Molecular Basis of Extramural Vascular Invasion (EMVI) in Colorectal Carcinoma.

BACKGROUND: Extramural vascular invasion (EMVI) is a known poor prognostic factor in colorectal carcinoma; however, its molecular basis has not been defined. This study aimed to assess the expression of molecular markers in EMVI positive colorectal carcinoma to understand their tumor microenvironment. METHODS: Immunohistochemistry was performed on tissue microarrays of surgically resected colorectal cancer specimens for immunological markers, and BRAFV600E mutation (and on the tissue blocks for mismatch repair proteins). Automated quantification was used for CD8, LAG3, FOXP3, PU1, and CD163, and manual quantification was used for PDL1, HLA I markers (beta-2 microglobulin, HC10), and HLA II. The Wilcoxon rank-sum test was used to compare EMVI positive and negative tumors. A logistic regression model was fitted to assess the predictive effect of biomarkers on EMVI. RESULTS: There were 340 EMVI positive and 678 EMVI negative chemo naïve tumors. PDL1 was barely expressed on tumor cells (median 0) in the entire cohort. We found a significantly lower expression of CD8, LAG3, FOXP3, PU1 cells, PDL1 positive macrophages, and beta-2 microglobulin on tumor cells in the EMVI positive subset (p ≤ 0.001). There was no association of BRAFV600E or deficient mismatch repair proteins (dMMR) with EMVI. PU1 (OR 0.8, 0.7-0.9) and low PDL1 (OR 1.6, 1.1-2.3) independently predicted EMVI on multivariate logistic regression among all biomarkers examined. CONCLUSION: There is a generalized blunting of immune response in EMVI positive colorectal carcinoma, which may contribute to a worse prognosis. Tumor-associated macrophages seem to play the most significant role in determining EMVI.

Detrimental impact of symptom-detected colorectal cancer.

BACKGROUND: The incidence and mortality rates of colorectal cancer (CRC) have been steadily decreasing, largely attributable to screening colonoscopies that either remove precancerous lesions or identify CRC earlier. We aimed to assess the prognostic difference between colorectal cancers diagnosed by screening (SC), diagnostic (DC), or surveillance (SU) colonoscopies. METHODS: All 1809 surgically treated patients with primary CRC diagnosed through colonoscopy at our tertiary center (2004-2015) were extracted from a prospectively maintained database. Oncologic outcomes were compared, including multivariate Cox regression. RESULTS: Diagnostic patients presented with more advanced disease (15.0% vs. 53.2% (SC) and 55.3% (SU) AJCC I, P < 0.001), subsequently leading to impaired survival and higher recurrence rates (P < 0.001). After adjustment for age, ASA-score and gender, oncologic outcomes remained significantly worse after DC. Hazard ratios (HR) of overall mortality (OS) compared to DC were 0.36 for SC and 0.58 for SU (P < 0.001). Adjusted HRs of disease-free survival (DFS) were 0.43 and 0.32, respectively (P < 0.001). Worse outcomes in OS withstood adjustment for stage, tumor site and (neo)adjuvant treatment (SC: HR 0.46, P < 0.001; SU: HR 0.73, P = 0.036). The benefits of SC were particularly seen in colon cancer, stages I-II and female patients. With regard to DFS, outcomes were less profound and mainly true in early stage disease and surveillance patients. CONCLUSIONS: This study demonstrates the enormous impact of asymptomatic screening in CRC. Patients with CRC diagnosed through screening or surveillance had a significantly better prognosis compared to patients who presented symptomatically. This emphasizes the importance of screening.

Perineural Invasion Is a Prognostic but not a Predictive Factor in Nonmetastatic Colon Cancer.

