Molecularly determined total tumour load in lymph nodes of stage I-II colon cancer patients correlates with high-risk factors. A multicentre prospective study.
ABSTRACT: Stage I-II (pN0) colorectal cancer patients are surgically treated although up to 25 % will eventually die from disease recurrence. Lymph node (LN) status is an independent prognostic factor in colorectal cancer (CRC), and molecular tumour detection in LN of early-stage CRC patients is associated with an increased risk of disease recurrence and poor survival. This prospective multicentre study aimed to determine the relationship between LN molecular tumour burden and conventional high-risk factors in stage I-II colon cancer patients. A total of 1940 LN from 149 pathologically assessed pN0 colon cancer patients were analysed for the amount of tumour cytokeratin 19 (CK19) messenger RNA (mRNA) with the quantitative reverse transcription loop-mediated isothermal amplification molecular assay One-Step Nucleic Acid Amplification. Patient's total tumour load (TTL) resulted from the sum of all CK19 mRNA tumour copies/?L of each positive LN from the colectomy specimen. A median of 15 LN were procured per case (IQR 12;20). Molecular positivity correlated with high-grade (p < 0.01), mucinous/signet ring type (p = 0.017), male gender (p = 0.02), number of collected LN (p = 0.012) and total LN weight per case (p < 0.01). The TTL was related to pT stage (p = 0.01) and tumour size (p < 0.01) in low-grade tumours. Multivariate logistic regression showed independent correlation of molecular positivity with gender, tumour grade and number of fresh LN [AUC = 0.71 (95 % CI = 0.62-0.79)]. Our results show that lymph node CK19 mRNA detection correlates with classical high-risk factors in stage I-II colon cancer patients. Total tumour load is a quantitative and objective measure that may help to better stage early colon cancer patients.
Project description:Colorectal cancer (CRC) screening programs result in the detection of early-stage asymptomatic carcinomas suitable to be surgically cured. Lymph nodes (LN) from early CRC are usually small and may be difficult to collect. Still, at least 12 LNs should be analyzed from colectomies, to ensure a reliable pN0 stage. Presurgical endoscopic tattooing improves LN procurement. In addition, molecular detection of occult LN tumor burden in histologically pN0 CRC patients is associated with a decreased survival rate. We aimed to study the impact of presurgical endoscopic tattooing on the molecular detection of LN tumor burden in early colon neoplasms.A prospective cohort study from a CRC screening-based population was performed at a tertiary academic hospital. LNs from colectomies with and without preoperative endoscopic tattooing were assessed by two methods, hematoxylin and eosin (HE), and RT-LAMP, to detect tumor cytokeratin 19 (CK19) mRNA. We compared the amount of tumor burden and LN yields from tattooed and non-tattooed specimens.HE and RT-LAMP analyses of 936 LNs were performed from 71 colectomies containing early carcinomas and endoscopically unresectable adenomas (8 pT0, 17 pTis, 27 pT1, 19 pT2); 47 out of 71 (66.2 %) were tattooed. Molecular positivity correlated with the presence of tattoo in LN [p < 0.001; OR 3.1 (95 % CI 1.7-5.5)]. A significantly higher number of LNs were obtained in tattooed specimens (median 17 LN vs. 14.5 LN; p = 0.019).Endoscopic tattooing enables the analysis of those LNs most prone to harbor tumor cells and improves the number of LN harvested.
