Abstract
Background: Distant metastatic disease remains the main cause of colorectal cancer (CRC) mortality, but our knowledge on how cancer cells travel from the primary tumor to a secondary site is ...limited. Lymph node metastases (LNM) play a central role in the staging of CRC patients since they are currently viewed as the gateway to distant metastases. However, in recent years additional forms of locoregional spread with varying prognostic impact have been identified, with tumor deposits (TD) having significantly more impact than LNM. The biological explanation for the difference in prognostic impact between LNM and TD is lacking, while this is essential for a more comprehensive understanding of the role of these biomarkers CRC spread. Therefore, in this study, shotgun proteomics were used to compare the biological phenotype of TD and LNM.
Methods: From 12 CRC patients, one TD and one LNM were included for paired protein analyses. Proteins were isolated from formalin-fixed paraffin-embedded tissue after which a filter aided sample preparation method was performed. Then, the samples were analyzed by liquid-chromatography tandem mass-spectrometry, and after data handling and filtering, 5578 differentially expressed proteins were used for downstream analyses. Differences in expression were visualized using heatmaps and volcano plots, and enrichment analyses as well as gene set enrichment was performed. All analyses were performed using R version 4.1.2.
Results: Among the main findings was that the proteins ASPN, MRC2, SPON1, MXRA5, BGN, LUM, and PLOD2 were overexpressed in TD. These proteins play a role in stimulating pro-tumorigenic processes such as migration, invasion, and epithelial to mesenchymal transition. For the enrichment analyses all proteins with a Fold change of less than -1 and more than 1 were included. Enrichment analyses using the KEGG pathways showed more immune activity in the LNM, with upregulated B-cell and T-cell signaling (p<0.001), while TD showed more interaction with the extracellular matrix in the form of proteoglycans, focal adhesion, and ECM-receptor interaction (p<0.01). In addition, when hallmarks from the Molecular Signatures Database (MSigDB) were used for the enrichment analyses, TD showed the hallmark of epithelial mesenchymal transition (p <0.005).
Conclusions: This study shows that TD have a more aggressive and invasive phenotype compared to LNM on protein level. TD had a higher expression of proteins that promote pro-tumorigenic processes and a more extensive interaction with the extracellular matrix. Furthermore, the hallmark of epithelial mesenchymal transition is enriched in TD compared to LNM. These findings form a possible explanation for the strong prognostic impact of TD, and give insight into the heterogeneity of different modes of locoregional spread in CRC.
Citation Format: Nelleke P. Brouwer, Loth Webbink, Shannon Van Lent-Van Vliet, Pascal W. Jansen, Femke Simmer, Daniele V. Tauriello, Michiel Vermeulen, Iris D. Nagtegaal. Proteomics identifies differences in the biological phenotype of tumor deposits and lymph node metastases in colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 987.
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Background: Clinical lymph node staging by MRI and CT is important in stratification for neoadjuvant therapy in colorectal cancer. Overstaging may result in unnecessary ...neoadjuvant therapy, but understaging may refrain patients from adequate preoperative treatment. This study aims to provide insight in current daily practice in clinical lymph node staging in CRC in the Netherlands. Methods: All patients with primary CRC, diagnosed between 2003-2014, who underwent lymph node dissection were selected from the nationwide population-based Netherlands Cancer Registry (n=100,211). Trends in patient- and tumor-characteristics, and lymph node staging were analyzed. For the years 2011-2014, sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were calculated for clinical lymph node staging, with histology as the gold standard. Only patients without preoperative treatment were analyzed. Since prospective studies have shown that 5x5 Gy radiotherapy (RT) followed by total mesorectal excision within 10 days does not lead to nodal downstaging, an additional analysis was performed in this group. Results: The proportion clinically positive lymph nodes increased significantly between 2003-2014; from 7% to 22% for colon cancer and from 7% to 53% for rectal cancer. The proportion histological positive lymph nodes remained fairly stable over time (±35% colon, ±33% rectum). During 2011-2014, clinical lymph node staging was available in the registry in 86% of colon cancer patients, 92% of rectal cancer patients without neoadjuvant treatment and 95% of rectal cancer patients with 5x5 Gy RT. The parameters based on data from this period are presented in table 1. Conclusions: With a sensitivity and PPV of approximately 50%, clinical lymph node staging is about as accurate as flipping a coin. This leads to overtreatment in patients with rectal cancer with neoadjuvant RT. Acceptable specificity and NPV limit the risk of undertreatment. Table: see text
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Background: In colorectal cancer (CRC) mucinous adenocarcinoma (MC) and signet-ring cell carcinoma (SRCC) have been associated with differences in metastatic patterns compared to ...the more common adenocarcinoma (AC). This study systematically evaluates metastatic patterns of different histological subtypes and analyses metastatic disease based upon primary tumor localization. Methods: A nationwide retrospective review of pathological records of 5,813 patients diagnosed with CRC who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch Pathology Registry (PALGA). To validate metastatic patterns in rectal cancer patients, data was compared to the prospective randomized multicentre TME-trial that investigated efficacy of preoperative radiotherapy. Results: In the autopsy study 1,675 patients with CRC had metastatic disease. Metastatic disease was more frequently found in MC and SRCC than in AC (33.9%, 61.2% and 27.5%; P< 0.0001) and more often had metastases at multiple sites (58.6% and 70.7% versus 49.9%; P=0.001). AC more commonly metastasized to the liver compared with MC and SRCC, 73.0% versus 52.2% and 31.7% (P<0.0001). The occurrence of metastases exclusively to the liver was less common in MC and SRCC patients. In SRCC patients, liver metastases were almost always observed in combination with other metastases. MC and SRCC metastasized to the peritoneal surface frequently, 48.2% and 51.2%, compared with 20.1% in AC (P<0.0001). Colon cancer patients presented more frequently with intra-abdominal metastases, than rectal cancer patients. Rectal cancer patients presented more often with extra-abdominal metastases. Results from the TME-trial confirmed findings in rectal cancer patients from the autopsy study. Conclusions: There are profound differences in metastatic patterns between different histological subtypes and the localization of the primary tumor in CRC. Findings from this study should encourage to take histological subtype into account during pre-operative examination for metastases and during follow-up. Results also indicate that these factors should be considered a stratification factor in future research initiatives focusing on advanced disease.
