Early evaluation of risk stratification and clinical outcomes for patients with advanced breast cancer through combined monitoring of baseline circulating tumor cells and DNA.

PURPOSE: Early evaluation of tumor heterogeneity related to metastasis and outcomes is a major challenge in the management of advanced BCa in the clinic. Here we introduce the value of baseline CTCs and ctDNA to early differentiate clinical stages, tumor heterogeneity, and prognosis. EXPERIMENTAL DESIGN: We enrolled 254 stage IV and 38 stage III BCa patients and examined the baseline levels of CTCs, CTC-clusters, and plasma ctDNA before initiating therapies. Outcome including PFS, and OS were evaluated. RESULTS: The baseline CTCs for stage IV patients were approximately 9.5 times higher than those detected in stage III patients. Baseline CTC counts with a cutoff of 5 were significantly associated with prognosis. Within each stage, patients with <5 CTCs had longer PFS. Stage III patients with no CTCs exhibited the longest survival compared to patients with ≥1 CTC. CTC-clusters were only found in stage IV patients, among whom 15 stage IV patients with ≥5 CTC-clusters had the worst PFS compared to the 239 stage IV patients with <5 CTC-clusters. Similar outcomes were observed in 28 out of 254 stage IV patients who had at least 1 CTC-cluster detected, as these patients had shorter PFS. The major differences in ctDNA mutations between stage III and stage IV BCa were in PIK3CA and ESR1, which were associated with specific organ metastasis and worse outcomes. CONCLUSIONS: Assessing the baseline levels of CTCs, CTC-clusters, and mutational ctDNA profile could reliably aid in differentiation of clinical stage and early prediction of metastasis and outcomes in advanced BCa.

Prospective Evaluation of Circulating Tumor DNA using Next Generation Sequencing as a Biomarker during Neoadjuvant Chemotherapy in Localized Pancreatic Cancer.

OBJECTIVE: In this prospective study, we aim to characterize the prognostic value of circulating tumor DNA (ctDNA) by next-generation-sequencing (NGS) in patients undergoing neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: Circulating tumor DNA is a promising blood-based biomarker that is prognostic in several malignancies. Detection of ctDNA by NGS may provide insights regarding the mutational profiles in PDAC to help guide clinical decisions for patients in a potentially curative setting. However, the utility of ctDNA as a biomarker in localized PDAC remains unclear. METHODS: Patients with localized PDAC were enrolled in a prospective study at Northwestern Medicine between October 2020 and October 2022. Blood samples were collected to perform targeted tumor agnostic NGS utilizing the Tempus x|F 105 gene panel at three timepoints: pre-therapy (at diagnosis), post-NAC, and after local therapy, including surgery. The relationship between ctDNA detection and CA19-9, and the prognostic significance of ctDNA detection were analyzed. RESULTS: 56 patients were included in the analysis. ctDNA was detectable in 48% at diagnosis, 33% post-NAC, and 41% after local therapy. After completion of NAC, patients with detectable ctDNA had higher CA19-9 levels versus those without (78.4 vs. 30.0, P=0.02). The presence of baseline ctDNA was associated with a CA19-9 response; those without ctDNA had a significant CA19-9 response following NAC (109.0 U/mL vs. 31.5 U/mL; P=0.01), while those with ctDNA present at diagnosis did not (198.1 U/mL vs. 113.8 U/mL; P=0.77). In patients treated with NAC, the presence of KRAS ctDNA at diagnosis was associated with and independently predicted worse progression-free-survival. CONCLUSION: This report demonstrates the prognostic value of ctDNA analysis with NGS in localized PDAC. NGS ctDNA is a biomarker of treatment response to NAC. KRAS ctDNA at diagnosis independently predicts worse survival in patients treated with NAC.

Comparison of perioperative and histopathologic outcomes among neoadjuvant treatment strategies for locoregional gastric cancer.

