Lai Mun Wang

Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer.

Background Tumor budding along the advancing front of colorectal adenocarcinoma is an early event in the metastatic process. A reproducible, prognostic budding scoring system based on outcomes in early stage colorectal cancer has not been established. Design One hundred twenty-eight T3N0M0 colorectal carcinoma patients with known outcome were identified. Tumor budding was defined as isolated tumor cells or clusters of <5 cells at the invasive tumor front. Tumor bud counts were generated in 5 regions at 200× by 2 pathologists (conventional bud count method). The median bud count per case was used to divide cases into low (median=0) and high budding (median ≥1) groups. Forty cases were reevaluated to assess reproducibility using the conventional and a novel rapid bud count method. Results Fifty-seven (45%) carcinomas had high and 71 (55%) had low budding scores. High budding was associated with an infiltrative growth pattern (P<0.0001) and lymphovascular invasion (P=0.005). Five-year cancer-specific survival was significantly poorer in high compared with low budding groups: 63% versus 91%, respectively, P<0.0001. Multivariate analysis demonstrated tumor budding to be independently prognostic (hazard ratio=4.76, P<0.001). Interobserver agreement was at least equivalent comparing the conventional to the rapid bud count methods: 87.5% agreement (κ=0.75) versus 92.5% agreement (κ=0.85), respectively. Conclusions Tumor budding is a strong, reproducible, and independent prognostic marker of outcome that is easily assessed on hematoxylin and eosin slides. This may be useful for identifying the subset of T3N0M0 patients at high risk of recurrence who may benefit from adjuvant therapy.

Multiparametric magnetic resonance for the non-invasive diagnosis of liver disease

Background & Aims With the increasing prevalence of liver disease worldwide, there is an urgent clinical need for reliable methods to diagnose and stage liver pathology. Liver biopsy, the current gold standard, is invasive and limited by sampling and observer dependent variability. In this study, we aimed to assess the diagnostic accuracy of a novel magnetic resonance protocol for liver tissue characterisation. Methods We conducted a prospective study comparing our magnetic resonance technique against liver biopsy. The individual components of the scanning protocol were T1 mapping, proton spectroscopy and T2⁎ mapping, which quantified liver fibrosis, steatosis and haemosiderosis, respectively. Unselected adult patients referred for liver biopsy as part of their routine care were recruited. Scans performed prior to liver biopsy were analysed by physicians blinded to the histology results. The associations between magnetic resonance and histology variables were assessed. Receiver-operating characteristic analyses were also carried out. Results Paired magnetic resonance and biopsy data were obtained in 79 patients. Magnetic resonance measures correlated strongly with histology (rs = 0.68 p <0.0001 for fibrosis; rs = 0.89 p <0.001 for steatosis; rs = −0.69 p <0.0001 for haemosiderosis). The area under the receiver operating characteristic curve was 0.94, 0.93, and 0.94 for the diagnosis of any degree of fibrosis, steatosis and haemosiderosis respectively. Conclusion The novel scanning method described here provides high diagnostic accuracy for the assessment of liver fibrosis, steatosis and haemosiderosis and could potentially replace liver biopsy for many indications. This is the first demonstration of a non-invasive test to differentiate early stages of fibrosis from normal liver.

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

Local recurrence after stenting for obstructing left‐sided colonic cancer

Self‐expanding metallic stents (SEMS) may be used in acute obstructing left‐sided colonic cancers to avoid high‐risk emergency surgery. However, oncological safety remains uncertain. This study evaluated the long‐term oncological outcome of SEMS as a bridge to elective curative surgery versus emergency resection.

Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy.

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M 
(2012) Histopathology 61, 562–575

International study group on rectal cancer regression grading : interobserver variability with commonly used regression grading systems

The aim of this study was to ascertain the level of concordance among gastrointestinal pathologists for regression grading in rectal cancers treated with neoadjuvant chemoradiation. Seventeen gastrointestinal pathologists participated using the Mandard, Dworak, and modified rectal cancer regression grading systems to grade 10 representative slides that were selected from 10 cases of rectal cancer treated with long-course neoadjuvant chemoradiation. The slides were scanned with a whole-slide scanner generating dynamic digitized images. The results showed very little concordance across the 3 grading systems, with κ values of 0.28, 0.35, and 0.38 for the Mandard, Dworak, and modified rectal cancer regression grading systems, respectively. In only 1 of 10 study cases was there unanimous grading concordance using the modified rectal cancer regression grading system. It was felt that these systems lacked precision and clarity for reproducible, accurate regression grading. The study concluded that there was a need for a simple, reproducible regression grading system with clear criteria, a cumulative or composite score taking into account all sections of the tumor bed that is sampled rather than the worst section (highest grade), and there should be a uniform method of sampling of these specimens.

Epithelial-mesenchymal transition (EMT) protein expression in a cohort of stage II colorectal cancer patients with characterized tumor budding and mismatch repair protein status.

