraoperative frozen section evaluation. Methodology A retrospective study was conducted in the Department of Histopathology, Liaquat National Hospital and Medical College, for a duration of two years. A total of 114 patients undergoing surgery for primary breast cancer were included in the study. All patients had clinically and radiologically negative axillary lymph nodes. SLN sampling was done using radioactive dye and sent for intraoperative consultation. The SLNs were sliced at 4-mm intervals and two TIC slides and three step-levels for frozen section were prepared, and the results were compared with final (paraffin) section histology. Results The sensitivity, specificity, and diagnostic accuracy of TIC was 83.7%, 98.5%, and 92.1%, respectively. Alternatively, the sensitivity, specificity, and diagnostic accuracy of frozen section was 93.9%, 100%, and 97.4%, respectively. The sensitivity of TIC and frozen section for detecting micrometastasis was 14.3% and 57.1%, respectively, with a diagnostic accuracy of 90.3% and 95.8%, respectively. Alternatively, with respect to macrometastasis, the sensitivity and specificity of TIC were 95.2% and 98.5%, respectively, while the sensitivity and specificity of frozen section were 100%. Conclusion TIC is a quick and effective technique for detecting breast cancer metastasis in axillary SLNs. Although frozen section had an overall higher sensitivity than TIC, the sensitivity of TIC for detecting macrometastasis was comparable to the frozen section. Therefore, we conclude that TIC is a good alternative to the frozen section in facilities where the frozen section is not available.

Axillary lymph node involvement is still an important predictor of recurrence and survival in breast cancer. Axillary staging was classically done by axillary lymph node dissection (ALND), but the introduction of sentinel lymph node biopsy (SLNB) has led to a progressive and continuing de-escalation in its use. Therefore, SLNB can now be considered the standard procedure for axillary staging in clinically No patients. Different studies have also begun to report that a positive sentinel node does not always require ALND, reducing the morbidity derived from this technique. Fears that this sentinel node approach might not be accurate for neoadjuyant chemotherapy have been allayed by several studies showing that post-neoadjuyant SLNB in clinical No patients reduces the rate of ALN D. This approach benefits from axillary pathological complete response with an acceptable false-negative rate. By contrast, however, cN1 disease still requires that we optimise the technique to reduce the rate of false negatives. Currently, SLNB is the best method for axillary staging in breast cancer, allowing patients to be treated according to risk of recurrence, and with good evidence that morbidity is lower than with other more radical techniques.

The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study, and 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1 mm portion of each lymph node was subjected to semi-serial sectioning at 200 μm intervals and examined by hematoxylin–eosin and immunohistochemistry with CK19; the remaining tissue was analyzed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/μL), the sensitivity of the OSNA assay was 92%, specificity was 82%, diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis., El objetivo de este estudio fue evaluar la eficacia de la amplificación de ácido nucleico en un solo paso (OSNA) para la detección de metástasis en el ganglio linfático centinela (GC) en comparación con la ultraestadificación patológica estándar en pacientes con cáncer de endometrio (CE) en estadio temprano. Se incluyeron en el estudio un total de 526 SLN de 191 pacientes con EC, y 379 SLN (147 pacientes) fueron evaluados por ambos métodos, OSNA y ultraestadificación patológica estándar. La porción central de 1 mm de cada ganglio linfático se sometió a un seccionamiento semiserie a intervalos de 200 μm y se examinó mediante hematoxilina-eosina e inmunohistoquímica con CK19; el tejido restante fue analizado por OSNA para ARNm de CK19. El ensayo OSNA detectó metástasis en el 19,7 % de los pacientes (14,9 % micrometástasis y 4,8 % macrometástasis), mientras que la ultraestadificación patológica detectó metástasis en el 8,8 % de los pacientes (3. 4% micrometástasis y 5,4% macrometástasis). Usando el valor de corte establecido para detectar metástasis SLN por OSNA en EC (250 copias/μL), la sensibilidad del ensayo OSNA fue del 92 %, la especificidad fue del 82 %, la precisión diagnóstica fue del 83 % y el valor predictivo negativo fue del 99 % Se registraron resultados discordantes entre ambos métodos en 20 pacientes (13,6%). OSNA resultó en una sobreestadificación en 12 pacientes (8,2%). OSNA podría ayudar en la identificación de pacientes que requieren tratamiento adyuvante en el momento del diagnóstico. Se registraron resultados discordantes entre ambos métodos en 20 pacientes (13,6%). OSNA resultó en una sobreestadificación en 12 pacientes (8,2%). OSNA podría ayudar en la identificación de pacientes que requieren tratamiento adyuvante en el momento del diagnóstico. Se registraron resultados discordantes entre ambos métodos en 20 pacientes (13,6%). OSNA resultó en una sobreestadificación en 12 pacientes (8,2%). OSNA podría ayudar en la identificación de pacientes que requieren tratamiento adyuvante en el momento del diagnóstico.

Specific biological properties of those circulating cancer cells that are the origin of brain metastases (BM) are not well understood. Here, single circulating breast cancer cells were fate-tracked during all steps of the brain metastatic cascade in mice after intracardial injection over weeks. A novel in vivo two-photon microscopy methodology was developed that allowed to determine the specific cellular and molecular features of breast cancer cells that homed in the brain, extravasated, and successfully established a brain macrometastasis. Those BM-initiating breast cancer cells (BMIC) were mainly originating from a slow-cycling subpopulation that included only 16% to 20% of all circulating cancer cells. BMICs showed enrichment of various markers of cellular stemness. As a proof of principle for the principal usefulness of this approach, expression profiling of BMICs versus non-BMICs was performed, which revealed upregulation of NDRG1 in the slow-cycling BMIC subpopulation in one BM model. Here, BM development was completely suppressed when NDRG1 expression was downregulated. In accordance, in primary human breast cancer, NDRG1 expression was heterogeneous, and high NDRG1 expression was associated with shorter metastasis-free survival. In conclusion, our data identify temporary slow-cycling breast cancer cells as the dominant source of brain and other metastases and demonstrates that this can lead to better understanding of BMIC-relevant pathways, including potential new approaches to prevent BM in patients. Implications: Cancer cells responsible for successful brain metastasis outgrowth are slow cycling and harbor stemness features. The molecular characteristics of these metastasis-initiating cells can be studied using intravital microscopy technology.