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy (NAC) and chemoradiation (NCRT) have demonstrated improved survival for gastric cancer. However, the optimal neoadjuvant treatment remains unclear. We sought to evaluate perioperative and histopathologic outcomes among neoadjuvant treatments for locoregional gastric cancer. METHODS: The National Cancer Database queried patients who received NAC or NCRT followed by resection for T2-T4 and/or node-positive gastric cancer (2006-2018). Logistic and Poisson regression assessed perioperative (30-day readmission, 30- and 90-day mortality, length of stay [LOS]) and histopathologic outcomes (pathologic complete response [PCR], margin status, and negative pathologic lymph nodes [ypN0]). Kaplan-Meier methods and Cox regression assessed overall survival (OS). RESULTS: Of 9831 patients, 4221 (42.9%) received NAC and 5610 (57.1%) NCRT. There were no differences in perioperative outcomes, apart from patients treated with NCRT exhibiting increased LOS (incidence rate ratio 1.09, 95% confidence interval [CI] 1.03-1.16). Patients who received NCRT were more likely to achieve PCR, margin-negative resection, and ypN0 (all p < 0.05). Median OS was 36.8 months for NAC and 33.6 months for NCRT (p < 0.001). NCRT independently predicted worse OS (vs. NAC, hazard ratio 1.10, 95% CI 1.03-1.18). CONCLUSION: NCRT was associated with better histologic tumor response although NAC was associated with improved OS. Better understanding prognostication through histologic assessment following neoadjuvant therapy is needed.

A systematic review of undifferentiated pleomorphic sarcoma of the chest wall.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) accounts for approximately 15% of all soft-tissue sarcoma (STS) cases and have a 5-year survival prognosis of around 60%. Due to its complexity, tumors are often identified by clinical and pathological exclusion. UPS is commonly found in the extremities, so finding them in the trunk and chest wall is rare. The primary objectives of this systematic review are: (I) identifying patient characteristics with lesion; (II) compiling patient outcomes following surgery; (III) identifying best therapy modalities; (IV) characterizing reported lesion histology; (V) assessing current surgical recommendations for resection; (VI) classifying lesions and their association with radiation. METHODS: The PRISMA framework was utilized to identify case reports and records providing information on UPS in the chest wall. Case reports and articles were screened for relevance, full-text accessibility, and if they contained the terms ("undifferentiated pleomorphic sarcoma", "breast", "chest wall", or "trunk") in their title or abstract. The PubMed database was the primary database, and the search criteria was "(undifferentiated pleomorphic sarcoma) AND ((breast) OR (trunk) OR (chest) OR (chest wall))" from 01/01/2003 to 05/21/2023. Given that these were case reports, bias risk and heterogeneity was not assessed due to its difficulty. Information from case reports were compiled into a table and a Chi-squared test was performed, but no meta-analysis was completed. RESULTS: Of 433 studies, 24 case reports and 22 records were selected to inform on UPS in the chest wall. The 24 case reports yielded 32 cases providing information on patient outcomes, tumor characteristics, and treatment. A meta-analysis was not performed, but literature was summarized to inform on treating the condition. Case reports were compiled into a table providing information on patient age, gender, tumor location, treatment modalities, margin distance, and other factors. CONCLUSIONS: Treatment of UPS involving the chest is extremely complex. Unlike typical UPS, it is more often found in women than in men, which is corroborated by the results of this study. This study also notes no difference in recurrence or metastasis between patient who were treated and those who were not treated with other therapies.

Weight loss during neoadjuvant chemotherapy impacts perioperative outcomes in patients undergoing surgery for pancreatic cancer.