BACKGROUND: Perineural invasion is associated with adverse oncological outcomes in colorectal cancer. However, data regarding the prognostic and predictive impact in colon cancer are scarce. OBJECTIVE: This study aims to clarify the role of perineural invasion in patients with nonmetastatic colon cancer. DESIGN: This study is a retrospective review of a prospectively maintained database. SETTINGS: This study took place at a tertiary medical center. PATIENTS: Patients with stage I to III colon cancer who underwent elective surgery at our tertiary center between 2004 and 2015 (n = 1145) were included. MEAN OUTCOME MEASURES: The primary long-term outcomes include disease-free survival, disease-specific survival, and overall survival. Differences were determined by multivariate Cox regression models adjusted for stage and potential confounders. RESULTS: Perineural invasion was identified in 215 patients (18.8%) and associated with emergency procedures, male sex, and advanced disease. Histopathological features including lymphatic and extramural vascular invasion, poor differentiation, and infiltrating tumor borders were correlated with perineural invasion. Compared with patients with perineural invasion-negative tumors, patients who had perineural invasion-positive tumors had worse disease-free, overall, and disease-specific survival (all p < 0.001). Moreover, patients with perineural invasion-positive node-negative disease had worse overall survival than patients with perineural invasion-negative node-positive disease (p < 0.001). After adjustment, perineural invasion remained significantly associated with worse disease-free survival (HR, 1.45; 95% CI, 1.03-2.03; p = 0.033), worse overall survival (HR, 1.75; 95% CI, 1.33-2.31; p < 0.001), and worse disease-specific survival (HR, 1.52; 95% CI, 1.00-2.30; p = 0.048). However, we did not find a significant predictive response with adjuvant chemotherapy in perineural invasion-positive node-negative tumors (HR, 2.10; 95% CI, 0.80-5.51; p = 0.122). The predictive value was only demonstrated in stage III disease with a significant impaired overall survival in patients with perineural invasion-positive tumors who did not receive adjuvant therapy (HR, 0.23; 95% CI, 0.13-0.40; p < 0.001). LIMITATIONS: This study was limited by its retrospective design. CONCLUSION: Our study confirms the prognostic value of perineural invasion in stage I to II and III colon cancer. However, patients with node-negative disease and perineural invasion did not significantly benefit from adjuvant therapy. More information regarding postoperative treatment in node-negative perineural invasion-positive colon cancer is required. See Video Abstract at http://links.lww.com/DCR/A988. LA INVASIÓN PERINEURAL COMO FACTOR PRONÓSTICO NO PREDICTIVO EN EL CÁNCER DE COLON NO METASTÁSICO: La invasión perineural se encuentra asociada a resultados oncológicos adversos en casos de cáncer colorrectal. Sin embargo, los datos sobre el impacto pronóstico y predictivo en caso de cáncer de colon son pocos. OBJETIVO: Definir el papel de la invasión perineural en pacientes con cáncer de colon no metastásico. DISEÑO:: Revisión retrospectiva de una base de datos alimentada prospectivamente. AJUSTES: Centro hospitalario de atención terciaria. PACIENTES: Todos aquellos portadores de un cáncer de colon estadío I-III que se sometieron a cirugía electiva en nuestro centro entre 2004-2015 (n = 1145). PRINCIPALES RESULTADOS: Los resultados a largo plazo incluyeron la supervivencia sin enfermedad, la supervivencia específica de la enfermedad y la supervivencia general. Las diferencias se determinaron mediante modelos de regresión multivariantes de Cox, ajustados para el control de factores de confusión durante el análisis por estratificación. RESULTADOS: La invasión perineural fué identificada en 215 pacientes (18.8%) y se la asoció con procedimientos de emergencia, al género masculino y a la enfermedad avanzada. Las características histopatológicas que incluyeron la invasión vascular linfática y extramural, la diferenciación deficiente y los bordes tumorales infiltrantes se correlacionaron con la invasión perineural. Comparativamente con los tumores sin invasión perineural, los pacientes positivos a la invasión perineural tuvieron una peor supervivencia general, libre y específica de la enfermedad (todos p < 0.001). Asimismo, aquellos pacientes con invasion-perineural con ganglios negativos tuvieron una supervivencia global mucho peor que aquellos pacientes con ganglios positivos e invasión perineural negativa (p < 0.001). Después del ajuste, la invasión perineural se asoció significativamente con una peor supervivencia sin la enfermedad (HR, 1.45; IC 95%, 1.03-2.03; p = 0.033), supervivencia general (HR, 1.75; IC 95%, 1.33-2.31; p <0.001), así como con una peor supervivencia específica de la enfermedad (HR, 1.52; IC 95%, 1.00-2.30; p = 0.048). Sin embargo, no encontramos una respuesta predictiva significativa con quimioterapia adyuvante en los tumores acompañados de invasion-perineural con ganglios negativos (HR, 2.10; IC del 95%, 0.80-5.51; p = 0.122). El valor predictivo solo fué demostrado en aquellos casos de estadio III con un deterioro significativo de la supervivencia global en pacientes con tumores perineurales positivos a la invasión y que no recibieron tratamiento adyuvante (HR, 0.23; IC 95%, 0.13-0.40; p < 0.001). LIMITACIONES: Diseño retrospectivo. CONCLUSIÓN:: Nuestros resultados confirman el valor pronóstico de la invasión perineural en el cáncer de colon estadios I-II y III. Sin embargo, los pacientes con enfermedad ganglionar negativa e invasión perineural no se beneficiaron significativamente de la terapia adyuvante. Se requiere más información sobre el tratamiento postoperatorio en el cáncer de colon positivo para la invasión perineural con ganglios negativos. Vea el Resumen del video en http://links.lww.com/DCR/A988.

