Limited wedge resection for T1 colon cancer (LIMERIC-II trial) - rationale and study protocol of a prospective multicenter clinical trial.

BACKGROUND: The sole presence of deep submucosal invasion is shown to be associated with a limited risk of lymph node metastasis. This justifies a local excision of suspected deep submucosal invasive colon carcinomas (T1 CCs) as a first step treatment strategy. Recently Colonoscopy-Assisted Laparoscopic Wedge Resection (CAL-WR) has been shown to be able to resect pT1 CRCs with a high R0 resection rate, but the long term outcomes are lacking. The aim of this study is to evaluate the safety, effectiveness and long-term oncological outcomes of CAL-WR as primary treatment for patients with suspected superficial and also deeply-invasive T1 CCs. METHODS: In this prospective multicenter clinical trial, patients with a macroscopic and/or histologically suspected T1 CCs will receive CAL-WR as primary treatment in order to prevent unnecessary major surgery for low-risk T1 CCs. To make a CAL-WR technically feasible, the tumor may not include > 50% of the circumference and has to be localized at least 25 cm proximal from the anus. Also, there should be sufficient distance to the ileocecal valve to place a linear stapler. Before inclusion, all eligible patients will be assessed by an expert panel to confirm suspicion of T1 CC, estimate invasion depth and subsequent advise which local resection techniques are possible for removal of the lesion. The primary outcome of this study is the proportion of patients with pT1 CC that is curatively treated with CAL-WR only and in whom thus organ-preservation could be achieved. Secondary outcomes are 1) CAL-WR's technical success and R0 resection rate for T1 CC, 2) procedure-related morbidity and mortality, 3) 5-year overall and disease free survival, 4) 3-year metastasis free survival, 5) procedure-related costs and 6) impact on quality of life. A sample size of 143 patients was calculated. DISCUSSION: CAL-WR is a full-thickness local resection technique that could also be effective in removing pT1 colon cancer. With the lack of current endoscopic local resection techniques for > 15 mm pT1 CCs with deep submucosal invasion, CAL-WR could fill the gap between endoscopy and major oncologic surgery. The present study is the first to provide insight in the long-term oncological outcomes of CAL-WR. TRIAL REGISTRATION: CCMO register (ToetsingOnline), NL81497.075.22, protocol version 2.3 (October 2022).

Tumour deposits are a significant prognostic factor in gastric cancer - a systematic review and meta-analysis.

AIMS: Tumour deposits (TDs) are clusters of cancer cells in the soft tissue that are discontinuous from the primary tumour. In this review we are exploring their relevance for prognosis in patients with gastric cancer. METHODS AND RESULTS: A literature search was performed to identify studies providing data on TDs and prognosis in gastric cancer patients. Eight papers were included in the meta-analysis, which was carried out in terms of risk ratios (RR) and hazard ratios (HR) with 95% confidence interval (95% CI). Of 7445 patients, 1551 had TDs (20.9%). TDs were associated with a decreased overall survival (OS) in univariate (HR = 2.82, 95% CI = 1.9-4.3) and multivariate analyses (HR = 1.65, 95% CI = 1.3-2.1). TDs were also associated with known prognostic factors such as synchronous metastatic disease (RR = 9.5), invasion depth (RR = 1.8), lymph node metastasis (RR = 1.7), lymphatic invasion (RR = 1.7), vascular invasion (RR = 2.6) and poor differentiation (RR = 1.2). CONCLUSIONS: We found a strong indication that TDs are independent predictors of prognosis in patients with gastric cancer; hence, TDs should be included in the staging of gastric cancers.

Colorectal metastasis to the gallbladder mimicking a primary gallbladder malignancy: histopathological and molecular characteristics.

