Stratification of lymph node metastases as macrometastases, micrometastases, or isolated tumor cells has no clinical implication in patients with cervical cancer: Subgroup analysis of the SCCAN project.

BACKGROUND: In cervical cancer, presence of lymph-node macrometastases (MAC) is a major prognostic factor and an indication for adjuvant treatment. However, since clinical impact of micrometastases (MIC) and isolated tumor-cells (ITC) remains controversial, we sought to identify a cut-off value for the metastasis size not associated with negative prognosis. METHODS: We analyzed data from 967 cervical cancer patients (T1a1L1-T2b) registered in the SCCAN (Surveillance in Cervical CANcer) database, who underwent primary surgical treatment, including sentinel lymph-node (SLN) biopsy with pathological ultrastaging. The size of SLN metastasis was considered a continuous variable and multiple testing was performed for cut-off values of 0.01-1.0 mm. Disease-free survival (DFS) was compared between N0 and subgroups of N1 patients defined by cut-off ranges. RESULTS: LN metastases were found in 172 (18%) patients, classified as MAC, MIC, and ITC in 79, 54, and 39 patients, respectively. DFS was shorter in patients with MAC (HR 2.20, P = 0.003) and MIC (HR 2.87, P < 0.001), while not differing between MAC/MIC (P = 0.484). DFS in the ITC subgroup was neither different from N0 (P = 0.127) nor from MIC/MAC subgroups (P = 0.449). Cut-off analysis revealed significantly shorter DFS compared to N0 in all subgroups with metastases ≥0.4 mm (HR 2.311, P = 0.04). The significance of metastases <0.4 mm could not be assessed due to limited statistical power (<80%). We did not identify any cut-off for the size of metastasis with significantly better prognosis than the rest of N1 group. CONCLUSIONS: In cervical cancer patients, the presence of LN metastases ≥0.4 mm was associated with a significant negative impact on DFS and no cut-off value for the size of metastasis with better prognosis than N1 was found. Traditional metastasis stratification based on size has no clinical implication.

Clinical utility of artificial intelligence assistance in histopathologic review of lymph node metastasis for gastric adenocarcinoma.

BACKGROUND: Advances in whole-slide image capture and computer image analyses using deep learning technologies have enabled the development of computer-assisted diagnostics in pathology. Herein, we built a deep learning algorithm to detect lymph node (LN) metastasis on whole-slide images of LNs retrieved from patients with gastric adenocarcinoma and evaluated its performance in clinical settings. METHODS: We randomly selected 18 patients with gastric adenocarcinoma who underwent surgery with curative intent and were positive for LN metastasis at Chiba University Hospital. A ResNet-152-based assistance system was established to detect LN metastases and to outline regions that are highly probable for metastasis in LN images. Reference standards comprising 70 LN images from two different institutions were reviewed by six pathologists with or without algorithm assistance, and their diagnostic performances were compared between the two settings. RESULTS: No statistically significant differences were observed between these two settings regarding sensitivity, review time, or confidence levels in classifying macrometastases, isolated tumor cells, and metastasis-negative. Meanwhile, the sensitivity for detecting micrometastases significantly improved with algorithm assistance, although the review time was significantly longer than that without assistance. Analysis of the algorithm's sensitivity in detecting metastasis in the reference standard indicated an area under the curve of 0.869, whereas that for the detection of micrometastases was 0.785. CONCLUSIONS: A wide variety of histological types in gastric adenocarcinoma could account for these relatively low performances; however, this level of algorithm performance could suffice to help pathologists improve diagnostic accuracy.

Characterizing isolated tumor cells in regional lymph nodes of early endometrial cancer.