The impact of postoperative morbidity on survival in patients with metastatic colon and rectal cancer.

INTRODUCTION: Avoiding postoperative morbidity is essential in patients with advanced cancer. To further improve treatment in stage IV colorectal cancer, knowledge about risk factors which effect short- and long-term outcomes is important. METHODS: All stage IV colon and rectal cancer who underwent elective surgery between 2004 and 2015 were included (n = 345). We compared resectable colon and rectal patients, and unresectable colon and rectal cancer patients. RESULTS: Median follow-up duration was 22.2 (unresectable) and 56.7 months (resectable) with no difference in tumor location. Colon cancer patients were more often considered unresectable (P < .001). Rectal procedures were correlated with a higher morbidity rate and a longer surgical duration (P < .001). In the resectable cohort, obese patients, open procedures and prolonged surgery were independently associated with postoperative complications. Considering the palliative group, neoadjuvant treatment and age were correlated with worse outcomes. Morbidity was not associated with long-term outcomes in the resectable cohort. However, unresectable patients who developed respiratory (hazard ratio [HR]: 7.53) or cardiac (HR: 3.75) complications and patients with an American Society of Anesthesiologists-score III to IV (HR: 1.51) had an impaired survival. CONCLUSION: Our results emphasize the need for an adequate preoperative assessment to identify patients at risk for postoperative complications and impaired survival.

Impact of intramural and extramural vascular invasion on stage II-III colon cancer outcomes.

BACKGROUND AND OBJECTIVES: Vascular invasion, in particular extramural venous invasion (EMVI), is a pathologic characteristic that has been extensively studied in rectal cancer but rarely in colon cancer. This study aims to evaluate its prognostic role in stage II-III colon cancer. METHODS: All stage II-III colon cancer patients who underwent surgery between 2004 and 2015 were reviewed. We compared patients without invasion, with intramural invasion only (IMVI), EMVI only, and both IMVI/EMVI (n = 923). RESULTS: EMVI was associated with other high-risk features, including T4, N+ disease, lymphatic, and perineural invasion (P < 0.001). EMVI+ patients had higher rates of locoregional and distant recurrence and subsequently disease-specific mortality (stage-II, odds ratio [OR] 3.64; P = 0.001; stage-III OR, 1.94; P = 0.009), whereas outcomes were comparable between IMVI and no vascular invasion (OR, 1.21; P = 0.764; OR, 1.28, P = 0.607, respectively). The adjusted HRs for EMVI+ patients on disease-free survival, and disease-specific survival were 2.07 ( P < 0.001) and 1.67 ( P = 0.027), respectively. Moreover, EMVI+ stage-II patients fared worse than EMVI- stage-III patients, even after adjusting for adjuvant chemotherapy. CONCLUSION: EMVI is a strong predictor for worse oncologic outcomes in stage II-III colon cancer patients, whereas IMVI is not. It is also associated with worse outcomes compared in patients with higher stage disease who are EMVI negative.