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Background: The aim of this study was to analyze the association between radiotherapy (RT) for rectal cancer and the development of second primary tumors. Methods: Data on all ...surgically treated, non-metastasized primary rectal cancer patients diagnosed between 1989 and 2007 were retrieved from a population-based cancer registry and retrospectively reviewed. To estimate the cumulative incidence of a second tumor, Fine and Gray’s competing risk model was used with death as a competing event. Standardized incidence ratios (SIR’s) were calculated for comparison with the incidence of primary tumors in the general population, taking in account sex, age and calendar year. Results: The cohort consisted of 29,214 patients of which 15,454 patients had undergone (chemo)RT. Median follow-up was 6.2 years (range 0-24). 3655 patients were diagnosed with at least one second primary tumor of which 808 patients had pelvic tumors. The SIR for any second tumor was 1.14 (95% confidence interval CI 1.10-1.17), resulting in 23.3/10,000 excess cases per year. RT reduced the cumulative incidence of second pelvic tumors compared to patients who received no RT (SHR 0.70, 95% CI 0.61-0.81). Second pelvic tumors were more common in patients who underwent post-operative RT than in patients who underwent pre-operative RT (SHR 1.37, 95% CI 1.10-1.70). Organ-specific analyses showed that second prostate tumors were less common in patients who received RT compared to patients who received no RT (SHR = 0.51, 95% CI 0.43-0.62). RT also reduced the risk for a second primary tumor in the rectum(sigmoid) compared to patients who did not receive RT (SHR 0.59 95% CI 0.37-0.94). Patients who received post-operative RT had higher chances of developing a second rectum(sigmoid) tumor then patients who received pre-operative RT (SHR 2.25, 95% CI 1.07-4.73). Patients without RT had worse overall survival than patients who received RT (hazard ratio 1.22, 95% CI 1.19-1.26). Conclusions: In this nationwide study, patients with previous rectal cancer had a slightly increased chance of developing another primary tumor compared with the general population. We found a protective effect of RT on the development of secondary pelvic tumors, predominantly for prostate cancer.
* Context.--A standardized detailed surgical pathology report is the cornerstone of gastric cancer management. Objective.--To guide management and prognostication for patients with gastric carcinomas ...globally, the International Collaboration on Cancer Reporting aimed to produce an evidence-based international pathology reporting data set with a panel of globally recognized expert pathologists and clinicians. Design.--Based on published guidelines/data sets for gastric carcinomas, a working draft was developed by the chair of the expert panel of pathologists and clinicians. The draft was then circulated to the panel and discussed in a series of teleconferences and email communications until consensus was achieved. The draft data set was uploaded on the International Collaboration on Cancer Reporting Web site for public comment. The data set was reviewed in consideration of the feedback, and a final version was approved by the panel. Results.--This data set was developed for gastrectomy specimens for primary gastric carcinomas, including neuroendocrine carcinomas and mixed neuro-endocrine-non-neuroendocrine neoplasms. Well-differentiated neuroendocrine tumors, nonepithelial malignancies, and secondary tumors were excluded from this data set. The final data set contains 15 core (required) elements and 8 noncore (recommended) elements. A commentary is provided for each element. Conclusions.--The International Collaboration on Cancer Reporting has published freely available, evidence-based data sets for gastric cancer reporting. Standardized reporting has been shown to improve patient care and facilitates data exchange and analysis for quality assurance, cancer epidemiology, and clinical and basic research. (Arch Pathol Lab Med. 2022;146:1072-1083; doi: 10.5858/arpa.2021-0225-OA)
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The duodenum is the main site for (pre-) malignant extracolonic manifestations in patients with familial adenomatous polyposis (FAP). Changes in the E-cadherin/
β-catenin complex play a pivotal role ...in the development of malignancies. Loss of E-cadherin has been described in association with loss of SMAD4. To elucidate the pathways leading to the development of duodenal adenomas in patients with FAP, the distributions of E-cadherin, SMAD4, and
β-catenin were analyzed. Furthermore, differences between the duodenum and colon were evaluated. Normal FAP duodenum (n = 13) and FAP duodenal adenomas (n = 50; total, 21 patients) were compared with non-FAP duodenal adenomas (n = 7) and normal non-FAP duodenum (n = 15) by immunohistochemical staining for extracellular and intracellular E-cadherin,
β-catenin, and SMAD4. Colonic biopsies of 10 patients with FAP were also studied, as well as non-FAP colonic adenomas (n = 26) and non-FAP normal colon (n = 12). Compared with the intracellular component of E-cadherin that was present in all cases, a significant loss of extracellular E-cadherin was observed in both duodenal and colonic adenomas and normal tissue of patients with FAP. Nuclear localization of
β-catenin was more often observed in duodenal FAP adenomas compared with non-FAP adenomas. Loss of nuclear SMAD4 was seen in the duodenum and, to a higher degree, in the colon of patients with FAP, as well as non-FAP patients. The loss of extracellular E-cadherin in the normal duodenal and colonic mucosa of patients with FAP might play a role in the high susceptibility of these tissues for (pre-) malignant transformation.
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