OBJECTIVE: To examine the characteristics of isolated tumor cells (ITCs) in regional lymph nodes of early-stage endometrial cancer. METHODS: This is a retrospective cohort study examining the National Cancer Institute's Surveillance, Epidemiology, and End Result Program. The study population was 6472 women with non-metastatic, node-negative T1 endometrial cancer who underwent primary hysterectomy and surgical nodal evaluation. Multivariable binary logistic regression model was used to identify the independent characteristics for ITCs. Postoperative therapy according to ITCs status was also assessed with propensity score weighting. RESULTS: ITCs were seen in 111 (1.7%) cases. In a multivariable analysis, ITCs were largely associated with tumor factors including deep myometrial invasion (T1b versus T1a, 4.0% versus 1.0%, adjusted-odds ratio [aOR] 3.42, P < 0.001) and larger tumor size (>4 versus ≤4 cm, 3.0% versus 1.6%, aOR 1.55, P = 0.037). Moreover, women undergoing sentinel lymph node (SLN) biopsy had a higher likelihood of identifying ITCs compared to those undergoing lymphadenectomy (LND): 2.7% for SLN alone, 3.7% for SLN/LND, and 1.2% for LND alone (aOR ranged 2.60-2.99, P < 0.001). Women who had ITCs identified were more likely to receive postoperative therapy (81.8% versus 31.7%, P < 0.001), including external beam radiotherapy (EBT) alone (25.1% versus 3.2%) and chemotherapy/EBT (16.3% versus 1.9%). Similar associations were observed in the low-risk group (stage IA, grade 1-2 endometrioid, 78.4% versus 9.2%, P < 0.001), including EBT alone (35.3% versus 0.6%). CONCLUSION: This study suggests that a SLN protocol can identify more ITCs in the regional lymph nodes of early endometrial cancer. Deep myometrial invasion and large tumor size were associated with increased risk of ITCs. Postoperative therapy is offered more frequently in the setting of ITCs with variable treatment patterns, warranting further outcome studies and practice guidelines.

Oncologic outcomes of endometrial cancer in patients with low-volume metastasis in the sentinel lymph nodes: An international multi-institutional study.

OBJECTIVE: To assess oncologic outcomes in endometrial cancer patients with low-volume metastasis (LVM) in the sentinel lymph nodes (SLNs). METHODS: Patients with endometrial cancer and SLN-LVM (≤2 mm) from December 3, 2009, to December 31, 2018, were retrospectively identified from 22 centers worldwide. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV, adnexal involvement, or unknown adjuvant therapy (ATx) were excluded. RESULTS: Of 247 patients included, 132 had isolated tumor cell (ITC) and 115 had micrometastasis (MM). Overall 4-year recurrence-free survival (RFS) was 77.6% (95% CI, 70.2%-85.9%); median follow-up for patients without recurrence was 29.6 (interquartile range, 19.2-41.5) months. At multivariate analysis, Non-endometrioid (NE) (HR, 5.00; 95% CI, 2.50-9.99; P < .001), lymphovascular space invasion (LVSI) (HR, 3.26; 95% CI, 1.45-7.31; P = .004), and uterine serosal invasion (USI) (HR, 3.70; 95% CI, 1.44-9.54; P = .007) were independent predictors of recurrence. Among 47 endometrioid ITC patients without ATx, 4-year RFS was 82.6% (95% CI, 70.1%-97.2). Considering 18 ITC patients with endometrioid grade 1 disease, without LVSI, USI, or ATx, only 1 had recurrence (median follow-up, 24.8 months). CONCLUSIONS: In patients with SLN-LVM, NE, LVSI, and USI were independent risk factors for recurrence. Patients with any risk factor had poor prognosis, even when receiving ATx. Patients with ITC and grade 1 endometrioid disease (no LVSI/USI) had favorable prognosis, even without ATx. Further analysis (with more patients and longer follow-up) is needed to assess whether ATx can be withheld in this low-risk subgroup.

Detection and prognostic significance of isolated tumor cells and micrometastases in pelvic lymph nodes of patients with early ovarian clear cell carcinoma.