AIMS: Outcomes of colorectal cancer (CRC) treatment and survival have steadily improved during the past decades, accompanied by an increased risk of developing second primary tumours and metastatic tumours at unusual sites. Metastatic CRC can show mucosal colonisation, thereby mimicking a second primary tumour. This potential confusion could lead to incorrect diagnosis and consequently inadequate treatment of the patient. The aim of this study was to differentiate between metastatic CRC and a second primary (gallbladder cancer, GBC) using a combination of standard histopathology and molecular techniques. METHODS AND RESULTS: Ten consecutive patients with both CRC and GBC were identified in our region using the Dutch National Pathology Archive (PALGA). Two patients served as negative controls. Histology of GBC was reviewed by nine pathologists. A combination of immunohistochemistry, microsatellite analysis, genomewide DNA copy number analysis and targeted somatic mutation analysis was used to aid in differential diagnosis. In two patients, CRC and GBC were clonally related, as confirmed by somatic mutation analysis. For one case, this was confirmed by genomewide DNA copy number analysis. However, in both cases, pathologists initially considered the GBC as a second primary tumour. CONCLUSIONS: Metastatic CRC displaying mucosal colonisation is often misinterpreted as a second primary tumour. A combination of traditional histopathology and molecular techniques improves this interpretation, and lowers the risk of inadequate treatment.

The value of intramural vascular invasion in colorectal cancer - a systematic review and meta-analysis.

Extramural venous invasion (EMVI) is a well-known prognostic factor in colorectal cancer (CRC). Vascular invasion within the bowel wall, intramural vascular invasion (IMVI), has received less attention and its incidence and prognostic importance in CRC is not completely known. A systematic literature search was performed focusing on the impact of IMVI in CRC. Data were analysed using Review Manager version 5.3 on incidence and clinical endpoints local recurrence, 5-year cancer-specific survival (CSS) and 5-year overall survival (OS). Meta-analysis was performed in terms of risk ratios (RR) and hazard ratios (HR) with 95% confidence interval (95% CI). Of the initial 1199 papers identified by our search strategy, 20 were included in this meta-analysis. Of the 8078 included patients, 1008 patients had IMVI (12.5%). Studies that re-examined histological slides showed a higher incidence of IMVI compared to studies extracting IMVI from pathology reports (17.6 versus 7.7%, P < 0.001). Detection of IMVI increased significantly with the use of additional staining (22.9 versus 12.3%, P < 0.001). IMVI was associated with a decreased CSS HR: 1.6, 95% CI 1.2-2.2 in multivariate analysis). A borderline significant effect was observed for IMVI on local recurrence (RR: 1.5, 95% CI: 0.98-2.3) and OS (RR: 1.2, 95% CI: 1.0-1.4). In conclusion, despite the limited number of studies, there is a clear association with outcome in the presence of IMVI. This warrants more attention to this under-reported prognostic factor.

Lymphatic Invasion is an Independent Adverse Prognostic Factor in Patients with Colorectal Liver Metastasis.

BACKGROUND: For a selection of patients with colorectal liver metastases (CRLM), liver resection is a curative option. In order to predict long-term survival, clinicopathologic risk scores have been developed, but little is known about histologic factors and their prognostic value for disease-free and overall survival. The objective of the present study was to assess possible prognostic histologic factors in patients with solitary CRLM treated with liver resection who did not receive neoadjuvant treatment. METHODS: Patients with solitary CRLM who underwent liver resection between 1992 and 2011 were evaluated for clinical prognostic factors. Histologic analyses on tumor thickness at the tumor-normal interface, presence of a fibrotic capsule, intrahepatic vascular invasion, lymphatic invasion, or bile duct invasion and perineural growth were performed, using immunohistochemistry. RESULTS: A total of 124 patients were analyzed with a median follow-up of 41 months (range 1-232 months). There was no association between histologic factors and disease-free survival in multivariate analysis. In multivariate analysis, intrahepatic lymphatic invasion was associated with a decreased overall survival (41.9 vs. 61.0 months; p = 0.041), especially in combination with vascular invasion (n = 15) (28.1 vs. 62.2 months; p < 0.0001). In addition, size over 50 mm (29.2 vs. 65.9 months; p = 0.004) and interval less than 12 months between resection of the primary tumor and diagnosis of liver metastasis (49.0 vs. 91.5 months: p = 0.019) were also independent adverse prognostic factors. CONCLUSIONS: Intrahepatic lymphatic invasion, especially in combination with vascular invasion, is an important adverse prognostic factor for overall survival in patients with solitary CRLM after liver resection.

Histopathological evaluation of resected colorectal cancer liver metastases: what should be done?