Project description:BACKGROUND: Current histopathological staging procedures in colon carcinomas depend on midline division of the lymph nodes with one section of haematoxylin & eosin (H&E) staining only. By this method, tumour deposits outside this transection line may be missed and could lead to understaging of a high-risk group of stage UICC II cases, which recurs in ∼20% of cases. A new diagnostic semiautomated system, one-step nucleic acid amplification (OSNA), detects cytokeratin (CK) 19 mRNA in lymph node metastases and enables the investigation of the whole lymph node. The objective of this study was to assess whether histopathological pN0 patients can be upstaged to stage UICC III by OSNA. METHODS: Lymph nodes from patients who were classified as lymph node negative after standard histopathology (single (H&E) slice) were subjected to OSNA. A result revealing a CK19 mRNA copy number >250, which makes sure to detect mainly macrometastases and not isolated tumour cells (ITC) or micrometastases only, was regarded as positive for lymph node metastases based on previous threshold investigations. RESULTS: In total, 1594 pN0 lymph nodes from 103 colon carcinomas (median number of lymph nodes per patient: 14, range: 1-46) were analysed with OSNA. Out of 103 pN0 patients, 26 had OSNA-positive lymph nodes, resulting in an upstaging rate of 25.2%. Among these were 6/37 (16.2%) stage UICC I and 20/66 (30.3%) stage UICC II patients. Overall, 38 lymph nodes were OSNA positive: 19 patients had one, 3 had two, 3 had three, and 1 patient had four OSNA-positive lymph nodes. CONCLUSIONS: OSNA resulted in an upstaging of over 25% of initially histopathologically lymph node-negative patients. OSNA is a standardised, observer-independent technique, allowing the analysis of the whole lymph node. Therefore, sampling bias due to missing investigation of certain lymph node tissue can be avoided, which may lead to a more accurate staging.
Project description:BACKGROUND:Regional lymph node (LN) metastasis is a strong and well-established prognostic factor in colon cancer, and recent data suggest a prognostic value of detecting micrometastases and isolated tumor cells in regional LNs. The aim of the study was to investigate the clinical relevance of detecting sentinel lymph node (SLN) metastases in colon cancer patients by measuring the novel metastasis marker PHGR1 mRNA. METHODS:Using quantitative reverse-transcription polymerase chain reaction, we measured PHGR1 mRNA levels in SLNs and primary tumors from 206 patients surgically treated for stage I to III colon cancer and 52 normal LNs from patients undergoing surgery for benign colon diseases. The prognostic impact of these findings was evaluated by Kaplan-Meier analysis and Cox proportional-hazards regression. RESULTS:Compared to normal LNs, elevated PHGR1 mRNA levels were detected in SLNs from 56 (89%) of the 63 patients with pN+ disease. Furthermore, 68 (48%) of the 143 node-negative (pN0) patients had elevated PHGR1 mRNA levels in SLNs, suggesting occult metastases. With a median follow-up of 7.2 years, a significantly shorter recurrence-free (P=.005) and disease-specific (P=.02) survival was observed in patients with elevated PHGR1 mRNA levels in SLNs. Multivariable modeling showed that the SLN PHGR1 mRNA level was an independent prognostic factor. However, when the survival analyses were restricted to pN0 patients, no significant prognostic information was found. CONCLUSION:Measuring PHGR1 mRNA in SLNs provided independent prognostic information on operable colon cancer patients but not in the pN0 subgroup.
Project description:INTRODUCTION: Molecular lymph node (LN) staging in early colorectal cancer (CRC) has demonstrated to be more precise than conventional histopathology pN staging. Tumor budding (TB) and poorly differentiated clusters (PDCs) are associated with LN metastases, recurrences, and lower survival in CRC. We evaluated the correlation between the total tumor load (TTL) in LNs from CRC surgical specimens with patient outcome, TB, and PDC. <h4>METHODS:</h4> In this retrospective multicentre study, 5,931 LNs from 342 stage I–III CRC were analyzed by both hematoxylin and eosin and molecular detection of tumor cytokeratin 19 mRNA by one-step nucleic acid amplification. TB and PDC were evaluated by hematoxylin and eosin and cytokeratin 19 immunohistochemistry. <h4>Results:</h4> One-step nucleic acid was positive in 38.3% patients (n = 131). Tumor Budding was low in 45% cases, intermediate in 25%, and high in 30%. Poorly Differentiated Clusters were low-grade G1 in 53%, G2 in 32%, and G3 in 15%. TB and PDC correlated with TTL, high-grade, lymphovascular and perineural invasion, pT, pN and stage (P < 0.001). TB, PDC, and TTL ? 6,000 copies/µL were associated with worse overall survival (P = 0.002, P = 0.013, and P = 0.046) and disease-free survival (P < 0.001). <h4>Discussion:</h4> The implementation of more sensitive molecular methods to assess LN status is a promising alternative approach to pN staging, which could be integrated to other factors to help risk stratification and management of patients with early-stage CRC. This study demonstrates the correlation of the amount of LN tumor burden with TB and PDCs. TTL is related to the outcome and could be used as a new prognostic factor in CRC (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/CTG/A512).