BACKGROUND: While use of neoadjuvant chemotherapy (NAC) in pancreatic adenocarcinoma (PDAC) downstages cancers to be eligible for resection, weight loss during the neoadjuvant period due to cancer progression, gastric outlet obstruction, or neoadjuvant therapy itself is an area of concern. The goal of this study is to determine the effect of weight loss during NAC on perioperative outcomes of pancreatectomies. METHODS: The NSQIP database 2014-2019 was utilized to study patients who received NAC for PDAC and underwent significant weight loss, defined as at least 10 % body weight loss in the six months prior to surgery. Univariate and multivariate analyses were conducted using Fisher's Exact Test, Pearson's Chi-squared Test, and logistic regression. RESULTS: Of the 5590 PDAC patients who received NAC, 913 (16%) experienced significant weight loss. Patients who experienced significant weight loss were more likely to experience at least one complication compared to those who did not undergo weight loss (42.2% vs. 38.7%, p = 0.023). Those who had significant weight loss were more likely to undergo unplanned intubation postoperatively (3.8% vs 2.2 %, p = 0.004), have postoperative ventilator need >48 h (3.7% vs 1.8%, p < 0.001), have postoperative septic shock (3.9% vs 1.8 %, p < 0.001), and undergo reoperation (6.0% vs 4.3%, p = 0.027). However, there were no differences for pancreatic fistula (7.7% vs 9.3 %, p = 0.15), readmission rates (15% vs 15 %, p = 0.7), or 30-day mortality (1.5% vs 1.2%, p = 0.5). Utilizing logistic regression, BMI (OR: 1.05, p = 0.032), significant weight loss (OR = 1.18, p = 0.025), sex (OR = 1.26 with female baseline, p < 0.001), history of COPD (OR = 1.39, p = 0.012), hypertensive medication use (OR = 1.18, p = 0.004), and pancreatic radiotherapy (OR = 1.16, p = 0.010) were independent preoperative predictors of a post-operative complication. CONCLUSIONS: Nutritional measures to stabilize weight during NAC should be considered to decrease post-pancreatectomy complications.

The differential effect of neoadjuvant chemotherapy and chemoradiation on nodal downstaging in pancreatic adenocarcinoma.

BACKGROUND/OBJECTIVES: Neoadjuvant chemotherapy (NCT) and chemoradiotherapy (NCRT) enhance resectability in patients with pancreatic adenocarcinoma (PDAC). This study compares the effect of NCT and NCRT on lymph nodal downstaging and survival. METHODS: The 2004-2016 National Cancer Database Pancreas Participant User File was used to identify patients who underwent surgery for PDAC. Fisher's exact, Wilcoxon rank-sum, multivariate logistic regression, and log-rank were used. Downstaging was defined as clinically node-positive patients who demonstrated node-negativity on pathology. RESULTS: Of 42,545 patients meeting criteria, 3311 received NCT and 1511 received NCRT. After surgery for clinically node-positive disease, 23.3% of NCT patients and 41.3% of NCRT patients demonstrated nodal downstaging. Younger age and lower tumor grade independently predicted downstaging. Downstaging after neoadjuvant therapy was associated with improved survival versus no nodal treatment response (29.8 vs. 22.8 months, p < 0.001). Downstaging by NCT was associated with improved overall survival versus downstaging by NCRT (37.5 vs. 26.6 months, p = 0.001). No survival difference existed between those with no nodal response after NCT or NCRT (p = 0.101). CONCLUSIONS: Although nodal downstaging is more likely post-NCRT, survival is superior in those downstaged post-NCT. Overall survival is determined by the systemic burden of disease. Post-therapy histologic analysis may be less prognostic post-NCRT.

The inaccuracies of gastric adenocarcinoma clinical staging and its predictive factors.

INTRODUCTION: Accurate clinical staging (CS) of gastric adenocarcinoma is important to guide treatment planning. Our objectives were to (1) assess clinical to pathologic stage migration patterns for patients with gastric adenocarcinoma, (2) identify factors associated with inaccurate CS, and (3) evaluate the association of understaging with survival. METHODS: The National Cancer Database was queried for patients who underwent upfront resection for stage I-III gastric adenocarcinoma. Multivariable logistic regression was used to detect factors associated with inaccurate understaging. Kaplan-Meier analyses and cox proportional hazards regression were performed to assess overall survival (OS) for patients with inaccurate CS. RESULTS: Of 14 425 analyzed patients, 5781 (40.1%) patients were inaccurately staged. Factors associated with understaging included treatment at a Comprehensive Community Cancer Program, presence of lymphovascular invasion, moderate to poor differentiation, large tumor size, and T2 disease. Based on overall CS, median OS was 51.0 months for accurately staged patients and 29.5 months for understaged patients (<0.001). CONCLUSION: Clinical T-category, large tumor size, and worse histologic features lead to inaccurate CS for gastric adenocarcinoma, impacting OS. Improvements to staging parameters and diagnostic modalities focusing on these factors may improve prognostication.

Surgeon-Led Clinical Trials in Pancreatic Cancer.

