Gerhard Schenkirsch

The clinical significance of lymph node size in colon cancer

To date, the clinical value of lymph node size in colon cancer has been investigated only in a few studies. Only in radiological diagnosis is lymph node size routinely recognized, and nodes ≥10 mm in diameter are considered pathologic. However, the few studies regarding this topic suggest that lymph node size is not a reliable indicator of metastatic disease. Moreover, we hypothesized that increasing lymph node size is associated with favorable outcome. By performing a morphometric study, we investigated the clinical significance of lymph node size in colon cancer in terms of metastatic disease and prognosis. A cohort of 237 cases with excellent lymph node harvest (mean lymph node count: 33±17) was used. The size distribution in node-positive and -negative cases was almost identical. In all, 151 out of the 305 metastases detected (49.5%) were found in lymph nodes with diameters ≤5 mm. Only 25% of lymph nodes >10 mm showed metastases. Minute lymph nodes ≤1 mm were involved only very rarely (2 of 81 cases). In 67% of the cases, the largest positive lymph node was <10 mm. The prognostic relevance of lymph node size was investigated in a subset of 115 stage I/II cases. The occurrence of ≥7 lymph nodes that were >5 mm in diameter was significantly associated with better overall survival. Our data show that lymph node size is not a suitable factor for preoperative lymph node staging. Minute lymph nodes have virtually no role in correct histopathological lymph node staging. Finally, large lymph nodes in stage I/II disease might indicate a favorable outcome.

Tumour budding, uPA and PAI‐1 are associated with aggressive behaviour in colon cancer

The proteases PAI‐1 and uPA play a major role in extracellular matrix degradation, which facilitates tumour progression. Tumour budding is a histomorphological expression of enhanced tumour cell migration.

Methylene blue-assisted lymph node dissection technique is not associated with an increased detection of lymph node metastases in colorectal cancer

Lymph node staging is of paramount importance for prognosis estimation and therapy stratification in colorectal cancer. A high number of harvested lymph nodes is associated with an improved outcome. Methylene blue-assisted lymph node dissection effectively improves the lymph node harvest and ensures sufficient staging. Now, the effect on node positivity rate and stage-related outcome was investigated. The study cohort with advanced lymph node dissection consisted of 669 colorectal cancer cases of all stages, which were collected between 2007 and 2012. A historical collection of 663 cases investigated with conventional techniques between 2002 and 2004 served as control. Lymph node harvest was dramatically improved in the study group with mean lymph node numbers of 34±17 vs 13±5 (P<0.001) and sufficient staging rates of 98% vs 62% (P<0.001). However, neither the rate of nodal positive cases (37% vs 37%; P=0.98) nor the rate of N2 cases differed between the two groups (14% vs 13%; P=0.80). Furthermore, no differences were found concerning the outcome in both groups. The advanced lymph node dissection technique guarantees adequate histopathological lymph node staging in virtually all cases of colorectal cancer and is therefore extremely helpful. The hypothesis that it also provides a higher sensitivity in detecting metastases, however, could be not proved.

Shift from cytoplasmic to nuclear maspin expression correlates with shorter overall survival in node-negative colorectal cancer

Maspin has been characterized as a potent tumor suppressor in many in vitro and in vivo studies. In contrast, in stage III colon cancer, an association with shorter overall survival as well as sensitivity to chemotherapy was found for cases with nuclear maspin expression. Because 20% of node-negative colorectal cancer cases show a fatal clinical course, we hypothesized that immunohistochemical maspin expression could be of help to identify higher-risk cases. Therefore, we analyzed survival in a study employing 156 cases of stage I/II colorectal cases. Immunohistochemical cytoplasmic and/or nuclear maspin expression was found in 72% and 48% of the cases, respectively. Significant correlations between cytoplasmic expression and high tumor grade (P < .01) and between nuclear expression and tumor budding (P < .001) were shown. No differences concerning overall survival and immunohistochemical maspin expression were found when the complete collective was analyzed. However, evaluation of the pT3 cases revealed a highly significant worse mean overall survival of cases with a combination of nuclear expression and cytoplasmic loss of maspin compared to cases with the opposite expression pattern nuclear loss and cytoplasmic expression (mean overall survival 40 versus 63 months, respectively; P < .001). The other possible combinations (complete positive and complete negative) showed intermediate mean overall survival times with 54 and 49 months, respectively. Our findings suggest a compartment-dependent function of maspin in colorectal cancer, which can be useful in identifying stage II cases with a higher risk for fatal outcome with a possible benefit from adjuvant chemotherapy.