Project description:The presence of lymph node metastases remains the most reliable prognostic predictor and the gold indicator for adjuvant treatment in colon cancer (CC). In spite of a potentially curative resection, 20 to 30% of CC patients testing negative for lymph node metastases (i.e. pN0) will subsequently develop locoregional and/or systemic metastases within 5 years. The presence of occult nodal isolated tumor cells (ITCs) and/or micrometastases (MMs) at the time of resection predisposes CC patients to high risk for disease recurrence. These pN0(micro+) patients harbouring occult micrometastases may benefit from adjuvant treatment. The purpose of the present study is to delineate the subset of pN0 patients with micrometastases (pN0(micro+)) and evaluate the benefits from adjuvant chemotherapy in pN0(micro+) CC patients.EnRoute+ is an open label, multicenter, randomized controlled clinical trial. All CC patients (age above 18 years) without synchronous locoregional lymph node and/or systemic metastases (clinical stage I-II disease) and operated upon with curative intent are eligible for inclusion. All resected specimens of patients are subject to an ex vivo sentinel lymph node mapping procedure (SLNM) following curative resection. The investigation for micrometastases in pN0 patients is done by extended serial sectioning and immunohistochemistry for pan-cytokeratin in sentinel lymph nodes which are tumour negative upon standard pathological examination. Patients with ITC/MM-positive sentinel lymph nodes (pN0(micro+)) are randomized for adjuvant chemotherapy following the CAPOX treatment scheme or observation. The primary endpoint is 3-year disease free survival (DFS).The EnRoute+ study is designed to improve prognosis in high-risk stage I/II pN0(micro+) CC patients by reducing disease recurrence by adjuvant chemotherapy.ClinicalTrials.gov: NCT01097265.
Project description:BACKGROUND:Recent studies suggest that surgical lymph node (LN) evaluation may be omitted in select elderly breast cancer patients as it may not influence adjuvant therapy decisions. To evaluate differences in adjuvant therapy receipt and overall survival (OS), we compared clinically node-negative (cN0) elderly patients who did and did not undergo axillary surgery. METHODS:Patients aged ?70 years in the National Cancer Database (2004-2014) with cT1-3, cN0 breast cancer were divided into two cohorts-those with surgical LN evaluation (one or more nodes removed) and those without (no nodes removed). Propensity scores were used to match patients based on age, year of diagnosis, tumor grade, cT stage, estrogen receptor status, and Charlson-Deyo comorbidity score. A Cox proportional hazards model was used to estimate the effect of LN surgery on OS. RESULTS:Overall, 133,778 patients were matched, of whom 102,247 patients (76.4%) underwent nodal surgery. Patients undergoing nodal surgery were more likely to receive chemotherapy (pN1-3: 22.2%; pN0: 5.8%; cN0-no nodal surgery: 2.8%; p < 0.001), radiation (pN1-3: 49.7%; pN0: 47.5%; cN0-no nodal surgery: 26%; p < 0.001), and endocrine therapy (pN1-3: 72%; pN0: 58.5%; cN0-no nodal surgery: 46.5%; p < 0.001). After adjustment for known covariates, patients who did not undergo nodal surgery had a worse OS (hazard ratio 1.66, 95% confidence interval 1.61-1.70). CONCLUSIONS:For elderly cN0 breast cancer patients, axillary surgery was associated with higher rates of adjuvant therapy and improved OS. A selective approach to omitting nodal surgery should be considered in elderly patients with cN0 breast cancer as axillary staging may influence subsequent treatment decisions and long-term outcomes.
