Although molecular prognostic and predictive biomarkers have taken central stage in gastrointestinal cancer research, new or redefined histomorphological “biomarkers” also contribute considerable information to prognosis and possibly response to therapy. This topic investigates some of these up-and-coming or newly defined histomorphological features as prognostic and potential predictive biomarkers, including the possible limitations regarding their inclusion into standard pathology routine.

University of Bern

School of Medicine, Tokai University

Frontiers in Oncology

Gastrointestinal Cancers

New Morphological Markers of Gastrointestinal Cancers

ObjectiveThe aim of this study is to evaluate the prognostic significance of intraoperative peritoneal lavage cytology (PLC) in pancreatic invasive ductal adenocarcinoma.</sec>MethodsIntraoperative PLC was evaluated in 162 patients with resectable pancreatic invasive ductal adenocarcinoma. The results were analyzed for correlations with clinicopathological parameters and/or prognoses.</sec>ResultsIn the 162 cases of resectable pancreatic ductal adenocarcinoma, 18 (11%), 141 (87%), and 3 (2%) were positive, negative, and equivocal for intraoperative PLC, respectively. Intraoperative PLC positivity was associated with older patients (over 65 years), large tumor size (over 35 mm), tumor location in the body/tail of the pancreas, and distant metastasis. Univariate analysis showed that larger tumor sizes (≥35 mm, P = 0.001), lymph node metastases (P = 0.005), distant metastasis (P = 0.004), advanced stage (stage IIB or III, P = 0.006), advanced tumor histological grade (G3, P < 0.001), or positive intraoperative PLC (P = 0.002) are associated with a shorter survival. Multivariate analysis revealed that larger tumor sizes (≥35 mm, P = 0.026), lymph node metastasis (P = 0.021), advanced tumor histological grade (G3, P < 0.001), and positive intraoperative PLC (P = 0.002) were independent prognostic factors.</sec>ConclusionIntraoperative PLC is an independent prognostic factor for resectable pancreatic invasive ductal adenocarcinoma.</sec>

Objective: The aim of this study is to evaluate the prognostic significance of intraoperative peritoneal lavage cytology (PLC) in pancreatic invasive ductal adenocarcinoma.Methods: Intraoperative PLC was evaluated in 162 patients with resectable pancreatic invasive ductal adenocarcinoma. The results were analyzed for correlations with clinicopathological parameters and/or prognoses.Results: In the 162 cases of resectable pancreatic ductal adenocarcinoma, 18 (11%), 141 (87%), and 3 (2%) were positive, negative, and equivocal for intraoperative PLC, respectively. Intraoperative PLC positivity was associated with older patients (over 65 years), large tumor size (over 35 mm), tumor location in the body/tail of the pancreas, and distant metastasis. Univariate analysis showed that larger tumor sizes (≥35 mm, P = 0.001), lymph node metastases (P = 0.005), distant metastasis (P = 0.004), advanced stage (stage IIB or III, P = 0.006), advanced tumor histological grade (G3, P &lt; 0.001), or positive intraoperative PLC (P = 0.002) are associated with a shorter survival. Multivariate analysis revealed that larger tumor sizes (≥35 mm, P = 0.026), lymph node metastasis (P = 0.021), advanced tumor histological grade (G3, P &lt; 0.001), and positive intraoperative PLC (P = 0.002) were independent prognostic factors.Conclusion: Intraoperative PLC is an independent prognostic factor for resectable pancreatic invasive ductal adenocarcinoma.

Positive Intraoperative Peritoneal Lavage Cytology is a Negative Prognostic Factor in Pancreatic Ductal Adenocarcinoma: A Retrospective Single-Center Study

Histomorphological features of colorectal cancers (CRC) represent valuable prognostic indicators for clinical decision making. The invasive margin is a central feature for prognostication shaped by the complex processes governing tumor–host interaction. Assessment of the tumor border can be performed on standard paraffin sections and shows promise for integration into the diagnostic routine of gastrointestinal pathology. In aggressive CRC, an extensive dissection of host tissue is seen with loss of a clear tumor–host interface. This pattern, termed “infiltrative tumor border configuration” has been consistently associated with poor survival outcome and early disease recurrence of CRC-patients. In addition, infiltrative tumor growth is frequently associated with presence of adverse clinicopathological features and molecular alterations related to aggressive tumor behavior including BRAFV600 mutation. In contrast, a well-demarcated “pushing” tumor border is seen frequently in CRC-cases with low risk for nodal and distant metastasis. A pushing border is a feature frequently associated with mismatch-repair deficiency and can be used to identify patients for molecular testing. Consequently, assessment of the tumor border configuration as an additional prognostic factor is recommended by the AJCC/UICC to aid the TNM-classification. To promote the assessment of the tumor border configuration in standard practice, consensus criteria on the defining features and method of assessment need to be developed further and tested for inter-observer reproducibility. The development of a standardized quantitative scoring system may lay the basis for verification of the prognostic associations of the tumor growth pattern in multivariate analyses and clinical trials. This article provides a comprehensive review of the diagnostic features, clinicopathological associations, and molecular alterations associated with the tumor border configuration in early stage and advanced CRC.