Histological reporting of hepatic resections of colorectal liver metastases (CRLMs) is limited to confirmation of diagnosis and evaluation of resection margins. More exhaustive diagnostic reporting might be warranted. Here, we critically and systematically review the potentially important histological prognostic factors in CRLM. Histological features such as intrahepatic spread, resection margins, and tumour response to neoadjuvant chemotherapy have been defined. Intrahepatic spread (venous, lymphatic, bile duct and perineural invasion) was evaluated in a number of studies. Meta-analysis demonstrated a clear correlation between 5-year overall survival and both portal vein invasion (RR 1.8, 95% CI 1.3-2.5) and lymphatic invasion (RR 1.7, 95% CI 1.4-2.0). The impact of hepatic vein invasion and bile duct invasion on outcome is not clear. Perineural invasion was linked to survival in one study. Resection margin is an important prognostic factor; however, the significance of the width of negative margins remains controversial. Various studies have evaluated tumour response to neoadjuvant chemotherapy, but different grading systems were used, and definite recommendations cannot be made. In conclusion, with the high incidence of CRLM and the increase in the number of hepatic resections, we need well-defined prognostic factors, studied in homogeneous patient populations, to optimize diagnostic work-up. This review identifies several of these factors.

Diagnostic value of radiological staging and surveillance for T1 colorectal carcinomas: A multicenter cohort study.

BACKGROUND: The role of radiological staging and surveillance imaging is under debate for T1 colorectal cancer (CRC) as the risk of distant metastases is low and imaging may lead to the detection of incidental findings. OBJECTIVE: The aim of this study was to evaluate the yield of radiological staging and surveillance imaging for T1 CRC. METHODS: In this retrospective multicenter cohort study, all patients of 10 Dutch hospitals with histologically proven T1 CRC who underwent radiological staging in the period 2000-2014 were included. Clinical characteristics, pathological, endoscopic, surgical and imaging reports at baseline and during follow-up were recorded and analyzed. Patients were classified as high-risk T1 CRC if at least one of the histological risk factors (lymphovascular invasion, poor tumor differentiation, deep submucosal invasion or positive resection margins) was present and as low-risk when all risk factors were absent. RESULTS: Of the 628 included patients, 3 (0.5%) had synchronous distant metastases, 13 (2.1%) malignant incidental findings and 129 (20.5%) benign incidental findings at baseline staging. Radiological surveillance was performed among 336 (53.5%) patients. The 5-year cumulative incidence of distant recurrence, malignant and benign incidental findings were 2.4% (95% confidence interval (CI): 1.1%-5.4%), 2.5% (95% CI: 0.6%-10.4%) and 18.3% (95% CI: 13.4%-24.7%), respectively. No distant metastatic events occurred among low-risk T1 CRC patients. CONCLUSION: The risk of synchronous distant metastases and distant recurrence in T1 CRC is low, while there is a substantial risk of detecting incidental findings. Radiological staging seems unnecessary prior to local excision of suspected T1 CRC and after local excision of low-risk T1 CRC. Radiological surveillance should not be performed in patients with low-risk T1 CRC.

Impact of ≥ 0.1-mm free resection margins on local intramural residual cancer after local excision of T1 colorectal cancer.

Background and study aims A free resection margin (FRM) > 1 mm after local excision of a T1 colorectal cancer (CRC) is known to be associated with a low risk of local intramural residual cancer (LIRC). The risk is unclear, however, for FRMs between 0.1 to 1 mm. This study evaluated the risk of LIRC after local excision of T1 CRC with FRMs between 0.1 and 1 mm in the absence of lymphovascular invasion (LVI), poor differentiation and high-grade tumor budding (Bd2-3). Patients and methods Data from all consecutive patients with local excision of T1 CRC between 2014 and 2017 were collected from 11 hospitals. Patients with a FRM ≥ 0.1 mm without LVI and poor differentiation were included. The main outcome was risk of LIRC (composite of residual cancer in the local excision scar in adjuvant resection specimens or local recurrence during follow-up). Tumor budding was also assessed for cases with a FRM between 0.1 and 1mm. Results A total of 171 patients with a FRM between 0.1 and 1 mm and 351 patients with a FRM > 1 mm were included. LIRC occurred in five patients (2.9 %; 95 % confidence interval [CI] 1.0-6.7 %) and two patients (0.6 %; 95 % CI 0.1-2.1 %), respectively. Assessment of tumor budding showed Bd2-3 in 80 % of cases with LIRC and in 16 % of control cases. Accordingly, in patients with a FRM between 0.1 and 1 mm without Bd2-3, LIRC was detected in one patient (0.8%; 95 % CI 0.1-4.4 %). Conclusions In this study, risks of LIRC were comparable for FRMs between 0.1 and 1 mm and > 1 mm in the absence of other histological risk factors.