The review also highlights key landmark adjuvant, neoadjuvant and perioperative trials with an emphasis on surgeon-run clinical trials that have helped to define the pancreatic cancer treatment paradigms.

Measuring response to neoadjuvant therapy using biomarkers in pancreatic cancer: a narrative review.

BACKGROUND AND OBJECTIVE: Pancreatic cancer is the 4th leading cause of cancer death in the US, with incidence increasing over the last 20 years. Recently neoadjuvant therapy (NAT) has emerged as an important tool in improving resectability and overall survival. The objective is to describe and discuss the current literature on the use of biomarkers in measuring response to NAT in pancreatic adenocarcinoma. METHODS: An electronic review of PubMed, Google Scholar and Cochrane was performed to obtain key literature on serum, imaging, clinical, and histologic biomarkers utilized to measure response to NAT in pancreatic cancer. This literature review included publications in English written between January 1, 2011 to March 31, 2022. KEY CONTENT AND FINDINGS: An overview of four categories of biomarkers was evaluated for their utility in assessing both pathologic response and overall survival following NAT in pancreatic adenocarcinoma. Serum CA19-9 as well as CT radiomic features, FDG PET response and development of histologic grading system all show promise as markers of response to NAT. CONCLUSIONS: While multiple promising modalities exist, all require some form of standardization in terms of predicting response to NAT. Further investigation and large-scale studies to evaluate the efficacy of various imaging modalities are necessary. Additionally, there needs to be standardization of histologic grading system post NAT, and consensus on CA19-9 cutoff values in determining NAT response.

Neoadjuvant Chemotherapy Is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer.

PURPOSE: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood. DESIGN: We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes. RESULTS: In the multi-institutional resection cohort, immune cells exhibited substantial heterogeneity across patient tumors and were located predominantly in stromal regions. Unsupervised clustering using immune cell densities identified four main patterns of immune cell infiltration. One pattern, seen in 20% of tumors and characterized by abundant T cells (T cell-rich) and a paucity of immunosuppressive granulocytes and macrophages, was associated with improved patient survival. Neoadjuvant chemotherapy was associated with a higher CD8:CD4 ratio, greater M1:M2-polarized macrophage ratio, and reduced CD15+ARG1+ immunosuppressive granulocyte density. Within neoadjuvant-treated tumors, 72% showed a T cell-rich pattern with low immunosuppressive granulocytes and macrophages. M1-polarized macrophages were located closer to tumor cells after neoadjuvant chemotherapy, and colocalization of M1-polarized macrophages and tumor cells was associated with greater tumor pathologic response and improved patient survival. CONCLUSIONS: Neoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment toward an anti-tumorigenic state associated with improved patient survival.

Identification of high-risk germline variants for the development of pancreatic cancer: Common characteristics and potential guidance to screening guidelines.

Pancreatic cancer (PC) is a product of a variety of environmental and genetic factors. Recent work has highlighted the influence of hereditary syndromes on pancreatic cancer incidence. The purpose of this review is to identify the high-risk syndromes, common variants, and risks associated with PC. The study also elucidates common characteristics of patients with these mutations, which is used to recommend potential changes to current screening protocols for greater screening efficacy. We analyzed 8 syndromes and their respective variants: Hereditary Breast and Ovarian Cancer (BRCA1/2), Familial Atypical Multiple Mole Melanoma Syndrome (CDKN2A), Peutz-Jeghers Syndrome (STK11), Lynch Syndrome (PMS2, MLH1, MSH2, MSH6, EPCAM), Ataxia Telangiectasia (ATM), Li-Fraumeni Syndrome (TP53), Fanconi Anemia (PALB2), and Hereditary Pancreatitis (PRSS1, SPINK1, CFTR). Of 587 studies evaluated, 79 studies fit into our inclusion criteria. Information from each study was analyzed to draw conclusions on these variants as well as their association with pancreatic cancer. Information from this review is intended to improve precision medicine and improve criteria for screening.

Prospective Phase II Trials Validate the Effect of Neoadjuvant Chemotherapy on Pattern of Recurrence in Pancreatic Adenocarcinoma.