Objective This study aimed to establish intraoperative diagnostic criteria of sentinel lymph node (SLN) micro-/macrometastasis on the basis of tissue rinse liquid-based cytology (TRLBC) in gynecological cancer. Methods We enrolled 214 patients with gynecological cancer who underwent rapid diagnosis of SLN metastasis on the basis of TRLBC from a total of 490 SLNs. For slides that were classified as positive for atypical cells on cytological inspection, we counted the number of clusters (an atypical cell mass consisted of three or more cells) and the number of single cells (an atypical cell other than clusters). Receiver operating characteristic (ROC) analysis was applied to determine the efficiency of predicting SLN micro-/macrometastasis. Results On cytological inspection, 36 slides were classified as positive for atypical cells, while 21 slides (4.3%) were true positive, 15 (3.1%) were false positive, and 454 (92.6%) were true negative. There were no false negative results in this study. The area under the ROC curve for the number of cluster was superior to that for the number of single cells for distinguishing micro-/macrometastasis from negative/isolated tumor cells (0.86 vs. 0.67, P = 0.032). The optimum cut-off value of the number of clusters was 5 for distinguishing these two categories. Conclusions TRLBC is a highly sensitive alternative for detecting SLN metastasis as a rapid intraoperative diagnosis. Counting the number of atypical cell clusters might be useful for distinguishing micro-/macrometastasis from isolated tumor cells.

Introduction Lymph node metastases are considered a major risk factor in endometrial carcinoma patient management and nodal assessment is an integral part of staging. While still under investigation sentinel node biopsy has been established in many centers. It has been shown that histopathologic ultrastaging leads to an increased detection of isolated tumor cells (ITC) and micrometastases (MIC). However, the clinical impact of ITC and MIC is not yet clearly defined. The aim of this study was to retrospectively perform histopathologic ultrastaging in a large series of endometrial carcinoma patients all of which have been treated at the Tuebingen University Women’s Hospital. Method Patients with sentinel node biopsy during endometrial carcinoma surgery were identified. All cases with negative sentinel nodes, were submitted to retrospective histopathologic ultrastaging (5 × 100μm intervals followed by 500μm sections and immunohistochemical pancytokeratine staining of the entire lymphnode). Results A total of n=159 cases was available, of which in 5/159 (3.0%) case positive nodes were detected during initial routine pathology workup (pT1a,G3: n=1; pT1b,G1: n=1; pT1b,G3: n=2; pT2,G2: n=1). After retrospective ultrastaging additional micrometastases were identified in n=3 cases (pT1a,G1; pT1a,G2; pT1a,G3), isolated tumor cells in n=2 cases (pT1a,G3; pT1b,G3), a macrometastasis was revealed in one case (pT1b,G3). Overall 11/159 cases (6,7%) were finally reported positive. Conclusion In our cohort histopathologic ultrastaging of endometrial carcinoma sentinel nodes led to a substantially increased detection rate of nodes with isolated tumor cells, micro- and macrometastases. We suggest that histopathologic ultrastaging should be mandatory in endometrial carcinoma sentinel lymph node workup.

This study presents a mechanism-based receptor-targeted cellular therapy approach to treat breast to brain metastasis., Basal-like breast cancer (BLBC) shows brain metastatic (BM) capability and overexpresses EGFR and death-receptors 4/5 (DR4/5); however, the anatomical location of BM prohibits efficient drug-delivery to these targetable markers. In this study, we developed BLBC-BM mouse models featuring different patterns of BMs and explored the versatility of estem cell (SC)–mediated bi-functional EGFR and DR4/5-targeted treatment in these models. Most BLBC lines demonstrated a high sensitivity to EGFR and DR4/5 bi-targeting therapeutic protein, EVDRL [anti-EGFR VHH (EV) fused to DR ligand (DRL)]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the EV domain facilitated in augmenting DR4/5-DRL binding and enhancing DRL-induced apoptosis. EVDRL secreting stem cells alleviated tumor-burden and significantly increased survival in mouse models of residual-tumor after macrometastasis resection, perivascular niche micrometastasis, and leptomeningeal metastasis. This study reports mechanism based simultaneous targeting of EGFR and DR4/5 in BLBC and defines a new treatment paradigm for treatment of BM.

The metastatic cascade is a highly plastic and dynamic process dominated by cellular heterogeneity and varying metabolic requirements. During this cascade, the three major metabolic pillars, namely biosynthesis, RedOx balance, and bioenergetics, have variable importance. Biosynthesis has superior significance during the proliferation-dominated steps of primary tumour growth and secondary macrometastasis formation and only minor relevance during the growth-independent processes of invasion and dissemination. Consequently, RedOx homeostasis and bioenergetics emerge as conceivable metabolic key determinants in cancer cells that disseminate from the primary tumour. Within this review, we summarise our current understanding on how cancer cells adjust their metabolism in the context of different microenvironments along the metastatic cascade. With the example of one-carbon metabolism, we establish a conceptual view on how the same metabolic pathway can be exploited in different ways depending on the current cellular needs during metastatic progression.