Pathways of spread in rectal cancer: a reappraisal of the true routes to distant metastatic disease.

Rectal cancer can spread in a number of ways which have been previously recognised and validated as prognostic markers. These routes of spread are not adequately recognised in the stage grouping of the tumour-node-metastasis system, which focuses predominantly on the depth of invasion and nodal status, thus limiting its prognostic accuracy. Tumour spread involving veins occurs in 40% of patients. Venous channels have greater direct access to distant sites by means of a vascular 'anatomical highway'. This rapid spread of tumour cells to distant metastatic sites by veins cannot occur by means of lymph node pathways. Thus, lymph nodes have been overestimated in their importance. Distinction between local tumour spread (lymph node metastases, perineural and lymphatic invasion) and tumour spread mediated by a direct vascular pathway to distant dissemination (extramural venous invasion and tumour deposits) must be made as the implications for prognosis and choice of treatment are not likely to be equal. Improved precision of radiological and pathological assessment is needed to scrutinise and carefully document each route of tumour spread. Only with this accurate information will it be possible to correctly weight each feature and develop a more prognostically accurate staging method that would allow separation of true high- and low-risk groups and subsequent improvements in patient care.

Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis.

Purpose Colorectal cancer (CRC) treatment is largely determined by tumor stage. Despite improvements made in the treatment of various types of metastatic disease, staging has not been refined. The role of tumor deposits (TDs) in staging remains debated. We have assessed the relation of TDs with metastatic pattern to evaluate whether TDs might add significant new information to staging. Methods We performed a systematic literature search that was focused on the role of TDs in CRC. Studies with neoadjuvant-treated patients were excluded. Data on stage, histologic factors, and outcome were extracted. Data from four large cohorts were analyzed for the relevance of the presence of TDs, lymph node metastases (LNMs), and extramural vascular invasion (EMVI) on the pattern of metastases and outcomes. Results Of 10,106 included patients with CRC, 22% presented with TDs. TDs are invariably associated with poor outcome. Presence of TDs was associated with presence of LNMs and EMVI. In a pairwise comparison, effects of TD were stronger than those of both LNMs and EMVI. In the logistic regression model, TDs in combination with LNMs is the strongest predictor for liver (odds ratio [OR], 5.5), lung (OR, 4.3) and peritoneal metastases (OR, 7.0). Presence of EMVI adds information for liver and lung metastases, but not for peritoneal metastases. Conclusion We have shown that TDs are not equal to LNMs or EMVI with respect to biology and outcome. We lose valuable prognostic information by allocating TDs into nodal category N1c and only considering TDs in the absence of LNMs. Therefore, we propose that the number of TDs should be added to the number of LNMs to derive a final N stage.

Perineural Invasion is a Strong Prognostic Factor in Colorectal Cancer: A Systematic Review.