Is There a Drawback of Converting a Laparoscopic Colectomy in Colon Cancer?

BACKGROUND: Laparoscopic resection is well established in the treatment of colon cancer. However, conversion rates remain high and the impact of conversion is disputed. MATERIAL AND METHODS: We retrospectively identified 1347 patients who underwent surgery for colon cancer between 2004 and 2014 at our tertiary center. Morbidity and oncological outcomes were compared between patients who underwent successfully completed laparoscopic surgery (LS), planned open surgery (OS), and conversion to open surgery (CS). Long-term analysis included patients with stage I-III disease. In addition, we performed propensity score matching to adjust for the heterogeneity and selection bias between the treatment groups. RESULTS: Of all patients, 505 underwent LS, 789 underwent OS, and 53 underwent CS, which corresponded to a conversion rate of 9.5%. Conversion was associated with male gender, left-sided tumors, and stage III disease. Length of stay, morbidity, and readmission rates were lower for LS patients. Kaplan-Meier curves demonstrated worse overall, disease-specific, and disease-free survival in CS than LS, with similar outcomes to OS. However, after propensity score matching, CS was only associated with admission duration and the requirement of blood transfusion, whereas survival outcomes were comparable between all groups. CONCLUSIONS: CS is associated with adverse short- and long-term outcomes compared to LS. However, when accounting for differences in baseline and pathologic features, CS remained only associated with a longer length of stay and more blood transfusions. Because outcomes were comparable between CS and OS, regardless of stage and other risk factors, our data support a surgeon's attempt to perform LS in patients with colon cancer.

Effects of local multivisceral resection for clinically locally advanced rectal cancer on long-term outcomes.

INTRODUCTION: Multivisceral resection is occasionally needed to obtain clear margins in patients with transmural rectal cancer. Most series demonstrate equivalent outcomes between those patients who undergo multivisceral resections and those who do not, provided an R0-resection is achieved. This study focuses solely on patients who received neoadjuvant treatment for clinically transmural rectal cancers and underwent a local multivisceral R0-resection. METHODS: A retrospective, single center analysis of consecutive series of patients who received a surgical R0-resection after neoadjuvant treatment for a clinically transmural, non-metastatic, primary rectal cancer. All patients were operated on between 2004 and 2015. RESULTS: A total of 279 patients was included, of whom 29 patients underwent a local multivisceral R0-resection (LMVR). These patients were more often female and less often diagnosed through screening. Pathologic AJCC-staging was significantly lower for non-LMVR patients, with more favorable tumor characteristics. LMVR patients demonstrated higher rates of distant disease recurrence, and impaired survival, even after adjusting for disease stage. CONCLUSION: An R0-resection after neoadjuvant therapy led to comparative local control of disease; however, patients with multivisceral resection had more distant recurrence and impaired survival, compared to those did not undergo a multivisceral resection. Further research should determine optimal postoperative care.

A Transverse Colectomy is as Safe as an Extended Right or Left Colectomy for Mid-Transverse Colon Cancer.

BACKGROUND: Although extended colectomy is often chosen for patients with transverse colon cancer, the optimal surgical approach for mid-transverse colon cancer has not been established. METHODS: We identified patients who underwent a transverse (TC) or an extended colectomy (EC) for mid-transverse colon cancer between 2004 and 2014. To adjust for potential selection bias between the groups, a propensity score matching analysis was performed. RESULTS: A total of 103 patients were included, of whom 63% underwent EC (right 47%, left 17%) and 37% TC. EC patients tend to have worse short-term outcomes. Although fewer lymph nodes were harvested after TC, 5-year overall (OS) ad disease-free survival (DFS) was comparable between the groups. When comparing long-term outcomes stage-by-stage, worse OS and DFS were seen in stage-II. All stage-II patients died of a non-cancer-related cause and recurrence occurred in pT4 TC patients who did not receive adjuvant therapy. The propensity-matched cohort demonstrated similar postoperative morbidity, but more laparoscopic procedures in EC. Additionally, TC tumors were correlated with poorer histopathological features and disease recurrence was only seen after TC. CONCLUSION: Our study underlines the oncological safety of a transverse colectomy for mid-transverse colon cancer. Although TC tumors were associated with poorer histopathological features, survival rates were comparable.