OBJECTIVE: The objective of this study was to characterize the patterns of first recurrence after curative-intent resection for pancreatic adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: We evaluated the first site of recurrence after neoadjuvant treatment as locoregional (LR) or distant metastasis (DM). To validate our findings, we evaluated the pattern from 2 phase II clinical trials evaluating neoadjuvant chemotherapy (NAC) in PDAC. METHODS: We identified site of first recurrence from a retrospective cohort of patients from 2011 to 2017 treated with NAC followed by chemoradiation and then an operation or an operation first followed by adjuvant therapy, and 2 separate prospective cohorts of patients derived from 2 phase II clinical trials evaluating patients treated with NAC in borderline-resectable and locally advanced PDAC. RESULTS: In the retrospective cohorts, 160 out of 285 patients (56.1%) recurred after a median disease-free survival (mDFS) of 17.2 months. The pattern of recurrence was DM in 81.9% of patients, versus LR in 11.1%. This pattern was consistent in patients treated with upfront resection and adjuvant chemotherapy (DM 83.0%, LR 16.9%) regardless of margin-involvement (DM 80.1%, LR 19.4%). The use of NAC did not alter pattern of recurrence; 81.7% had DM and 18.3% had LR. This pattern also remained consistent regardless of margin-involvement (DM 94.1%, LR 5.9%). In the Phase II borderline-resectable trial (NCI# 01591733) cohort of 32 patients, the mDFS was 34.2 months. Pattern of recurrence remained predominantly DM (88.9%) versus LR (11.1%). In the Phase II locally-advanced trial (NCI# 01821729) cohort of 34 patients, the mDFS was 30.7 months. Although there was a higher rate of local recurrence in this cohort, pattern of first recurrence remained predominantly DM (66.6%) versus LR (33.3%) and remained consistent independent of margin-status. CONCLUSIONS: The pattern of recurrence in PDAC is predominantly DM rather than LR, and is consistent regardless of the use of NAC and margin involvement.

Pathological treatment response has different prognostic implications for pancreatic cancer patients treated with neoadjuvant chemotherapy or chemoradiotherapy.

BACKGROUND: Pathological treatment effect of resected pancreatic adenocarcinoma after neoadjuvant therapy has prognostic implications. The impact for patients who received chemotherapy alone or chemoradiotherapy is not well defined. METHODS: Patients with localized pancreatic adenocarcinoma who had pancreatectomy after neoadjuvant therapy at 3 centers from 2011 to 2017 were retrospectively analyzed. The chemotherapy and chemoradiotherapy groups were evaluated separately. RESULTS: Of 525 patients, 148 received neoadjuvant chemotherapy and 377 received chemoradiotherapy. The chemoradiotherapy group had a better treatment effect (score 0: 10%, score 1: 30%, score 2: 42%, and score 3: 18%) than the chemotherapy group (score 0: 2%, score 1: 8%, score 2: 35%, and score 3: 55%) (P < .001). Median overall survival was similar between the 2 groups (25.8 vs 26.4 months). Median overall survival for score 0/1, 2, or 3 was 72.2, 38.5, and 20.0 months in the chemotherapy group and 37.9, 24.5, and 19.0 months in the chemoradiotherapy group. Score 2 in the chemotherapy group was associated with better overall survival compared to score 3 (adjusted hazard ratio: 0.49, P = .005), whereas only combined score 0/1 reached significance over score 2 for the chemoradiotherapy group (hazard ratio: 0.63, P = .006). CONCLUSION: The prognostic significance of pathological treatment effect for localized pancreatic adenocarcinoma differs for patients receiving neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy.