Background Lymph node metastasis is more likely in early-stage breast cancer with lower tumor-infiltrating lymphocyte (TIL) density. Therefore, we investigated the correlation between TILs and lymph node metastasis in cT1 breast cancer patients undergoing surgery and the usefulness of TILs in predicting sentinel lymph node metastasis (SLNM) in cT1N0M0 breast cancer. Methods We investigated 332 breast cancer patients who underwent surgery as the first-line treatment after preoperative diagnosis of cT1. A positive diagnosis of SLNM as an indication for axillary clearance was defined as macrometastasis in the sentinel lymph node (SLN) (macrometastasis: tumor diameter > 2 mm). Semi-quantitative evaluation of lymphocytes infiltrating the peritumoral stroma as TILs in primary tumor biopsy specimens prior to treatment was conducted. Results For SLN biopsy (SLNB), a median of 2 (range, 1–8) SLNs were pathologically evaluated. Sixty cases (19.4%) of SLNM (macrometastasis: 46, micrometastasis: 16) were observed. Metastasis was significantly greater in breast cancers with tumor diameter > 10 mm than in those with diameter ≤ 10 mm (p = 0.016). Metastasis was significantly associated with lymphatic invasion (p Conclusions Our results suggest a correlation between lymph node metastasis and tumor immune-microenvironment in cT1 breast cancer. TIL density may be a predictor of SLNM in breast cancer without lymph node metastasis on preoperative imaging.

Lungs, due to their high oxygen availability and vascularization, are an ideal environment for cancer cell migration, metastasis and tumour formation. These processes are directly connected with extracellular matrix (ECM) remodelling, resulting from cancer cell infiltration and preparation of the environment suitable for tumour growth. Herein, we compare the potential of fast, label-free and non-destructive methods of Fourier-transform infrared spectroscopy (FT-IR) in standard and high definition (HD) modes with nonlinear coherent anti-Stokes Raman scattering (CARS), second harmonic generation (SHG), two-photon excited fluorescence (TPEF) and a fluorescence lifetime imaging (FLIM) technique for lung metastasis detection. We show their potential in the detection of lung macrometastasis, in which we already observed the ECM remodelling. The CARS image revealed a dense cell fraction typical of ECM remodeling and reduction of the TPEF signal together with an increase of fluorescence lifetime predominantly due to NAD(P)H suggesting metabolic changes in the metastatic foci. FT-IR spectroscopy allowed not only for macrometastasis detection but also their stage definition based mainly on the analysis of proteins, RNA and glycogen fractions. The multimodal approach additionally suggested partial enzymatic degradation of elastin in ECM and collagen remodelling.

Objective: To evaluate the oncological outcomes of patients with low-volume metastasis compared to those with macrometastasis and negative nodes in endometrial cancer. Methods: A single institutional retrospective study was carried out, which included all patients with endometrial cancer who underwent surgical treatment between January 2007 and December 2016. We analyzed the progression-free survival (PFS) and overall survival (OS) of all patients after sentinel node biopsy and full nodal surgical staging according to their final pathological nodal status, focusing on the impact of the size of nodal metastasis. Results: A total of 270 patients were operated on during the study period, among them, 230 (85.2%) patients underwent nodal staging. On final pathology, 196 (85.2%) patients had negative lymph nodes, low-volume metastasis (LVM) was present in 14 (6.1%) patients: 6 (2.6%) patients had isolated tumor cells (ITCs) and 8 (3.5%) patients presented just micrometastasis, additionally, 20 (8.7%) patients presented macrometastasis. After a median (range) follow-up of 60 (0&ndash, 146) months, patients with macrometastasis showed a significantly worse PFS compared to LVM and node-negative patients (61.1% vs. 71.4% vs. 83.2%, respectively, p = 0.018), and similar results were obtained for 5-year OS (50% vs. 78.6% vs. 81.5%, respectively, p &lt, 0.001). Half of the patients presenting LVM did not receive adjuvant treatment. Moreover, LVM had a moderate nonsignificant decrease in 5-year PFS compared to node-negative patients. Conclusions: Patients with endometrial cancer and low-volume nodal metastasis demonstrated a better prognosis than those presenting macrometastasis. Low-volume metastasis did not show worse oncological outcomes than node-negative patients, although there was a slight decrease in progression-free survival.

Contains fulltext : 220457.pdf (Publisher’s version ) (Open Access) The incidence of endometrial cancer, the most common gynecological malignancy, is increasing as life expectancy and obesity both rise. Lymph node status is the most important predictor for outcome, yet routine lymphadenectomy does not confer a survival benefit and is associated with substantial surgical morbidity. In the last decade, sentinel lymph node (SLN) mapping has emerged as a feasible and accurate alternative to full lymphadenectomy. Yet, SLN has introduced a distinction between micro- and macrometastasis, and the entity of non-SLN involvement with their attendant impact on outcome. Included among the raised issues is the question of whether positive sentinel nodes should be followed by pelvic and/or para-aortic lymphadenectomy dependent on the presence of macrometastasis at frozen section or other criteria. Moreover, the proper adjuvant treatment for individual cases with micrometastasis and/or isolated tumor cells is unclear. Recently published data on this topic are summarized in order to optimize the current treatment algorithm as it relates to the results of SLN assessment in endometrial cancer.