BACKGROUND/PURPOSE: Ovarian clear cell carcinoma (OCCC) accounts for approximately 18% of all epithelial ovarian malignancies in Taiwan and portends a poor prognosis. Here, we sought to investigate whether immunohistochemistry with an anti-pan-cytokeratin antibody cocktail (AE1/AE3) can be used as an adjunct to hematoxylin and eosin (H&E) staining for improving the detection of isolated tumor cells (ITCs) and micrometastasis to pelvic lymph nodes (LNs). We also assessed whether these lesions may predict disease recurrence. METHODS: Pelvic lymphadenectomy specimens were obtained from 197 patients with stage 1 OCCC who had undergone surgery between 2000 and 2018 from Linkou and Kaohsiung Chang Gung Memorial Hospital. Immunohistochemical staining with AE1/AE3 was applied to a total of 1186 slides. Clusters of metastatic tumor cells, detected immunohistochemically, were classified as ITCs (clusters with diameters of ≤0.2 mm) or micrometastases (tumor cell clusters of >0.2 but ≤2.0 mm). We also assessed the diameter of metastases in patients with positive lymph nodes (stage IIIA1, n = 3, 7 positive nodes). RESULTS: Clusters with a positive AE1/AE3 staining were identified in five (2.53%) of the 197 patients (ITCs, n = 3; micrometastasis, n = 2). Four patients had no evidence of disease recurrence but a patient recurred at follow-up. Metastatic foci of patients with stage IIIA1 disease were all >2.0 mm in size. CONCLUSION: Immunohistochemical staining with AE1/AE3 can identify micrometastasis or ITCs in LNs missed on routine H&E staining. The role of micrometastasis in predicting recurrent OCCC and implementing on treatment strategies requires further investigation.

[Reporting and handling of lymphonodectomy specimens in gynecologic malignancies and sentinel lymph nodes]. / Leitlinienbasierte Aufarbeitung und Befundung von Lymphonodektomiepräparaten und Sentinel-Lymphknoten gynäkologischer Malignome.

The handling and reporting of resected lymph nodes in gynecologic cancer follows the recommendations of the German national guidelines and the recommendations of the International Collaboration of Cancer Reporting (ICCR) and the International Society of Gynecologic Pathologists (ISGyP). The definitions of micrometastases and isolated tumor cells are in accordance with the definition of the UICC (Union Internationale Contre le Cancer) and TNM system. Both findings must be reported as part of the pathology report and final tumor classification. It is mandatory to examine all excised lymph nodes with complete processing of all nodes up to 0.3 cm and slicing of all larger nodes in 0.2-cm wide intervals with complete processing of all lamellae. The amount of the resected lymph nodes in correlation to positive nodes, the metric dimension of the largest lymph node metastasis per lymph node region, and the presence of extracapsular extension of the lymph node deposits must be part of the pathology report. The handling and cutting of sentinel lymph nodes are similar to nonsentinel nodes. Within frozen section analyses and final processing from paraffin-embedded sentinel nodes, all nodes should be examined by three-step sections with an interval of about 200 µm. In cases of negative sentinel nodes on H&E staining, immunohistochemical ultrastaging should be performed.

Incidence of pelvic lymph node metastasis using modern FIGO staging and sentinel lymph node mapping with ultrastaging in surgically staged patients with endometrioid and serous endometrial carcinoma.

OBJECTIVE: We report the incidence of occult nodal metastasis in patients who underwent primary surgical staging for apparent early endometrioid or serous endometrial cancer with bilateral SLN mapping and enhanced pathology. Occult ovarian metastasis rates were also reported. METHODS: Patients with clinical stage I serous or endometrioid endometrial cancer who underwent primary staging surgery with successful bilateral SLN mapping from 1/2005-12/2018 were retrospectively evaluated. Rates of isolated tumor cells (ITCs), micro- and macrometastatic nodal disease, and occult ovarian involvement were reported. RESULTS: Of 1044 patients, 959 had endometrioid and 85 serous carcinoma. There were no positive SLNs among 510 patients with noninvasive FIGO grade 1/2 endometrioid carcinoma and < 1%ITCs. Grade 1: 4.5%(9/202) with inner-half and 10%(6/62) with outer-half myoinvasion had positive SLNs. Grade 2: rates were 4%(3/76) and 20%(8/41), respectively. Grade 3: 5%(1/20) with noninvasive, 3%(1/31) with inner-half, and 24%(4/17) with outer-half myoinvasion had positive SLNs. ITC incidence increased with depth of myoinvasion-25% of deeply invasive grade 1/2 and 18% of deeply invasive grade 3 tumors. Four (10%) of 41 patients with noninvasive serous endometrial carcinoma had ITCs or positive SLNs. There were no occult ovarian metastases with grades 1/2 disease, 2/68 (3%) with grade 3 disease, and 2/85 (2%) with serous endometrial carcinoma. CONCLUSION: Ultrastaging SLNs may be unwarranted in low-grade noninvasive endometrioid cancer but valuable in noninvasive serous carcinoma. Occult ovarian metastasis is uncommon in early endometrial carcinoma and occurs in 2-3% of high-risk histologies. Further research is needed to determine ITC significance, particularly with regard to adjuvant treatment.