Project description:This study was conducted to investigate prognosis and survival of patients undergoing distal subtotal gastrectomy with D2 and D2+ lymphadenectomy for patients with locally advanced gastric cancer. Overall survival rates of 416 patients with locally advanced gastric cancer were compared between D2 and D2+ lymphadenectomy. Univariate analysis and multivariate analysis was used to identify significant prognostic factors correlated with LN metastasis and prognosis. Univariate analysis identified tumor size, lymphatic vessel invasion, pT stage, pN stage, TNM stage, locoregional recurrence, and distant recurrence, to significantly correlate with prognosis; Tumor size, LVI, and pT stage were identified as independent factors correlating with LN metastasis. Multivariate analysis demonstrated that tumor size, pT stage, pN stage, locoregional recurrence, and distant recurrence were independent prognostic factors; Tumor size and pT stage were independent prognostic factors predicting LN metastasis. When comparing 5-year survival rates of patients who underwent D2 and D2+ lymphadenectomy, as stratified by pT stage and pN stage, a significant difference was found in pN3 patients, but not for pT2-4 and pN0-2 patients, or the patient cohort as a whole. In conclusion, D2 lymphadenectomy for patients with locally advanced gastric cancer undergoing distal subtotal gastrectomy was recommended, especially in eastern Asia.
Project description:Background: Lymph node (LN) positivity is a prognostic indicator in patients with colon cancer regardless of age, and age is an important parameter that impacts therapeutic recommendations. But little is known about the impact of age on LN positivity in patients with colon cancer. Methods: We analyzed 257,334 patients with colon cancer diagnosed from SEER database. Logistic regression was used to examine the association of age and LN positivity. Poisson regression was used to evaluate whether age was associated with the number of positive LNs. Results: LN positivity was inversely associated with age (P < .001 for each T stage). Age was predictive of LN positivity after adjustment for number of LNs examined and other covariates (P < .001 for each T stage). Adjusted odds ratios (ORs) for LN positivity for age 20 to 39 vs 80+ were 3.06 for stage T1 (95 % CI, 2.09 to 4.48), 2.46 for stage T2 (95 % CI, 2.00 to 3.02), 1.77 for stage T3 (95 % CI, 1.62 to 1.93), and 1.68 for stage T4 (1.51 to 1.86). Young age was a significant predictor of an increased number of positive LNs (P < .005 for each T stage). Conclusion: Young age at diagnosis is associated with an increased risk of LN positivity. LN examination and resection could aid younger patients more with detection and removal of metastasis. Guidelines that define postdetection interventions may be needed to limit the overtreatment of older patients, who may be vulnerable to unnecessary tests and treatments.
Project description:This study aimed to evaluate prognostic impacts of the number of lymph nodes (LNs) examined and LN ratio on cancer-specific mortality after surgery in patients with right-sided colon cancer (RCC) or left-sided colon cancer (LCC) using the Surveillance, Epidemiology, and End Results database. Number of LNs examined and LN ratio were treated as categorical and/or continuous. Competing risks proportional hazards regressions adjusted by propensity score were performed. All included patients had stage I, II, or III disease, and 45.1% of them had RCC. RCC and LCC patients with high level of LNs examined had better prognosis after segmental resection or hemicolectomy. RCC and LCC patients with higher LN ratio had worse prognosis regardless of surgery. Survival benefit of having high level of LNs examined was observed in RCC patients with stage I, II, or III disease, but only in LCC patients with stage II disease. Both higher LN ratio and high level of LN were negative prognostic factors for cancer-specific mortality in stage III patients regardless of tumor sidedness. In conclusion, RCC patients in various conditions had worse or comparable prognosis compared to their LCC counterparts, which reflected the severity of LN metastasis.
Project description:BACKGROUND:We tested the association of colon tumour sidedness with prognosis and with molecular subtypes recently shown to be predictive of oxaliplatin benefit in stage III colon cancer. METHODS:NSABP/NRG C-07 trial (N=1603) was used to determine association of tumour sidedness with molecular subtypes and recurrence-free survival (RFS) and overall survival (OS). RESULTS:Sidedness was associated with molecular subtypes except stem-like/CMS4 subtype. Patients with stage III, left-sided tumours showed superior OS but not RFS. Sidedness was not associated with prediction of oxaliplatin benefit when combined with 5-Fu+LV. However, greater benefit from oxaliplatin was observed in a small subset of stage III patients with left-sided, enterocyte-subtype tumours (interaction HR=0.17, P=0.01). CONCLUSIONS:Sidedness was associated with molecular subtypes and was predictive of OS in stage III colon cancer but was not predictive of RFS or oxaliplatin benefit in C-07. Molecular subtypes may provide more predictive value for oxaliplatin benefit than tumour sidedness.