An application of FTIR spectroscopic imaging for the identification and visualization of early micrometastasis from breast cancer to lungs in a murine model is shown. Spectroscopic and histological examination is focused on lung cross-sections derived from animals at the early phase of metastasis (early micrometastasis, EM) as compared to healthy control (HC) and late phase of metastasis (advanced macrometastasis, AM) using murine model of metastatic breast cancer with 4T1 cells orthotopically inoculated. FTIR imaging allows for a detailed, objective and label-free differentiation and visualization of EM foci including large and small micrometastases as well as single cancer cells grouped in clusters. An effect of the EM phase on the entire lung tissue matrix as well as characteristic biochemical profiles for HC and advanced macrometastasis were determined from morphological and spectroscopic points of view. The extraordinary sensitivity of FTIR imaging toward EM detection and discrimination of AM borders confirms its applicability as a complementary tool for the histopathological assessment of the metastatic cancer progression.

We compared the performance of near-infrared imaging using indocyanine green (ICG) with the radioisotope (ISO) method to detect sentinel lymph nodes (SLNs) in breast cancer, to analyze predictive factors for negative ICG identification. The study included 122 patients who underwent sentinel lymph node biopsy (SLNB) using the combined ISO and ICG technique for primary breast cancer. We assessed the putative association between pathologic/clinical variables and ICG failure to detect SLNs. The ISO identification rate was 96.7% and ICG identification 81.9%. Overweight patients or presence of macrometastasis in SLNB were associated with the risk of ICG failing to detect SLNs (P = 0.02).

Background The aim of this study is to elucidate the clinicopathological significances, including the prognostic role, of metastatic lymph node ratio (mLNR) and tumor deposit diameter in papillary thyroid carcinoma (PTC) through a retrospective review and meta-analysis. Methods We categorized the cases into high (≥ 0.44) and low mLNR (< 0.44) and investigated the correlations with clinicopathological parameters in 64 PTCs with neck level VI lymph node (LN) metastasis. In addition, meta-analysis of seven eligible studies was used to investigate the correlation between mLNR and survival. Results Among 64 PTCs with neck level VI LN metastasis, high mLNR was found in 34 PTCs (53.1%). High mLNR was significantly correlated with macrometastasis (tumor deposit diameter ≥ 0.2 cm), extracapsular spread, and number of metastatic LNs. Based on linear regression test, mLNR was significantly increased by the largest LN size but not the largest metastatic LN (mLN) size. High mLNR was not correlated with nuclear factor κB or cyclin D1 immunohistochemical expression, Ki-67 labeling index, or other pathological parameters of primary tumor. Based on meta-analysis, high mLNR significantly correlated with worse disease-free survival at the 5-year and 10-year follow-up (hazard ratio [HR], 4.866; 95% confidence interval [CI], 3.527 to 6.714 and HR, 5.769; 95% CI, 2.951 to 11.275, respectively). Conclusions Our data showed that high mLNR significantly correlated with worse survival, macrometastasis, and extracapsular spread of mLNs. Further cumulative studies for more detailed criteria of mLNR are needed before application in daily practice.

Sentinel node (SN) concept is being applied to early gastric cancer. However, when SNs are positive for metastasis, it is unclear how often LNs in other LN basins show metastasis. We aimed to investigate LN metastasis possibility in LN basins without SNs (non-SN basins). We determined risk factors for metastasis in non-SN basins and identified a prediction model for non-SN basin metastasis using classification and regression tree (CART) analysis. We enrolled 550 patients who were diagnosed with cT1N0M0 or cT2N0M0 gastric cancer with a single lesion and underwent SN mapping. We adopted a dual-tracer method using a radioactive colloid and blue dye to detect SNs. Of all, 45 (8.2%) patients had SN metastasis; we divided them into two groups: LN metastasis positive and LN metastasis negative in non-SN basins. Univariate analysis showed that the groups differed significantly regarding lymphatic invasion (p = 0.007), number of identified SNs (p = 0.032), and macrometastasis in SN basins (p = 0.005). The CART decision tree for predicting LN metastasis in non-SN basins had area under the curve value of 0.86. Moreover, there were significantly differences in cancer-specific survival (CSS) between the two groups (p = 0.028). Macrometastasis in SN basins, lymphatic invasion, and number of identified SNs ≥ 5 are risk factors for LN metastasis in non-SN basins among gastric cancer patients. We identified a prediction model with CART analysis; patients with macrometastasis in SN basins and lymphatic invasion were considered to be at the highest risk for LN metastasis.

In recent analyses of Merkel cell carcinoma, prognosis is poor even in stages I and II. We performed a monocentric retrospective study of 37 consecutive cases with Merkel cell carcinoma stage I to III treated with a combination of surgery and adjuvant radiation to evaluate progression-free and overall survival. The median primary tumour diameter was 17.9 mm. Cases consisted of 31 primary tumours, of which 13 had negative sentinel lymph node biopsy (IA n = 10 and IIA n = 3) and 18 no sentinel lymph node biopsy (IB n = 15 and IIB n = 3), 2 tumours with positive sentinel lymph node biopsy (IIIA) and 4 with local macrometastasis (IIIB). The median age was 71 years and the median follow-up was 60.4 months. The 5-year progression-free survival was 83.8% and 5-year disease-specific survival was 95.7% (overall survival 93.0%). So far, our results show a high survival rate with combined treatment of surgery and adjuvant radiotherapy in early tumour stages of Merkel cell carcinoma.