Diagnostic criteria of sentinel lymph node micrometastasis or macrometastasis based on tissue rinse liquid-based cytology in gynecological cancer.

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.

Isolated tumor cells in the regional lymph nodes in patients with squamous cell carcinoma of the esophagus are rarely observed but often represent part of a true metastasis.

The most common malignancy of the esophagus is squamous cell carcinoma (SCC) and regional lymph node metastases are an important prognostic factor. Isolated tumor cells (ITCs) are defined as single tumor cells or small clusters of tumor cells not exceeding 0.2 mm. The prognostic role of ITCs is not clear. This study aimed to determine the prevalence of ITCs in regional lymph nodes in patients with esophageal SCC and to investigate how frequently ITCs represent part of a true metastasis. Surgical specimens from 100 patients with SCC of the esophagus were included. All original H&E stained slides containing lymph nodes were reviewed by two gastrointestinal pathologists. In lymph nodes containing ITCs, additional levels were cut and stained with a H&E- and a cytokeratin stain. Areas of tumor cells that measured >0.2 mm on the deeper sections were classified as metastases. A total of 2460 lymph nodes were examined. ITCs were detected in 10 lymph nodes (0.4%) from nine patients (9%). Deeper sections revealed metastases in five out of the 10 lymph nodes (50%). ITCs in regional lymph nodes of patients with SCC of the esophagus is a rare finding compared with patients with adenocarcinoma of the esophagogastric junction. However, deeper sections often revealed metastases. Therefore, in patients with SCC of the esophagus, we recommend additional sectioning and immunohistochemical examination of lymph nodes when ITCs are detected on the first slide.

Low-volume disease in endometrial cancer: The role of micrometastasis and isolated tumor cells.

Nodal assessment represents an integral part of staging procedure for endometrial cancer. The widespread diffusion of sentinel node mapping determinates a phenomenon of migration from stage I to stage III disease, especially for low-risk endometrial cancer patients. The adoption of sentinel node mapping and pathological ultrastaging increase the detection of low volume disease (i.e., micrometastasis and isolated tumor cells), being low volume disease detected in >30% of patients with positive nodes. The prognostic role of low volume disease is discussed as well as the possible adjuvant strategies for patients diagnosed with micrometastasis and isolated tumor cells. The role of further prospective treatments in endometrial cancer, including molecular and genetic profiling, is critically reviewed.

Prospective clinical trial of robotic sentinel lymph node assessment with isosulfane blue (ISB) and indocyanine green (ICG) in endometrial cancer and the impact of ultrastaging (NCT01818739).

OBJECTIVES: To assess the performance sentinel lymph node (SLN) biopsy and effect of ultrastaging in clinically early stage endometrial cancer. METHODS: Patients with endometrial cancer prospectively enrolled after informed consent was obtained. The cervix was injected superficially with 1 mL of ISB and 1 mL of ICG (diluted 1:25) at 3 and 9 o'clock each. SLN biopsy was followed by complete pelvic lymphadenectomy (aortic lymphadenectomy at the discretion of the surgeon). Lymph nodes (LNs) were analyzed by standard sectioning with H&E; ultrastaging of SLN was done retrospectively and blinded to treating physicians. RESULTS: 204 patients received dye injections. In 184 (90.2%) patients at least one SLN was identified. Of all patients, 138 (68%) had bilateral mapping. In the patients with successful mapping of a hemipelvis, ICG detected SLNs in 83% and ISB in 64% of cases (p < 0.0001). Median BMI (kg/m2) for patients with successful mapping was 35.7 compared to 40.1 for those who did not map (p = 0.01). Twenty-three (11.3%) patients had positive LNs. Applying the SLN algorithm, positive nodes were detected in 21/23 (91.3%). The negative predictive value (NPV) was 98.9% (95% CI: 96.01% to 99.71%). Eleven patients had positive SLN with isolated tumor cells (ITCs) or micrometastases detected on ultrastaging. Including these patients, 34 (17%) had positive LNs, increasing the NPV to 99% and sensitivity to 94%. There were no recurrences in patients with ITCs only. CONCLUSIONS: SLN assessment in endometrial cancer is feasible and safe with high NPV (99%). ICG was more effective in detecting SLN compared to ISB. Although ultrastaging detected additional positive LNs, treatment based on standard sectioning appears reasonable but further research is needed.