Histomorphological features of colorectal cancers (CRC) represent valuable prognostic indicators for clinical decision making. The invasive margin is a central feature for prognostication shaped by the complex processes governing tumor&#x2013;host interaction. Assessment of the tumor border can be performed on standard paraffin sections and shows promise for integration into the diagnostic routine of gastrointestinal pathology. In aggressive CRC, an extensive dissection of host tissue is seen with loss of a clear tumor&#x2013;host interface. This pattern, termed &#x201c;infiltrative tumor border configuration&#x201d; has been consistently associated with poor survival outcome and early disease recurrence of CRC-patients. In addition, infiltrative tumor growth is frequently associated with presence of adverse clinicopathological features and molecular alterations related to aggressive tumor behavior including BRAFV600 mutation. In contrast, a well-demarcated &#x201c;pushing&#x201d; tumor border is seen frequently in CRC-cases with low risk for nodal and distant metastasis. A pushing border is a feature frequently associated with mismatch-repair deficiency and can be used to identify patients for molecular testing. Consequently, assessment of the tumor border configuration as an additional prognostic factor is recommended by the AJCC/UICC to aid the TNM-classification. To promote the assessment of the tumor border configuration in standard practice, consensus criteria on the defining features and method of assessment need to be developed further and tested for inter-observer reproducibility. The development of a standardized quantitative scoring system may lay the basis for verification of the prognostic associations of the tumor growth pattern in multivariate analyses and clinical trials. This article provides a comprehensive review of the diagnostic features, clinicopathological associations, and molecular alterations associated with the tumor border configuration in early stage and advanced CRC.

The Tumor Border Configuration of Colorectal Cancer as a Histomorphological Prognostic Indicator

Multimodal therapy concepts have been successfully implemented in the treatment of locally advanced gastrointestinal malignancies. The effects of neoadjuvant chemo- or radiochemotherapy such as scarry fibrosis or resorptive changes and inflammation can be determined by histopathological investigation of the subsequent resection specimen. Tumor regression grading (TRG) systems which aim to categorize the amount of regressive changes after cytotoxic treatment mostly refer onto the amount of therapy induced fibrosis in relation to residual tumor or the estimated percentage of residual tumor in relation to the previous tumor site. Commonly used TRGs for upper gastrointestinal carcinomas are the Mandard grading and the Becker grading system, e.g., and for rectal cancer the Dworak or the Rödel grading system, or other systems which follow similar definitions. Namely for gastro-esophageal carcinomas these TRGs provide important prognostic information since complete or subtotal tumor regression has shown to be associated with better patient’s outcome. The prognostic value of TRG may even exceed those of currently used staging systems (e.g., TNM staging) for tumors treated by neoadjuvant therapy. There have been some limitations described regarding interobserver variability especially in borderline cases, which may be improved by standardization of work up of resection specimen and better training of histopathologic determination of regressive changes. It is highly recommended that TRG should be implemented in every histopathological report of neoadjuvant treated gastrointestinal carcinomas. The aim of this review is to disclose the relevance of histomorphological TRG to accomplish an optimal therapy for patients with gastrointestinal carcinomas.

Multimodal therapy concepts have been successfully implemented in the treatment of locally advanced gastrointestinal malignancies. The effects of neoadjuvant chemo- or radiochemotherapy such as scarry fibrosis or resorptive changes and inflammation can be determined by histopathological investigation of the subsequent resection specimen. Tumor regression grading (TRG) systems which aim to categorize the amount of regressive changes after cytotoxic treatment mostly refer onto the amount of therapy induced fibrosis in relation to residual tumor or the estimated percentage of residual tumor in relation to the previous tumor site. Commonly used TRGs for upper gastrointestinal carcinomas are the Mandard grading and the Becker grading system, e.g., and for rectal cancer the Dworak or the R&#xf6;del grading system, or other systems which follow similar definitions. Namely for gastro-esophageal carcinomas these TRGs provide important prognostic information since complete or subtotal tumor regression has shown to be associated with better patient&#x2019;s outcome. The prognostic value of TRG may even exceed those of currently used staging systems (e.g., TNM staging) for tumors treated by neoadjuvant therapy. There have been some limitations described regarding interobserver variability especially in borderline cases, which may be improved by standardization of work up of resection specimen and better training of histopathologic determination of regressive changes. It is highly recommended that TRG should be implemented in every histopathological report of neoadjuvant treated gastrointestinal carcinomas. The aim of this review is to disclose the relevance of histomorphological TRG to accomplish an optimal therapy for patients with gastrointestinal carcinomas.