The aim of the present study was to assess the sensitivity, specificity and practicality of using a one-step nucleic acid amplification (OSNA) assay during breast cancer staging surgery to predict and discriminate between at least 2 involved nodes and more than 2 involved nodes and facilitate the decision to provide axillary conservation in the presence of a low total axillary node tumour burden. A total of 700 consecutive patients, not treated with neo-adjuvant chemotherapy, received intraoperative sentinel lymph node (SLN) analysis using OSNA for cT1-T3 cN0 invasive breast cancer. Patients with at least one macrometastasis on whole-node SLN analysis underwent axillary lymph node dissection (ALND). The total tumour load (TTL) of the macrometastatic SLN sample was compared with the non-sentinel lymph node (NSLN) status of the ALND specimen using routine histological assessment. In total, 122/683 patients (17.9%) were found to have an OSNA TTL indicative of macrometastasis. In addition, 45/122 (37%) patients had NSLN metastases on ALND with a total positive lymph node burden exceeding the American College of Surgeons Oncology Group Z0011 trial threshold of two macrometastatic nodes. The TTL negative predictive value was 0.975 [95% confidence interval (CI), 0.962–0.988]. The area under the curve for the receiver operating characteristic curve was 0.86 (95% CI, 0.81–0.91), indicating that SLN TTL was associated with the prediction (and partitioning) of total axillary disease burden. OSNA identifies a TTL threshold value where, in the presence of involved SLNs, ALND may be avoided. This technique offers objective confidence in adopting conservative management of the axilla in patients with SLN macrometastases.

Background Sentinel lymph node (SLN) biopsy is the current prognostic tool for clinically node-negative breast cancer patients. If the SLN reveals macrometastasis, axillary lymph node dissection (ALND) is recommended. However, the use of ALND in patients with micrometastasis is debated. The objective of this study was to assess the utilization of ALND in the treatment of micrometastatic breast cancer. Methods An IRB approved, retrospective study of a pooled dataset of breast cancer patients with micrometastatic disease on SLN biopsy was performed. Patients diagnosed from 1999-2016 were identified via query of a single-institution National Comprehensive Cancer Network (NCCN) breast cancer database as well as a prospective tumor board. Results A total of 91 patients were diagnosed with micrometastatic nodal disease. The median age at diagnosis was 56 y (range: 31-85); median follow-up time was 47 mo (range: 0-203 mo). 42/91(46.2%) patients had ALND of which 37/42 (88.1%) were a second operation; 3/42(7.1%) patients had additional positive nodes found at ALND. 44/91 (48.4%) patients received radiation. 7/91 (7.7%) patients had a recurrence, 5/7 local, including one axillary (2.1%; patient declined ALND). Conclusions Given that the risk of lymphedema after ALND ranges between 20%-53%, the morbidity of ALND may far exceed the likelihood of detecting further nodal involvement in women with micrometastatic disease: 7.1% in this series.

We aimed to evaluate whether obese women experience more advanced invasive breast carcinoma (IBC) with a higher number of involved lymph nodes, higher range of axillary lymph node ratio (LNR) and presence and size of extracapsular extension as it may have an impact on prognosis and management. 245 patients diagnosed with IBC were divided into normal weight (NW), overweight (OW) and obese (OB) groups. Patients were divided into high range of LNR (LNR over or equal to 0.2) and low LNR (LNR less than 0.2). The extracapsular extension dimensions were measured on the original slides of each case and grouped into ≤ 1 mm and > 1 mm. 84 patients (33.07%) were OW, 72 (29.38%) OB and 91 (37.14%) NW. 45.7% of cases had macrometastasis in the axillary lymph nodes. NW patients had significantly fewer metastatic lymph nodes (p = 0.05) than in the OW/OB groups. There was no statistically significant difference between BMI groups according to the LNR (p = 0.66). Out of 111 cases with macrometastasis, 58 cases (52.25%) had extracapsular extension (ECE) (11.7% NW, 24.32% OW and 16.22% OB). Significantly more OW patients presented extranodal invasion (p = 0.04). We found no statistically significant relationship between the extracapsular extension diameter and BMI groups (p = 0.1).

Metastasis and growth in neoplastic lesions requires the multistep regulation of microenvironmental factors. We aimed to elucidate the microenvironmental changes in the process of lymphatic metastasis of lung squamous cell carcinoma. We examined the morphological characteristics of 102 cases of primary tumor (PT), 50 of intralymphatic tumor (ILT), 51 of lymph node (LN) micrometastasis (LN-Mic; ≤2 mm in size), and 82 of LN macrometastasis (LN-Mac; ≥10 mm in size). Afterwards we evaluated the expression of nine molecules (epidermal growth factor receptor, fibroblast growth factor receptor 2, CD44, aldehyde dehydrogenase 1, Podoplanin, E-cadherin, S100A4, geminin, and ezrin) in matched PT, ILT, LN-Mic, and LN-Mac from 23 of these cases. The number of smooth muscle actin α-positive fibroblasts, CD34-positive microvessels and CD204-positive macrophages were also examined. As a result, the mitotic index of tumor cells was significantly lower in ILT and LN-Mic than PT and LN-Mac (P

Objectives Ultra-staging (US) of sentinel lymph nodes (SLN) increases the detection of nodal metastases. US protocols vary among gynecologic pathologists, and internationally accepted guidelines are still not available. This study compares two US protocols (US-A vs US-B) in early stage cervical (CC) and endometrial cancers (EC) (table 1). Methods We retrospectively evaluated patients with clinical stage I endometrial cancer (EC) or stage IA-IB1 cervical cancer (CC) who underwent primary surgery with SLN biopsy from November 2010 to October 2017. Results 229 patients were analyzed (161 ECs and 68 CCs). The rate of positive node disease was: 22% with US-A protocol and 12% with US-B protocol (p=0.09) for EC patients; 22% and 10% (p=0.18) for CC patients. Macrometastasis, micrometastases, and ITC were 31%, 61% and 8%, respectively with US-A protocol; 43%, 40% and 17%, respectively with US-B protocol (p=0.272). Mean size of nodal metastasis was 5.4±6.3 mm for US-A and 3.2±4.3 mm for US-B protocol (p=0.09). On multivariate analysis including grade and LVSI, the US method was not associated with the detection of nodal metastases. Conclusions Approximately 50% of the nodal metastases detected by US of SLNs were low-volume metastases. In this study, the detection of positive node disease was not associated with the type of US protocol used. Larger multicenter prospective studies are advisable to confirm these results.