Sentinel lymph nodes (SLN) in endometrial cancer: The relationship between primary tumor histology, SLN metastasis size, and non-sentinel node metastasis.

OBJECTIVES: To examine sentinel lymph node pathology and describe relationships to uterine pathology, non-sentinel pelvic lymph nodes, and para-aortic lymph nodes. METHODS: Patients with apparent uterine-confined endometrial cancer underwent robotic hysterectomy, SLN mapping, completion pelvic lymphadenectomy (LND), and para-aortic (PaLND) directed by frozen section. Patients were risk stratified by histology: low-risk (LR) endometrioid <50% depth-of-invasion (DOI), intermediate-risk (IR) endometrioid ≥50% DOI, and high-risk (HR) type II histology for comparison to other pelvic/aortic metastases. RESULTS: 414 patients were stratified: 275 LR, 80 IR, and 59 HR cases. PaLND was performed in 84.2% of IR/HR patients and 25.1% LR patients. Pelvic node metastasis was detected in 11.6% LR, 50.0% IR, and 39.0% HR patients. PaLN metastasis was detected in 2.9% LR, 11.3% IR, and 16.9% HR patients. Proportionally, isolated tumor cells (ITC) SLNs were more common in LR or IR vs. HR group (51.6% and 44.7% vs. 15.0%, p < 0.05). The SLN false negative rates (FNR) were 0% LR, 2.5% IR, and 5.1% HR. Non-sentinel pelvic node metastases were present in 28(31.5%) of all SLN+ cases, but only 3(8.3%) of SLN with ITC. PaLN metastasis was found in 18.8% LR, 11.8% IR, and 33.3% HR cases with ITC SLNs. After controlling for DOI, LVSI, and grade, ITC-positive SLNs had a significant association with non-sentinel pelvic and aortic metastasis (p = 0.03 and p = 0.008, respectively). CONCLUSIONS: Patients with HR histology have more micro/macro-metastases in both SLNs and non-SLN metastases compared to LR/IR patients. SLN ITCs were associated with a clinically significant incidence of PaLN metastasis across all histology risk groups. There were no cases of isolated aortic node metastasis in this study. SLN mapping had an increased, although clinically acceptable FNR in the HR cohort compared to LR patients.

Long-term breast cancer survival in relation to the metastatic tumor burden in axillary lymph nodes.

PURPOSE: The clinical significance of lymph node micrometastases and isolated tumor cells (ITCs) in breast cancer is still controversial. After a median follow-up of 52 months, a report from the Swedish Multicenter Cohort Study presented a worse cancer-specific and event-free survival for patients with micrometastases than node-negative individuals, but could not demonstrate a significant difference in overall survival (OS). Due to the tendency of breast cancer to relapse after more than 5-10 years, we now report the long-term survival of the cohort. METHODS: Between September 2000 and January 2004, 3355 breast cancer patients were included in a prospective cohort. Sentinel lymph node biopsy was always performed. Patients were classified in four groups according to their overall nodal stage: node negative (N0, 2372), ITCs (113), micrometastases (123), and macrometastases (747). Kaplan-Meier survival estimates and Cox proportional hazard regression models were applied. RESULTS: Median follow-up was 156 months. Ten-year cancer-specific survival and OS were significantly lower in case of micrometastases than in N0 (84.7 vs. 93.5%, p = 0.001, and 75.5 vs. 84.2%, p = 0.046, respectively). In case of macrometastases, corresponding survival rates were 82.8 and 74.3%. Only for those aged less than 50 years, cancer-specific survival and OS were significantly worse in case of ITCs than N0. Patients with micrometastases received less often chemotherapy than those with macrometastases (24.4 vs. 53.9%). CONCLUSIONS: Lymph node micrometastases in breast cancer have a prognostic significance. This study demonstrates a similar survival for patients with micrometastases and those with macrometastases, possibly due to systemic undertreatment.