Agrin in the Muscularis Mucosa Serves as a Biomarker Distinguishing Hyperplastic Polyps from Sessile Serrated Lesions.

PURPOSE: Sessile serrated lesions (SSL) are precursors to colon carcinoma, and their distinction from other polyps, in particular hyperplastic polyps (HP), presents significant diagnostic challenges. We evaluated expression patterns in colonic polyps of previously identified colon carcinoma-associated extracellular matrix (ECM) proteins to identify markers distinguishing SSLs from other polyps. EXPERIMENTAL DESIGN: Gene-expression analyses of ECM proteins were performed using publicly available data on preneoplastic colonic polyps. In parallel, we evaluated by IHC the expression of agrin (AGRN) in over 400 colonic polyps, including HP, SSL with and without dysplasia, traditional serrated adenomas (TSA), and tubular adenomas (TA), and compared the consistency of standard histologic diagnosis of SSLs by experienced gastrointestinal pathologists with that of AGRN IHC. RESULTS: Differential gene expression analysis and IHC identified AGRN, serine peptidase inhibitor (SERPINE2), and TIMP metallopeptidase inhibitor 1 (TIMP1) elevated in SSLs and HPs but decreased in TAs and absent in normal colon. AGRN-positive basal laminae were noted in all TA, TSA, HP, and SSL in distinguishable patterns, whereas other polyps and normal mucosa were negative. SSL with or without dysplasia consistently showed IHC staining for AGRN in the muscularis mucosae, which was absent in HP, TSA, TA, and other polyps. In contrast, histologic evaluation showed only weak interobserver agreement (kappa value = 0.493) in distinguishing SSLs. CONCLUSIONS: Muscularis mucosae-based AGRN immunostaining is a novel biomarker to distinguish SSL from HP, TSA, and TA, with a specificity of 97.1% and sensitivity of 98.9% and can assist in diagnosis of morphologically challenging colonic polyps.

Do Stage I Colorectal Cancers with Lymphatic Invasion Require a Different Postoperative Approach?

BACKGROUND: Although stage I colorectal cancer has an excellent prognosis after complete surgical resection, disease recurrence still occurs. This study aimed to assess prognostic risk factors in this early stage of disease. METHODS: All non-neoadjuvantly treated stage I colon (CC) and rectal (RC) patients who underwent a surgical resection between 2004 and 2015 were identified. Clinicopathological differences and long-term oncological outcomes were compared. RESULTS: CC patients (n = 433) were older and had more pre-existing comorbidities. RC patients (n = 86) were associated with more T2 tumors, venous invasion, and higher rates of 30-day morbidity. In multivariate analysis, lymphatic invasion was found to be an independent predictor for disease recurrence (OR 4.57, P = 0.010) and worse disease-free survival (HR 4.26, P = 0.012). This was particularly true for distant recurrence, with eight times higher hazard ratios when lymphatic invasion was present (HR 8.02, P < 0.001). T2 tumors were at risk, though no significant association was found (OR 3.86, P = 0.051; HR 3.61, P = 0.065, respectively). CONCLUSIONS: Lymphatic invasion was strongly associated with worse DFS, in particular distant recurrence. This subgroup of stage I patients might benefit from a more intensive follow-up and maybe should be considered for adjuvant therapy.

The Impact of a Multivisceral Resection and Adjuvant Therapy in Locally Advanced Colon Cancer.