Number of Intratumoral T Lymphocytes Is Associated With Lymph Node Size, Lymph Node Harvest, and Outcome in Node-Negative Colon Cancer

OBJECTIVES We postulated that lymph node (LN) harvest and LN size are influenced by immunologic effects. METHODS To investigate this hypothesis, we performed a retrospective analysis of 170 node-negative colon cancer cases to evaluate the density of intratumoral T lymphocytes (ITLs). CD3- and CD8-positive T cells were counted using a digital system. RESULTS The ITL density was significantly increased in cases with sufficient LN harvest and high numbers of LNs larger than 5 mm (LN5). High ITL numbers were associated with improved cancer-specific survival. The analysis of the immune score revealed a significantly different cancer-specific outcome (P = .024), with no cancer-related death in the group with the highest score. The immune score and tumor budding were independently prognostic. CONCLUSIONS ITL density is independently prognostic and associated with LN harvest and LN size. The immune response is very likely the true explanation for the known prognostic effect of the LN harvest in colon cancer.

Tumour stage distribution and survival of malignant melanoma in Germany 2002–2011

BackgroundOver the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients.MethodsPooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival.ResultsThe number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97–0.97), sex (OR 1.18, 95% CI 1.11–1.25), date of diagnosis (OR 1.05, 95% CI 1.04–1.06), ‘diagnosis during screening’ (OR 3.24, 95% CI 2.50–4.19) and place of residence (OR 1.23, 95% CI 1.16–1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8–83.9%).ConclusionsNo distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.

The role of lymph node size and FOXP3+ regulatory T cells in node-negative colon cancer

Recently, we demonstrated that the intratumoural density of CD3+ and CD8+ T cells is independently prognostic and associated with lymph node (LN) harvest and LN size in node-negative colon cancer. We assumed that FOXP3+ T cells (Tregs) could be inversely associated with these LN features. Therefore, we performed a retrospective immunohistochemical analysis using an already well-characterised collection of stage I/II colon cancer cases. Receiver operating characteristic analysis revealed the optimal cut-off for predicting cancer-related death to be 70 FOXP3+ Tregs/mm2 at the invasion front. Other than T-stage, none of the relevant histopathological parameters were associated with the density of FOXP3+ cells. In particular, no relation to LN size and count were found. Cancer-specific survival was significantly improved in cases with high densities (115 vs 86 months; p=0.026) in univariable but not in multivariable analysis. In contrast to other cancers, FOXP3+ T cells are associated with a favourable outcome.

Tumor Budding, uPA, and PAI-1 in Colorectal Cancer: Update of a Prospective Study

Aims. The prognostic role of the proteases uPA and PAI-1, as well as tumor budding, in colon cancer, has been investigated previously. Methods. We provide 6-year follow-up data and results of the validation set. The initial test set and validation set consisted of 55 colon cancers and 68 colorectal cancers, respectively. Tissue samples were analyzed for uPA and PAI-1 using a commercially available Enzyme-Linked Immunosorbent Assay (ELISA). Tumor budding was analyzed on cytokeratin-stained slides. Survival analyses were performed using cut-offs that were determined previously. Results. uPA was not prognostic for outcome. PAI-1 showed a trend towards reduced cancer specific survival in PAI-1 high-grade cases (68 versus 83 months; P = 0.091). The combination of high-grade PAI-1 and tumor budding was associated with significantly reduced cancer specific survival (60 versus 83 months; P = 0.021). After pooling the data from both sets, multivariate analyses revealed that the factors pN-stage, V-stage, and a combination of tumor budding and PAI-1 were independently prognostic for the association with distant metastases. Conclusions. A synergistic adverse effect of PAI-1 and tumor budding in uni- and multivariable analyses was found. PAI-1 could serve as a target for anticancer therapy.