Patterns of FIRST recurrence of stage IIIC1 endometrial cancer with no PARAAORTIC nodal assessment.

OBJECTIVE: To assess the rates and distribution of first recurrence in patients with FIGO stage IIIC1 endometrial cancer (EC) who did not undergo paraaortic dissection at surgical staging. METHODS: We retrospectively selected all (n = 207) stage IIIC1 patients treated at a single institution from 5/1993-1/2017. Sites of first recurrence were identified, disease-free (DFS) and overall survival (OS) calculated, multivariate logistic regression performed to identify factors associated with recurrence. RESULTS: Three-year DFS and OS were 66.5% and 85.7%, respectively. The most common histology was endometroid (64.2%). Three-year DFS was 81% (SE±3.8%) endometrioid vs. 39.5% (SE±6.6%) non-endometrioid (P < 0.001). Three-year OS was 96.9% (SE±1.8%) endometrioid vs. 65.6% (SE±6.7%) non-endometrioid (P < 0.001). Sixty-two (30.1%) patients recurred. Patterns of recurrence were: 14 (8.3%) multiple sites, 17 (8.2%) abdominal, 14 (6.8%) extra-abdominal, 17 (8.3%) isolated nodal (8 of these (3.9%) paraaortic). Patients with isolated tumor cells (ITCs) in lymph nodes only had 12/71 (17%) recurrence rate vs. 50/135 (37%) for patients with micro-/macrometastasis. On univariate analysis, grade (HR 4.67 95%CI 1.5-14.5, P = 0.008), histology (HR 4.9 95%CI 2.6-9.3, P < 0.001), myometrial invasion (HR 1.9 95%CI 1.04-3.5, P = 0.04), pelvic washing (HR 2.2 95%CI 1.1-4.5, P = 0.03), tumor volume in pelvic LNs (ITC vs. micro-/macrometastasis; HR 0.3 95%CI 0.2-0.7, P = 0.003) were associated with recurrence. On multivariate analysis, only histology was associated with recurrence (HR 7.88 95%CI 3.43-18.13, P < 0.001). CONCLUSIONS: Isolated paraaortic recurrence in stage IIIC1 EC is uncommon. Micro-/macrometastasis were associated with twice the recurrence rate compared to ITC. These data will help clinicians counsel patients with stage IIIC1 EC regarding paraaortic assessment.

Clinical significance of isolated tumor cells and micrometastasis in low-grade, stage I endometrial cancer.

INTRODUCTION: Ultrastaging in endometrial cancer (EC) led to increased detection of isolated tumor cells (ITC, ≤0.2 mm) and micrometastases (MM, 0.2-2 mm), with unclear effect on prognosis. Our aim was to characterize the impact of ITC and MM on the outcome of these patients. METHODS: Grade 1 to 2 stage I endometrioid EC patients with nodal ITC (n = 11) or MM (n = 12) between 2012 and 2018 were retrospectively compared to a matched group of lymph node negative (n = 18) patients based on age, body mass index, grade, myometrial invasion, and lymphovascular space invasion (LVI) status using propensity score analysis (1:1). Mann-Whitney U tests were performed on continuous variables and χ2 tests on categorical variables. Progression-free survival (PFS) was the main endpoint. RESULTS: All MM and 81% of ITC had LVI. More ITC/MM patients received RT and chemotherapy (91.7% vs 18.4%; 70.8% vs 4.5%, respectively; P < 0.01) without significant difference in treatment-related toxicities (25% vs 27.3% grade 1%-2% and 20.8% vs 9.1% grade 2-3; P = 0.538) or PFS (29.2 vs 25 months; P = 0.828). Two distant recurrences occurred in MM patients after 2.5 years; one lung and one para-aortic lymph node. CONCLUSION: With adjuvant treatment, ITC/MM in otherwise well-differentiated stage I endometrial cancer have similar outcomes to matched LN- patients.

Evaluation of sentinel lymph node biopsy prior to axillary lymph node dissection: the role of isolated tumor cells/micrometastases and multifocality/multicentricity-a retrospective study of 1214 breast cancer patients.