BACKGROUND: Multivisceral resection for locally advanced colon cancer is mandatory to achieve complete tumor resection. We aimed to determine if local multivisceral resections (LMR) for pT4 and pT3 tumors impact perioperative and long-term oncological outcomes. METHODS: All stage II or III colon cancer patients who had surgery between 2004 and 2014 were identified. We analyzed patients with non-multivisceral resections (NMR) for pT4 tumors vs. pT4-LMR. In addition, outcomes were compared to both NMR and LMR pT3 patients. RESULTS: LMR was performed in 55 (29.7%) of all patients with pT4 tumors and in 48 (8.9%) of all patients with pT3 tumors. The most commonly involved areas of extension were the abdominal wall and the small intestine. Transverse colon cancer was correlated with LMR. Morbidity rates were comparable between NMR and LMR, with the exception of higher rates of blood transfusion and postoperative ileus. Over one third of all pT4-NMR patients developed recurrent disease, which was higher compared to all other groups. Subsequently, overall and disease-specific survival, as well as disease-free survival (DFS), was worse for pT4-NMR, even after adjustment for pTN-staging, adjuvant therapy, and R0 resection. Furthermore, when analyzing only curative resections, radial margin < 1 cm along with nodal disease was independent predictor for worse DFS. Long-term outcomes were comparable between pT4-LMR and pT3 patients. CONCLUSIONS: Multivisceral resection for locally advanced colon cancer preserves long-term oncological outcomes without increased postoperative morbidity. Moreover, LMR in pT3 tumors does not contribute to postoperative morbidity. Our study underlines the feasibility and importance of performing LMR when locally advanced cancer is suspected.

Do packed red blood cell transfusions really worsen oncologic outcomes in colon cancer?

BACKGROUND: Data from small retrospective studies have argued that perioperative packed red blood cell transfusions may increase the risk of developing metastatic recurrence in cancer patients. This study tests this assumption in a large cohort spanning a decade of operatively treated colon cancer patients. METHODS: All patients undergoing primary resection of a colon cancer at a tertiary care center between 2004-2014 (n = 1,423) were included in a retrospective review of a prospectively maintained data repository. Survival and disease-free survival were compared and also adjusted in multivariable Cox regression standardized for follow-up, American Society of Anesthesiologists score, age, sex, postoperative chemotherapy, baseline staging, and tumor grade. RESULTS: Of the 1,423 patients, 305 (21.4%) received a perioperative packed red blood cell transfusion during their index admission. During follow-up, overall mortality was greater in patients who received perioperative packed red blood cell (53.1% vs 30.9%; P < .001); however, there were no appreciable differences in rates of long-term distant recurrence (in patients without baseline metastasis 11.1% vs 13.9%; P = .25), or disease-specific mortality (21.3% vs 17.3%; P = .104; without baseline metastasis: 8.6% vs 8.9%; P = .89). Similarly, multivariable Cox regression showed no statistical difference in recurrence (hazard ratio: 0.83, 95% confidence interval, 0.83-1.26; P = .38) or disease-specific mortality (hazard ratio: 1.12, 95% confidence interval, 0.83-1.51; P = .47). CONCLUSION: Mortality rates were significantly greater in patients with perioperative packed red blood cell transfusions, a finding that is backed by a body of evidence that associates perioperative packed red blood cell transfusion with comorbidity and serious illness, but contrary to earlier evidence, findings in our cohort do not support a hypothesis that perioperative perioperative packed red blood cell transfusions have a detrimental effect on recurrence rates of operatively treated colon cancer patients.

[The 'interesting case' and patient privacy: handling patient data in medical education]. / De 'interessante casus' en patiëntprivacy: Omgaan met patiëntgegevens in het medisch onderwijs.

The use of patient histories has become an essential part of medical education. Patient histories are important for the relevance, effectiveness and appeal of medical education. The sharing of patient-related information in education and further training is expected to increase in the coming years. The sharing of patient information with colleagues, students or other interested parties can conflict with the rules protecting patient privacy. The most important rule in this context is that it is the patients who decide whether their cases can be shown to others for educational purposes. Patient consent is not required if the data or images used have been fully anonymized. If the information can be traced to the patient, consent is required, preferably documented in writing. The teaching physician is responsible for the storage, protection and destruction of patient data and for controlling access to information.