Pancreatic Cancer: A Review.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is a relatively uncommon cancer, with approximately 60 430 new diagnoses expected in 2021 in the US. The incidence of PDAC is increasing by 0.5% to 1.0% per year, and it is projected to become the second-leading cause of cancer-related mortality by 2030. Observations: Effective screening is not available for PDAC, and most patients present with locally advanced (30%-35%) or metastatic (50%-55%) disease at diagnosis. A multidisciplinary management approach is recommended. Localized pancreas cancer includes resectable, borderline resectable (localized and involving major vascular structures), and locally advanced (unresectable) disease based on the degree of arterial and venous involvement by tumor, typically of the superior mesenteric vessels. For patients with resectable disease at presentation (10%-15%), surgery followed by adjuvant chemotherapy with FOLFIRINOX (fluorouracil, irinotecan, leucovorin, oxaliplatin) represents a standard therapeutic approach with an anticipated median overall survival of 54.4 months, compared with 35 months for single-agent gemcitabine (stratified hazard ratio for death, 0.64 [95% CI, 0.48-0.86]; P = .003). Neoadjuvant systemic therapy with or without radiation followed by evaluation for surgery is an accepted treatment approach for resectable and borderline resectable disease. For patients with locally advanced and unresectable disease due to extensive vascular involvement, systemic therapy followed by radiation is an option for definitive locoregional disease control. For patients with advanced (locally advanced and metastatic) PDAC, multiagent chemotherapy regimens, including FOLFIRINOX, gemcitabine/nab-paclitaxel, and nanoliposomal irinotecan/fluorouracil, all have a survival benefit of 2 to 6 months compared with a single-agent gemcitabine. For the 5% to 7% of patients with a BRCA pathogenic germline variant and metastatic PDAC, olaparib, a poly (adenosine diphosphate [ADB]-ribose) polymerase inhibitor, is a maintenance option that improves progression-free survival following initial platinum-based therapy. Conclusions and Relevance: Approximately 60 000 new cases of PDAC are diagnosed per year, and approximately 50% of patients have advanced disease at diagnosis. The incidence of PDAC is increasing. Currently available cytotoxic therapies for advanced disease are modestly effective. For all patients, multidisciplinary management, comprehensive germline testing, and integrated supportive care are recommended.

Impact of the COVID-19 Pandemic on Cancer Clinical Trials.

The COVID-19 pandemic has had widespread impact on healthcare, resulting in modifications to how we perform cancer research, including clinical trials for cancer. The impact of some healthcare workers and study coordinators working remotely and patients minimizing visits to medical facilities impacted clinical trial participation. Clinical trial accrual dropped at the onset of the pandemic, with improvement over time. Adjustments were made to some trial protocols, allowing telephone or video-enabled consent. Certain study activities were permitted to be performed by local healthcare providers or at local laboratories to maximize patients' ability to continue on study during these challenging times. We discuss the impact of COVID-19 on cancer clinical trials and changes at the local, cooperative group, and national level.

Contemporary trials evaluating neoadjuvant therapy for resectable pancreatic cancer.

While the use of neoadjuvant therapy is well-accepted in the treatment of borderline resectable and locally advanced pancreatic cancers, the benefit of neoadjuvant chemotherapy in patients with resectable disease has been a topic of debate. Recently, key trials evaluating neoadjuvant chemotherapy for resectable pancreatic cancer have reported results. This review describes key clinical trials evaluating the use of preoperative therapy in patients with technically resectable pancreatic cancer with a focus on their contribution to the available evidence.

The role of oncologic resection and enucleation for small pancreatic neuroendocrine tumors.

BACKGROUND: Surgical management of small pancreatic neuroendocrine tumors (PNETs) is variable. Patients may undergo formal oncologic resection, encompassing regional lymphadenectomy, or enucleation. This study's aim was to understand if enucleation is adequate treatment for PNETs <2 cm METHODS: The US National Cancer Database (NCDB) from 2004 to 2016 was used to identify patients who underwent oncologic resection or enucleation for PNETs <2 cm. Fisher's exact test, log-rank, and logistic regression were used. RESULTS: Of 4083 patients, 75.6% underwent oncologic resection with a median (range) number of 8 (0-99) lymph nodes examined, and 24.1% underwent enucleation. Five-year overall survival rate was 89.7% in node-negative patients versus 82.1% in node-positive patients (p < 0.001). No survival difference existed between patients who underwent enucleation versus oncologic resection (5-yr OS of 88.5% vs 88.2%, p = 0.064). According to AJCC classification, 3776 patients were clinically-staged with evidence of node-negative disease. Of these, 75.1% underwent oncologic resection, of which 9.9% had node-positive disease after resection. Tumor grade and size independently predicted nodal upstaging after oncologic resection. CONCLUSION: One-tenth of patients with clinically node-negative disease were node-positive after surgery. Although this was not reflected in overall survival, patients who receive enucleation with higher grade and larger size may benefit from enhanced surveillance for locoregional recurrence.