Tumor Regression Grading of Gastrointestinal Carcinomas after Neoadjuvant Treatment

Pancreatic ductal adenocarcinoma (PDAC) ranks as the fourth commonest cause of cancer death while its incidence is increasing worldwide. For all stages, survival at 5 years is<5%. The lethal nature of pancreatic cancer is attributed to its high metastatic potential to the lymphatic system and distant organs. Lack of effective therapeutic options contributes to the high mortality rates of PDAC. Recent evidence suggests that epithelial-mesenchymal transition (EMT) plays an important role to the disease progression and development of drug resistance in PDAC. Tumor budding is thought to reflect the process of EMT which allows neoplastic epithelial cells to acquire a mesenchymal phenotype thus increasing their capacity for migration and invasion and help them become resistant to apoptotic signals. In a recent study by our own group the presence and prognostic significance of tumor budding in PDAC were investigated and an association between high-grade budding and aggressive clinicopathological features of the tumors as well as worse outcome of the patients was found. The identification of EMT phenotypic targets may help identifying new molecules so that future therapeutic strategies directed specifically against them could potentially have an impact on drug resistance and invasiveness and hence improve the prognosis of PDAC patients. The aim of this short review is to present an insight on the morphological and molecular aspects of EMT and on the factors that are involved in the induction of EMT in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) ranks as the fourth commonest cause of cancer death while its incidence is increasing worldwide. For all stages, survival at 5 years is&lt;5%. The lethal nature of pancreatic cancer is attributed to its high metastatic potential to the lymphatic system and distant organs. Lack of effective therapeutic options contributes to the high mortality rates of PDAC. Recent evidence suggests that epithelial-mesenchymal transition (EMT) plays an important role to the disease progression and development of drug resistance in PDAC. Tumor budding is thought to reflect the process of EMT which allows neoplastic epithelial cells to acquire a mesenchymal phenotype thus increasing their capacity for migration and invasion and help them become resistant to apoptotic signals. In a recent study by our own group the presence and prognostic significance of tumor budding in PDAC were investigated and an association between high-grade budding and aggressive clinicopathological features of the tumors as well as worse outcome of the patients was found. The identification of EMT phenotypic targets may help identifying new molecules so that future therapeutic strategies directed specifically against them could potentially have an impact on drug resistance and invasiveness and hence improve the prognosis of PDAC patients. The aim of this short review is to present an insight on the morphological and molecular aspects of EMT and on the factors that are involved in the induction of EMT in PDAC.

Role of Epithelial-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma: Is Tumor Budding the Missing Link?

Primary tumors of the colorectal cancers are assessed pathologically based on the tumor spread into the bowel wall. The assessment of serosal involvement, which may be relevant to pT4, can be challenging for pathologists, making the consistency of diagnoses questionable. As solutions to this problem, the following two strategies could be adopted. One would be to use special staining or immunohistochemical staining techniques for diagnostic assistance. The other would be to construct recommendations for the assessment of tumor spreading and to obtain a world-wide consensus on the criteria used to assess tumor spreading. Using elastic staining, we previously reported that peritoneal elastic laminal invasion (ELI) could be objectively determined and would likely contribute to a simplified and more objective stratification of deep tumor invasion around the peritoneal surface. We also noted the importance of sampling, staining, and histo-anatomical knowledge in the application of elastic staining during routine pathological diagnosis. Here we review the history of primary tumor stratification leading to the present TNM classification and report on the current status of pathological assessments made at our hospital to summarize what has been established and what is further required for the pathological diagnosis of tumor spreading in patients with colorectal cancer.

Primary tumors of the colorectal cancers are assessed pathologically based on the tumor spread into the bowel wall. The assessment of serosal involvement, which may be relevant to pT4, can be challenging for pathologists, making the consistency of diagnoses questionable. As solutions to this problem, the following two strategies could be adopted. One would be to use special staining or immunohistochemical staining techniques for diagnostic assistance. The other would be to construct recommendations for the assessment of tumor spreading and to obtain a world-wide consensus on the criteria used to assess tumor spreading. Using elastic staining, we previously reported that peritoneal elastic laminal invasion (ELI) could be objectively determined and would likely contribute to a simplified and more objective stratification of deep tumor invasion around the peritoneal surface. We also noted the importance of sampling, staining, and histo-anatomical knowledge in the application of elastic staining during routine pathological diagnosis. Here we review the history of primary tumor stratification leading to the present TNM classification and report on the current status of pathological assessments made at our hospital to summarize what has been established and what is further required for the pathological diagnosis of tumor spreading in patients with colorectal cancer.