Objectives We compared the traditional ultrastaging (SU) with the one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis in women with apparent early stage endometrial carcinoma (EC). Methods All women were surgically staged including SLN mapping. Nodes were cut perpendicular to the long axis and two adjacent 5 mm sections were cut at each of 2 levels 50 mm apart, and one slide was stained with H&E and the other with immunohistochemistry using the AE1/AE3 anticytokeratin antibody, and one negative control slide for a total of five slides per block. For OSNA analysis, the 2mm sections of the SLN were homogenized to form a lysate that was centrifuged and inserted into the RD100i instrument where for the isothermal amplification of CK19 mRNA. Results Totally 409 patients were included in the analysis (183 OSNA, 226 SU). Overall, 3521 lymph nodes were removed, of those 871 SLN’s (24.7%) were identified (381 OSNA, 490 SU). Sixty patients had metastasis on SLN’s (26 OSNA, 34 SU). Macrometastasis, micrometastases, and ITC were 25.7%, 68.6% and 5.7% for OSNA; 48.1%, 36.5% and 15.4% for SU (p = 0.015). ITC alone were recorded in 7 women (2 OSNA, 5 SU). Conclusions The OSNA assay detected a higher rate of micrometastasis and a lower rate macrometastasis and ITC compared to SU. The clinical and prognostic impact of ITC is still controversial. Further studies are needed to clarify the clinical impact of the OSNA assessment technique and the prognostic impact of ITC in patients with stage I EC.