Introduction: The relationship between tumor budding, epithelial-mesenchymal transition (EMT) protein expression, and survival has not been closely examined in stage II colorectal cancer (CRC). This study aimed to assess proteins implicated in EMT and to correlate their expression with tumor budding, microsatellite status, and survival. Methods: A total of 258 stage II CRCs were identified (tumor budding characterized in 122 cases). Immunohistochemistry for LAMC2, E cadherin, cathepsin L, and β catenin using tissue microarrays was performed. EMT and mismatch repair (MMR) protein expression were correlated with tumor budding and survival. Results: LAMC2 positivity (P < .001) and low membranous β catenin (P = .056) were associated with tumor budding. In a univariate survival analysis, tumor budding (P < .001), LAMC2 positivity (P < .03), and stromal cytoplasmic cathepsin L (P = .025) predicted poorer prognosis. Multivariate analysis showed tumor budding to be the only variable independently associated with survival: hazard ratio = 7.9 (95% confidence interval = 3-21); P < .001. Tumor budding was more frequent in microsatellite-stable (MSS) versus microsatellite-instable (MSI) tumors: 48% versus 26%, respectively; P = .087. MSS cases exhibited reduced membranous β catenin (P = .002) and increased cytoplasmic and nuclear β catenin (P < .001) compared with MSI cases. Conclusion: Epithelial mesenchymal protein expression plays a key role in tumor budding and prognosis in early-stage colorectal cancer and requires further evaluation.

Anatomical basis and histopathological changes resulting from selective internal radiotherapy for liver metastases

Background Knowledge that liver tumours preferentially take their blood supply from the arterial blood supply rather than the portal venous system can be used for local delivery of treatment or for embolisation to cut off the blood supply to tumours. Aims To present histological evaluation of malignant and non-malignant hepatic tissue of one such therapy, selective internal radiation therapy (SIRT) with yttrium-90 microspheres, to decipher its principal mechanism of action. Methods The H&E stained sections of hepatic resection specimens from three patients with liver metastases from colorectal (CRC) cancer, who underwent hepatic surgery 4–9 months following SIRT, were examined and the pathological changes documented. Results Resin microspheres were identified in the vascular tumour bed and vessels within the portal tracts of the background liver parenchyma. Microspheres were usually associated with giant cell reaction or histiocytes. In the tumour bed, tumour necrosis, mucinous alteration, collections of foamy histiocytes, ectatic vessels, calcification and fibrosis were observed. There was minimal cellular inflammatory response observed, suggestive of direct radiation injury as a non-immune mediated process. Conclusions We describe in detail the spectrum of histopathological changes in malignant tissue and liver parenchyma in patients with metastatic CRC treated with SIRT. Our findings are consistent with the hypothesis that the principal mechanism of action of SIRT appears to be via arterially directed delivery of highly radioactive microspheres in and around the vascular tumour bed rather than by micro-arterial embolisation.

Reporting trends of right-sided hyperplastic and sessile serrated polyps in a large teaching hospital over a 4-year period (2009–2012)

Aim An audit of serrated polyps diagnosed over a 4-year period: 2009 to 2012 was undertaken to ascertain the reporting trends of sessile serrated polyps (SSP). Methods All right sided hyperplastic polyps (HP) proximal to the splenic flexure and all polyps designated SSP were retrieved from the study period. Three pathologists blinded to the original diagnosis re-examined the slides. Recent American College of Gastroenterology guidelines for the diagnosis of SSP was utilised. Results No cases of SSP were diagnosed in 2009. In 2010, 32 right-sided cases were encountered, 83 confirmed in 2011 and 134 confirmed in 2012. The vast majority of these were right-sided. With regards to right-sided HP that were re-classified as SSP the data is as follows: 20 of 66 in 2009 (30%); 58 of 91 in 2010 (64%); 42 of 106 (40%) in 2011 and 69 of 206 in 2012 (33%). Conclusions This study has demonstrated an almost exponential increase in the diagnosis of SSP over a 4-year period. In addition, 30 to 64% of right-sided HP were re-classified as SSP over the 4-year period suggesting that greater awareness of the diagnostic criteria for SSP is required. SSP is an important precursor lesion in the serrated pathway of colorectal cancer. Its recognition is important for surveillance and therapeutic strategies.

Myofibroblast activation in colorectal cancer lymph node metastases.

Background:Myofibroblasts have an important role in regulating the normal colorectal stem cell niche. While the activation of myofibroblasts in primary colorectal cancers has been previously described, myofibroblast activation in lymph node metastases has not been described before.Methods:Paraffin-embedded lymph node sections from patients with macrometastases, micrometastases and isolated tumour cells were stained to identify myofibroblasts and to characterise the distribution of different cell types in tumour-containing lymph nodes. The extent of myofibroblast presence was quantified and compared with the size of the metastasis and degree of proliferation and differentiation of the cancer cells.Results:We show substantial activation of myofibroblasts in the presence of colorectal metastases in lymph nodes, which is intimately associated with glandular structures, both in micro- and macrometastases. The degree of activation is positively associated with the size of the metastases and the proportion of Ki67+ve cancer cells, and negatively associated with the degree of enterocyte differentiation as measured by CK20 expression.Conclusion:The substantial activation of myofibroblasts in tumour-containing lymph nodes strongly suggests that these metastatic cancer cells are still significantly dependent on their microenvironment. Further understanding of these epithelial–mesenchymal interactions could lead to the development of new therapies in metastatic disease.