PURPOSE: Sentinel lymph node biopsy (SLNB) alone has thus become an accepted surgical approach for patients with limited axillary metastatic disease. We investigated to what extent isolated tumor cells (ITC) or micrometastasis in SLNBs is associated with proven tumor cells or metastasis in non-sentinel lymph nodes. Furthermore, we investigated the feasibility of SLNB in multifocal and multicentric tumors as both entities have been considered a contraindication for this technique. METHODS: 1214 women suffering from T1 and T2 invasive breast cancer, with clinically and sonographically insuspect axillary status and undergoing primary breast cancer surgery including SLNB and axillary staging in case of SLN (sentinel lymph node) metastases, were recruited into this multicentered study. RESULTS: ITC and micrometastases were found in 2.01 and 21.4% of patients with SLN metastases (n = 299). Among patients with sentinel micrometastases, 4.7% showed further axillary micrometastases, while only two patients (3.1%) had two axillary macrometastases. Multifocal and multicentric tumors were diagnosed in 9.3 and 2.6% of our patients who at least had one SLN resected, respectively. Detection rates of SLNs did not differ between the cohorts suffering from unicentric and multifocal or multicentric disease. Moreover, the portion of tumor-free SLNs, the number of SLNs with metastasis as well as the mean number of resected SLNs did not differ. CONCLUSIONS: No patient with sentinel node micrometastases showed more than two axillary macrometastases. Multifocal and multicentric disease is no contraindication for SLNB.

Isolated tumor cells identified by sentinel lymph node mapping in endometrial cancer: Does adjuvant treatment matter?

OBJECTIVE: To evaluate the outcome and the role of adjuvant treatment in the management of patients with endometrial cancer and isolated tumor cells (ITCs) identified by SLN mapping. METHODS: This single center study identified all patients undergoing hysterectomy, salpingo-oophorectomy, lymphadenectomy and SLN mapping for endometrial cancer between November 2010 and December 2015. Data was prospectively collected. Progression-free survival was analyzed according to the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 519 patients were included. Overall, 85 patients (16.4%) were found to have SLN metastases of which 43 (51%) were macrometastasis, 11 (13%) micrometastasis (MM) and 31 (36%) ITC. Eleven (35%) of patients with ITCs received adjuvant chemotherapy±whole pelvic radiation therapy (WPRT), 10 (32%) received WPRT, and 10 (32%) received either no adjuvant treatment or vault brachytherapy (VBT) only. ITC patients received significantly less chemotherapy (p=0.0001) and WPRT (p=0.007) compared to patients with macrometastasis. Of note, ITC were not considered node positive in our study. With a median follow-up of 29months (range: 0-67), the progression free survival (PFS) at 3-years for the ITC patients was 95.5%, similar to node negative (87.6%) and micrometastasis patients (85.5%), but statistically better than patients with macrometastasis (58.5%) (p=0.0012). Only 1/31 patient with ITC recurred (IB, 7cm carcinosarcoma) despite adjuvant treatments. None of the ITC patients with endometrioid histology recurred (0/28) and none of the ITC patients who did not receive adjuvant treatment or VBT recurred (0/10). CONCLUSIONS: Patients with endometrial cancer found to have SLN ITCs have an excellent outcome. The use of adjuvant treatment should be tailored to uterine factors and histology and not solely based on the presence of ITCs. Patients with ITCs and otherwise low-risk uterine disease probably derive little benefit from receiving additional treatments. More studies are needed to confirm our results.

TBL1XR1 predicts isolated tumor cells and micrometastasis in patients with TNM stage I/II colorectal cancer.