La afectación ganglionar se ha considerado hasta el momento un factor relevante para la supervivencia, estadiaje y tipo de tratamiento de las pacientes diagnosticadas de cáncer de mama. Se define al ganglio centinela (GC) como el primer ganglio de una cadena linfática que recibe el flujo linfático desde el tumor primario. Si este ganglio no contiene células tumorales es poco probable que el resto de ganglios axilares presenten enfermedad metastásica (1). La identificación del ganglio centinela puede sustituir a la linfadenectomía axilar para el estudio de extensión regional en el cáncer de mama, evitando su morbilidad asociada (2). Hoy en día, está aceptada la realización de la biopsia selectiva del ganglio centinela en aquellos casos de carcinomas infiltrantes T1, T2 y T3 (siempre que la axila sea clínica, ecográfica y patológicamente negativa) y presente menos de 3 ganglios centinela positivos. También se realiza en los casos de carcinoma intraductal con indicación de mastectomía o alto riesgo para infiltración (≥ 3cm, tumor palpable, alto grado histológico o comedonecrosis) (3) (4) (5) (6) (7) (8). La BSGC está contraindicada en el caso de la verificación preoperatoria de afectación ganglionar mediante pruebas de imagen y confirmada con biopsia, en el carcinoma inflamatorio, si ha recibido radioterapia axilar previa a dosis de 50 Gy y en el carcinoma localmente avanzado que presente afectación ganglionar con extensión extranodal (3)(4). Se define como ganglio positivo aquél que presenta células tumorales metastásicas en el estudio histológico o más de 100 copias de mARN-CK19 en el estudio OSNA. Se clasifican como macrometástasis aquellos con más de 2 mm de diámetro sobre la laminilla o equivalencia en número de copias de ARNm-CK19 mayor o igual a 5000 copias (9) (10). Está demostrado que la existencia de células tumorales aisladas y las micrometástasis no precisan la realización de linfadenectomía axilar. Sin embargo, en la actualidad todavía existen controversias respecto a la indicación de linfadenectomía axilar respecto a los casos de macrometástasis con baja carga tumoral (igual o menor de 10000 - 15000 copias) o perfil de bajo riesgo (hasta dos GC metastásicos, estatus post-menopáusico, tamaño menor de 3 cm, grado histológico 1 o 2, receptores hormonales positivos, Her2 negativo, Ki67 ≤14%, cirugía conservadora). En estos casos, se podría obviar la linfadenectomía incorporando el tratamiento adyuvante con radioterapia (3)(11)(12). Todavía constituye indicación habitual de linfadenectomía axilar la carga tumoral mayor a 10.000-15.000 copias o las macrometástasis en aquellos casos que no son de “bajo riesgo” (3). Por otro lado, pueden existir casos con cánceres pequeños y axila clínicamente negativa, candidatos a cirugía conservadora de mama con radioterapia adyuvante y valoración preoperatoria negativa por imagen de la axila en los que podría obviarse la realización de la biopsia selectiva del ganglio centinela siempre y cuando las pacientes fueran sometidas a un adecuado seguimiento. Las tendencias actuales se dirigen hacia una cirugía cada vez menos invasiva, evitando la linfadenectomía axilar en un número cada vez mayor de pacientes, gracias a la realización de la biopsia selectiva del ganglio centinela. Los objetivos de este trabajo son identificar variables que puedan modificar la actitud terapéutica en el cáncer de mama, tanto en los casos de tumores avanzados con diagnóstico de macrometástasis en la biopsia selectiva del ganglio centinela, como en el caso de tumores de bajo grado o con características especiales, en los que podría obviarse el estudio del ganglio centinela. También son objetivos: analizar las tasas de recidiva y supervivencia según su estadio y diagnóstico del ganglio centinela y estudiar las posibles asociaciones de los factores pronósticos considerados con las recidivas y supervivencia. Se trata de un estudio retrospectivo consecutivo observacional multicéntrico de las pacientes diagnosticadas e intervenidas de cáncer de mama entre los años 2000 y 2014 en el hospital de la Ribera. Excluimos las pacientes con neoplasia de mama previa ipsilateral, metástásicas de inicio, con quimioterapia neoadyuvante, con historia clínica incompleta o intervenidas en otros hospitales. Estudiamos los antecedentes, los métodos diagnósticos de imagen e histológicos utilizados, el tipo de tumor, así como su estadio, el tipo de intervención quirúrgica, el ganglio centinela, el tratamiento adyuvante que ha recibido la paciente y el seguimiento hasta el 15 de marzo de 2018. Revisamos una población de 1641 pacientes intervenidas de cáncer de mama sin quimioterapia neoadyuvante, 1135 de las cuales tienen realizado GC. Encontramos un 14.85% de fallecidas y/o recidivas al finalizar el seguimiento, una supervivencia libre de enfermedad del 90.03% de las pacientes a los 5 años y del 82.36% a los 10 años y un 12.16% de recidivas. El estudio de Shigemizu muestra unas tasas de supervivencia libre de enfermedad a 11 años similares (76.5%) (13). De los 1135 casos en los que se ha realizado GC el 11.85% presentaron un GC afecto por macrometástasis y el 79.54% obtuvieron un GC negativo. Nuestra muestra presenta un mayor porcentaje de GCs negativos que el ensayo clínico NSABP B-32 (71.1%) (14), objetiva resultados similares a Dengel et al (82.4%) (15) y algo menores que Toshikawa et al (85%) (16) e Ibrahim-Zada et al (87%) (17). En nuestro análisis estadístico, aumenta el riesgo de GC positivo un 5.2% por cada incremento de tamaño tumoral de un mm y aparece 2.80 veces más riesgo si existe invasión linfovascular. Factores de riesgo similares muestran los estudios de Tapia (18) y de Zheng (19). Los tumores de estirpe triple negativo presentan menor riesgo de afectación ganglionar, factor ya comentado por Marazzo (20), Vane (21) y Ozbas (22). La proporción de pacientes con ganglios afectos adicionales a los ganglios centinela se incrementa de forma más acusada por encima de valores de OSNA de 12000 y la proporción de tumores con estos valores aumenta en función del tamaño tumoral, alcanzando el máximo en el tamaño a partir de 5 cm. Hay estudios que muestran un corte de TTL similar (10000 copias en el análisis de Piñero-Madrona et al (23) y 15000 en el de Fung et al (24)). Otros sin embargo proponen un corte mayor, como Peg et al (25) y el estudio NEOVATTL (26) que establecen el corte en 25000, Kubota en 54000 (27), Ohi en 100000 (28), Espinosa-Bravo en 120000 (29) y Nabais en 190000 (30). El 14.9% de los tumores con histología en biopsia previa in situ e infiltrante en la definitiva, tenían el ganglio centinela positivo, datos similares al estudio de Sakr (31) y al de Camp (32). Los tumores con ganglio centinela positivo tuvieron en todos los casos un tamaño de 11 mm o superior. Francis et al (33) y Miyake et al (34) establecen el corte en 20 mm y Huo en 15 mm (35). En cuanto a la mortalidad específica se produce un riesgo 3.33 veces superior en tumores con macrometástasis y 3.77 veces superior en tumores con GC no realizado, respecto a GC negativo y se incrementa el riesgo un 5.5% por cada ganglio positivo y un 88% en tumores con invasión linfovascular. Los estudios de Tonelloto (36) y Saadatmand (37) plasman este descenso de supervivencia. Los metanálisis de Gujam (38) y de Zhang (39) demuestran que la invasión linfovascular predice un pronóstico más pobre. La supervivencia libre de enfermedad (SLE) empeora un 3.7% por cada ganglio positivo y 3.14 veces más si se realiza linfadenectomía axilar. Los estudios de Ozcan (40) y Joo (41) y el ensayo ACOSOG Z0011 (11)(12) exponen que la omisión de la linfadenectomía en pacientes con afectación axilar ganglionar limitada no muestra una peor supervivencia. También empeora la SLE a partir de los 20 mm y en tumores con Ki67 alto, como objetiva en estudio de Inwald et al (42). Según los datos de nuestro estudio podemos exponer que los tumores menores de 5 cm, sin invasión linfovascular, cuyo análisis de GC por OSNA sea menor de 12000 copias tienen baja posibilidad de presentar ganglios adicionales afectos y, por tanto, pueden beneficiarse de la no realización de un vaciamiento axilar, ya que no mejora la supervivencia libre de enfermedad. La administración de quimioterapia neoadyuvante en pacientes con afectación ganglionar tampoco mejora la misma. Deberíamos también considerar la necesidad de la realización del ganglio centinela en las pacientes con bajo riesgo de afectación axilar (CDIS, carcinoma ductal y carcinoma lobulillar infiltrante puro de 10 mm o menos). Bibliografía: 1. Acea Nebril B, Candia Bouso B, Sobrido Prieto M, Ramos Boyero M. Biopsia del ganglio centinela en enfermas con cancer de mama. Estudio de evaluación técnica desde los criterios de la medicina basada en la evidencia. Asociación Española de Cirujanos; 2003. [consultado 31 de marzo de 2019] Disponible en: http://www.breastsurgeonsweb.com/wp-content/uploads/downloads/2012/10/516.pdf 2. Fougo JL, Dinis-Ribeiro M, Araújo C, Dias T, Reis P, Giesteira L, et al. Impacto de la linfadenectomía sobre la recurrencia axilar y la morbilidad del miembro superior en pacientes con cáncer de mama y ganglio centinela negativo. Estudio prospectivo aleatorizado. 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Background The ACOSOG Z0011 trial demonstrated safe omission of axillary lymph node dissection (ALND) in patients with one or two positive sentinel lymph nodes (SLNs) receiving breast conservative surgery, followed by whole breast irradiation and adjuvant systemic treatment. This study aims to evaluate the exportability of the ACOSOG Z0011 criteria in an Asian/Chinese cohort residing in Hong Kong. Methods Retrospective analysis of a prospectively maintained database in a University affiliated tertiary breast centre was performed from June 2014 to May 2019. All breast cancer patients with no palpable adenopathy before surgery, one or more positive sentinel lymph nodes on histological examination and no prior neoadjuvant systemic treatment were recruited. Patients were grouped as eligible or ineligible according to the ACOSOG Z0011 criteria. The eligible group was compared with the sentinel alone group in the ACOSOG Z0011 cohort. Results Two hundred and forty-eight patients were recruited into the study. Sixty patients (24%) met the ACOSOG Z0011 criteria and could potentially avoid ALND. A higher percentage of clinical T2 tumors were observed in our eligible group than in the ACOSOG Z0011 trial (P=0.002). The histological subtype, tumor grade, estrogen receptor (ER)/progestogen receptor (PR) status and lymphovascular invasion status did not differ. There was no statistically significant difference in the proportion of SLN micrometastasis and macrometastasis between the two groups. Conclusions This study demonstrated clinical similarities between our eligible cohort and the ACOSOG Z0011 cohort, which confirms exportability of the ACOSOG Z0011 criteria to a subset of population in Hong Kong.