Interobserver variability in the H&E-based assessment of tumor budding in pT3/4 colon cancer: does it affect the prognostic relevance?

Tumor budding is a mostly accepted adverse prognostic factor in colorectal carcinoma. It is on the cusp of a widespread use after agreement was reached recently on uniform assessment criteria. We investigated whether the interobserver variability has a direct influence on the prognostic relevance in pT3/4 colon cancer in the background of different levels of experience of the investigators. In total, six investigators with different levels of experience evaluated tumor budding on H&E slides in 244 cases with primary diagnosed (2002–2011) colon carcinoma (pT3/4, N+/−, M0). High-grade tumor budding/budding grade 3 (defined as majority assessment among the investigators) was significantly associated with an adverse outcome (overall survival p = 0.03, cancer-specific survival p = 0.08) and the occurrence of distant metastasis (p = 0.009). However, a detailed analysis of the rating results of the individual investigators revealed that only ratings of one investigator (advanced resident) were associated with an adverse outcome (p = 0.01 cancer-specific survival, overall survival p = 0.09, distant metastasis p = 0.002). The results of another investigator (consultant) were significantly associated with distant metastasis (p = 0.007). The kappa values among the investigators have a range between 0.077 and 0.357 (median 0.166). Total agreement of all investigators existed in 109 cases (44.7%). Our results demonstrate that the evaluation of tumor budding on H&E slides in pT3/4 colon cancer goes along with a considerable interobserver variability among investigators of different levels of experience. Furthermore, our results reveal that these findings directly influence the prognostic value.

Clinical Significance of International Union Against Cancer pn Staging and Lymph Node Ratio in Node-positive Colorectal Cancer after Advanced Lymph Node Dissection.

BACKGROUND: Lymph node retrieval in colorectal cancer can be improved by using advanced histopathological techniques like methylene blue-assisted lymph node dissection, which results in a doubling or even tripling of the lymph node count in comparison with conventional lymph node dissection techniques. However, it is not clear whether the established lymph node staging systems are suitable for predicting patients’ prognoses under these circumstances. OBJECTIVE: The aim of this study was to determine whether the current lymph node staging systems are suitable when advanced dissection methods are used. DESIGN: This is a retrospective cohort study. SETTING AND PATIENTS: We formed a study group (methylene blue-assisted lymph node dissection) of 293 patients and a control group (conventional lymph node dissection) of 232 patients, each with node-positive cases. Conventional pN staging according to the International Union Against Cancer, seventh edition, and lymph node ratio were applied. MAIN OUTCOME MEASURES: Overall survival was compared by using the different staging systems in a uni- and multivariable fashion. RESULTS: The lymph node ratio values were reduced in the advanced methylene blue-assisted lymph node dissection group in comparison with the conventional lymph node dissection group (0.1 vs 0.3, p < 0.001). Although pN staging proved to be reliable, the cutoff values for lymph node ratio staging had to be adapted. The new cutoffs (0.07, 0.15, and 0.34) were prognostic. However, multivariable analysis revealed pN staging and vascular invasion, but not lymph node ratio, as independently prognostic in the methylene blue-assisted lymph node dissection group. LIMITATIONS: The study group and historical control group are not perfectly balanced because the case number in the stage III subgroup of the control group is small. CONCLUSIONS: pN staging proved to be a robust prognostic marker in colorectal cancer under the circumstances of improved lymph node harvest. After adaptation of the cutoff values, lymph node ratio is also prognostic but not superior to pN staging.