BACKGROUND AND AIM: A considerable number of early-stage colorectal cancer (CRC) patients may develop cancer relapse or metastasis after curative surgery. Isolated tumor cells (ITC) and micrometastasis in lymph nodes (LNMM), which are undetectable by conventional pathological examination, may be one primary reason. Detection of ITC/LNMM is time-consuming and cost-ineffective; we aimed to find biomarkers in primary CRC tissues to help predicting ITC/LNMM status. METHODS: We enrolled 137 node-negative patients with early-stage CRC in this study. Existence of ITC/LNMM was identified by immunohistological staining with cytokeratin 20 in resected lymph nodes. Expression of transducin (ß)-like 1 X-linked receptor 1 (TBL1XR1) in primary CRC tissues was also investigated. Chi-squared test was performed to reveal the correlations between ITC/LNMM and clinicopathological characteristics. Univariate and multivariate analyses were used to determine independent prognostic factors. Knockdown experiment together with proliferation and invasion assays were carried out to explore molecular mechanisms between TBL1XR1 and ITC/LNMM. RESULTS: About 29.2% (40/137) patients were identified as ITC/LNMM positive, and most of them (32/40 cases, 80%) showed high TBL1XR1 expression in primary CRC tissues. Both ITC/LNMM and TBL1XR1 expression were independent prognostic factors for disease relapse or metastasis. In vitro experiments demonstrated that TBL1XR1 can regulate the expression of vascular endothelial growth factor C and epithelial-mesenchymal transition proteins, thus mediate the process of lymph node metastasis. CONCLUSIONS: Identification of ITC/LNMM is significant in evaluating clinical outcome and guiding adjuvant chemotherapy for early-stage CRC patients. TBL1XR1 overexpression in CRC tissues can serve as an efficient biomarker to predict the status of ITC/LNMM.

Prognostic significance of axillary dissection in breast cancer patients with micrometastases or isolated tumor cells in sentinel nodes: a nationwide study.

We estimated the impact of axillary lymph node dissection (ALND) on the risk of axillary recurrence (AR) and overall survival (OS) in breast cancer patients with micrometastases or isolated tumor cells (ITC) in sentinel nodes. We used the Danish Breast Cancer Cooperative Group (DBCG) database to identify patients with micrometastases or ITC in sentinel nodes following surgery for primary breast cancer between 2002 and 2008. A Cox proportional hazard regression model was developed to assess the hazard ratios (HR) for AR and OS between patients with and without ALND. We identified 2074 patients, of which 240 did not undergo further axillary surgery. The 5-year cumulated incidence for AR was 1.58 %. No significant difference in AR was seen between patients with and without ALND. The age adjusted HR for AR if ALND was omitted was 1.79 (95 % CI 0.41-7.80, P = 0.44) in patients with micrometastases and 2.21 (95 % CI 0.54-8.95, P = 0.27), in patients with ITC after a median follow-up of 6 years and 3 months. There was no significant difference in overall survival between patients with and without ALND, when adjusting for age, co-morbidity, tumor size, histology type, malignancy grade, lymphovascular invasion, hormone receptor status, adjuvant systemic treatment and radiotherapy, with a HR for death if ALND was omitted of 1.21 (95 % CI 0.86-1.69, P = 0.27) in patients with micrometastases and 0.96 (95 % CI 0.57-1.62, P = 0.89) in patients with ITC after a medium follow-up on 8 and 5 years. In this nationwide study, we found a low risk of AR on 1.58 % and we did not find a significantly increased risk of AR if ALND was omitted in patients with micrometastases or ITC in sentinel nodes. Furthermore, no significant difference in overall survival was seen between patients with and without ALND when adjusting for adjuvant treatment.

Detection of Cervical Lymph Node Micrometastases in Patients with Squamous Cell Carcinoma of the Oral Cavity, Pharynx and Larynx.

BACKGROUND: The goal of this prospective study was to determine the frequency of micrometastases in patients with squamous cell carcinoma (SCC) of the oral cavity, pharynx and larynx in whom elective neck dissection was indicated (cN0). PATIENTS AND METHODS: A total of 12 patients (10 males and 2 females) were enrolled in the study. The age ranged 42-73 years (median 62 years). Elective neck dissection was performed in all patients (8 ipsilateral, 4 bilateral) and a total of 256 lymph nodes were removed and sent for microscopic examination. RESULTS: The presence of tumor cells in cervical lymph nodes was found in 5/12 (42%) patients. Micrometastases of SCC were found in two patients and isolated tumor cells (ITC) in two other patients. In the remaining one patient with oropharyngeal SCC, a micrometastasis of papillary thyroid carcinoma (PTC) was detected. Positive lymph nodes were localized in level II in three patients with SCC of larynx, hypopharynx and tongue base, respectively, in level I in one patient with SCC of oral tongue and in level III in one patient with PTC. CONCLUSION: Our results indicate that SCC of head and neck has a high potential for creating micrometastases which frequency is higher compared to clinically detected macrometastases. Therefore, elective neck dissection or radiotherapy of the neck should be considered in patients with high risk of occult metastases or micrometastases.