Background and objectives The Axillary Lymph Node Dissection (ALND) is the standard treatment in patients with invasive breast cancer and sentinel node metastasis, but in 60% of the cases there is no further axillary neoplastic involvement, so this invasive intervention represents an overtreatment. The purpose of the study is to identify patients with low risk of additional nodal metastases, to omit ALND. Methods The MSKCC Additional nodal metastasis nomogram was applied on a sample of 175 patients with invasive breast cancer who underwent ALND after detection of macrometastasis with the extemporaneous examination of the sentinel lymph node. Patients were classified as "low risk" when the result of the nomogram was ≤50%. Sensitivity, specificity, positive and negative predictive values and AUC (Area Under Curve) of the ROC curve of the nomogram were then calculated. Results A cut-off by 50% yielded 92.3% sensitivity, 81,4% specificity, 80% positive predictive value and 92.9% negative predictive value. The ROC curve AUC in these patients was 0.885. Conclusions The MSKCC nomogram has proven to be an effective tool in estimating the axillary lymph node status and it can potentially be used to better select the patients with sentinel node macrometastasis who can actually benefit from ALND.

Sentinel lymph node biopsy (SLNB) is a minimally invasive technique to stage the axillary lymph node status. The burden of nodal metastasis is of great concern, as the clinical relevance and therapeutic implications of pN1mi and pN0(i+) in the sentinel lymph node (SLN) remain a matter of debate.We examined the pathological features of 901 patients above the age of 65 presenting with clinical T1-T2 N0M0 breast tumours (3 cm), detecting tumours related to llary non-sentinel node (NSN) metastases when the SLN was minimally involved.A total of 270 patients underwent complete axillary lymph node dissection (cALND) after their SLNB specimen tested positive for macrometastasis, micrometastasis and isolated tumour cells (ITCs). Seventy-six patients were diagnosed with micrometastatic disease pN1mi (27.5%), whilst ITCs (pN0i+) were detected in seven patients (2.5%). NSNs were found to be involved in two patients (2.6%) with micrometastases at the SLN. No further metastatic disease was detected in NSNs when the SLN contained ITCs. At a median follow-up period of 5.8 years, no axillary recurrence was observed among pN1mi and pN0(i+) patients. Lobular histotype, multicentricity and lymphovascular invasion were found to be associated with NSN involvement.The results from our case series are supported by IBCSG 23-01 level 1 evidence, which demonstrated a local recurrence rate of 1% in 'minimally involved not-surgical treated axilla'.Based on current evidence, we spare well-informed and consenting patients from further axillary surgery when the SLN is minimally involved in early breast cancer within an agreed protocol, whilst scheduling adjuvant treatment based on the patients' primary tumour characteristics.

Background. Publication of the results of the randomised ACOSOG Z0011 trial concerning the possibilities of conservative treatment of breast cancer patients with macrometastasis in the sentinel lymph node (SLN) increased the interest in this therapeutic option. The objective of the study was to assess the practical effects of the implementation of conclusions from the aforementioned study as well as clinical consequences of abandoning intraoperative verification of sentinel lymph nodes resected during the surgical procedure. Material and methods. A prospective analysis was made for 567 breast cancer patients subjected to sentinel node biopsy in the period 1 January to 31 October 2014. In the case of the group undergoing breast conserving treatment (BCT), routine intraoperative assessment of SLN was abandoned. The decision regarding potential radicalisation of the surgical procedure was delayed until final histopathological results were obtained. The results were compared with data from the period preceding the implementation of changes. Results. BCT was used in 73.4% of study subjects while breast amputation was performed in the remaining patients. Presence of metastatic lesions within the SLNs was detected in 23.5% of patients. In 31.8% of patients with SLN metastases, radicalisation of the surgery was abandoned versus 18.3% in the control group, 22.2% versus 5.1% in case of macrometastases; 28.0% versus 6.5% in patients undergoing BCT. These are significant results, p < 0.05). The percentage of patients subjected to reoperation was 6.9% versus 3.6% in the control group. Conclusions. Postponing the decision regarding the potential radicalisation of surgical treatment until the receipt of the final result of the histopathological sentinel node assessment may facilitate the choice of further treatment. Abandonment of routine intraoperative assessment of SLN allowed for a statistically significant increase in the percentage of follow-up axillary lymph node resection being abandoned. At the same time, no significant increase in the rate of reoperations was observed.