Perineural invasion (PNI) is a possible route for metastatic spread in various cancer types, including colorectal cancer (CRC). PNI is linked to poor prognosis, but systematic analyses are lacking. This study systematically reviews the frequency and impact of PNI in CRC. A literature search was performed using PubMed database from inception to January 1, 2014. Data were analyzed using Review Manager 5.3. A quality assessment was performed on the basis of modified REMARK criteria. Endpoints were local recurrence (LR), 5-year disease-free survival (5yDFS), 5-year cancer-specific survival (5yCSS), and 5-year overall survival (5yOS). Meta-analysis was performed in terms of risk ratios (RR) and hazard ratios (HR) with 95% confidence interval (95% CI). In this meta-analysis, 58 articles with 22,900 patients were included. PNI was present in 18.2% of tumors. PNI is correlated with increased LR (RR 3.22, 95% CI, 2.33-4.44) and decreased 5yDFS (RR 2.35, 95% CI, 1.66-3.31), 5yCSS (RR 3.61, 95% CI, 2.76-4.72), and 5yOS (RR 2.09, 95% CI, 1.68-2.61). In multivariate analysis PNI remains an independent prognostic factor for 5yDFS, 5yCSS, and 5yOS (HR 2.35, 95% CI, 1.97-3.08; HR 1.91, 95% CI, 1.50-2.42; and HR 1.85, 95% CI, 1.63-2.12, respectively). We confirmed the strong impact of PNI for LR and survival in CRC. The prognostic value of PNI is similar to that of well-established prognostic factors as depth of invasion, differentiation grade, lymph node metastases, and lymphatic and extramural vascular invasion. Therefore, PNI should be one of the factors in the standardized reporting of CRC and might be considered a high-risk feature.

Limited effect of lymph node status on the metastatic pattern in colorectal cancer.

Regional lymph node metastases in colorectal cancer (CRC) decrease outcome. Whether nodal metastases function as a biomarker, i.e. as a sign of advanced disease, or are in fact involved in the metastatic process is unclear. We evaluated metastatic patterns of CRC according to the lymph node status of the primary tumor.A retrospective review of 1393 patients with metastatic CRC who underwent autopsy in the Netherlands was performed. Metastatic patterns of regional lymph node positive and negative CRC were compared and validated by population-based data from the Eindhoven Cancer Registry (ECR).Patients with regional lymph node positive CRC more often developed peritoneal metastases (28% vs. 21%, p=0.003) and distant lymph node metastases (25% vs. 15%, p <0.001). Incidences of liver and lung metastases were comparable. Data from the ECR confirmed our findings regarding peritoneal (22.4% vs. 17.0%, p=0.003) and distant lymph node metastases (15.8% vs. 9.7%, p <0.001).Regional lymph node positive CRC show a slightly different dissemination pattern, with higher rates of peritoneal and distant lymph nodes metastases. Comparable incidences of liver and lung metastases support the hypothesis that dissemination to distant organs occurs independently of lymphatic spread.

Sequencing of RAS/RAF pathway genes in primary colorectal cancer and matched liver and lung metastases

Background: Mutations in the RAS/RAF pathway predict resistance to anti-epidermal growth factor receptor antibodies in colorectal cancer (CRC), and may be targets for future therapies. This study investigates concordance of BRAF, HRAS, KRAS, NRAS and PIK3CA mutation status in primary CRC with matched liver (n = 274), lung (n = 114) or combined liver and lung metastases (n = 14). Methods: Next generation sequencing was performed on DNA from formalin-fixed paraffin embedded CRC and matched liver and/or lung metastases, for recurrent mutations in BRAF, HRAS, KRAS, NRAS and PIK3CA and using the single-molecule molecular inversion probe method. Results: Paired sequencing results on all five genes were reached in 249 of the 402 cases (62%). The obtained number of unique reads was not always sufficient to confidently call the absence or presence of mutations for all regions of interest. The mutational status of matched pairs was highly concordant; 91.1% concordance for all five genes, 95.5% for KRAS, 99.1% for NRAS. Lung metastases more often harboured RAS mutations compared to liver metastases (71% vs. 48%, p < 0.001). Conclusions: In this large series of CRC we show that both primary tumors and corresponding metastases can be used to determine the mutational status for targeted therapy, given the high concordance rates. Next generation sequencing including a single molecule tags is feasible, however in combination with archival formalin-fixed paraffin embedded material is limited by coverage depth.

Current issues in the targeted therapy of advanced colorectal cancer.

Currently used cytotoxic drugs in the treatment of advanced colorectal cancer (ACC) are primarily the fluoropyrimidines, irinotecan, and oxaliplatin. The introduction of targeted therapy has increased the therapeutic arsenal. Two classes of monoclonal antibodies have been approved for clinical use in ACC: bevacizumab, an antibody against the vascular endothelial growth factor (VEGF), and cetuximab and panitumumab, antibodies against the epidermal growth factor receptor (EGFR). We review the current status of targeted therapy and the mechanism of action of monoclonal antibodies in ACC.