Granular-type Laterally Spreading Tumors Research Articles

TP53 mutation at early stage of colorectal cancer progression from two types of laterally spreading tumors.

Although most sporadic colorectal cancers (CRC) are thought to develop from protruded adenomas through the adenoma–carcinoma sequence, some CRC develop through flat lesions, so‐called laterally spreading tumors (LST). We previously analyzed epigenetic aberrations in LST and found that LST are clearly classified into two molecular subtypes: intermediate‐methylation with KRAS mutation and low‐methylation with absence of oncogene mutation. Intermediate‐methylation LST were mostly granular type LST (LST‐G) and low‐methylation LST were mostly non‐granular LST (LST‐NG). In the present study, we conducted a targeted exon sequencing study including 38 candidate CRC driver genes to gain insight into how these genes modulate the development of LST. We identified a mean of 11.5 suspected nonpolymorphic variants per sample, including indels and non‐synonymous mutations, although there was no significant difference in the frequency of total mutations between LST‐G and LST‐NG. Genes associated with RTK/RAS signaling pathway were mutated more frequently in LST‐G than LST‐NG (P = 0.004), especially KRAS mutation occurring at 70% (30/43) of LST‐G but 26% (13/50) of LST‐NG (P < 0.0001). Both LST showed high frequency of APC mutation, even at adenoma stage, suggesting its involvement in the initiation stage of LST, as it is involved at early stage of colorectal carcinogenesis via adenoma‐carcinoma sequence. TP53 mutation was never observed in adenomas, but was specifically detected in cancer samples. TP53 mutation occurred during development of intramucosal cancer in LST‐NG, but during development of cancer with submucosal invasion in LST‐G. It is suggested that TP53 mutation occurs in the early stages of cancer development from adenoma in both LST‐G and LST‐NG, but is involved at an earlier stage in LST‐NG.

Endoscopic predictors of deep submucosal invasion in colorectal laterally spreading tumors.

The depth of invasion of the bowel wall influences the treatment of colorectal laterally spreading tumors (LSTs). The aim of this study was to evaluate the risk factors and patterns of submucosal invasion in a large series of LSTs that were removed en bloc. Prospectively collected endoscopic and pathological data on a total of 822 LSTs, ≥ 10 mm in size and removed en block by endoscopic submucosal dissection (n = 670) or surgery (n = 152), were retrospectively analyzed. In 414 LSTs of the granular type, submucosal invasion was detected in 80 cases (19 %; 95 % confidence interval [CI] 16 - 23) and was deep (≥1000 μm) in 79 % of cases. The invasion site was under a large (≥ 10 mm) nodule (56 %), depression (28 %), or was multifocal (16 %). Risk factors for deep submucosal invasion on multivariate analysis were the presence of a large nodule (odds ratio [OR] 12, 95 %CI 2 - 59), depression (OR 59, 95 %CI 9 - 387), and invasive pit pattern (OR 33, 95 %CI 12 - 88). The sensitivity and specificity of invasive pit pattern for detection of deep submucosal invasion were 52 % (95 %CI 40 % - 64 %) and 98 % (95 %CI 96 % - 99 %), respectively.In 408 LSTs of the nongranular type, submucosal invasion was detected in 159 cases (39 %; 95 %CI 34 - 44) and was deep in 54 % of cases. The invasion site was under a submucosal mass-like elevation (10 %), depression (45 %), or was multifocal (45 %). Risk factors for deep submucosal invasion were the presence of a submucosal mass-like elevation (OR 8, 95 %CI 1 - 61), depression (OR 28, 95%CI 8 - 97), and invasive pit pattern (OR 79, 95%CI 25 - 256). Because of a substantial risk of submucosal invasion and multifocal invasion, granular type LSTs with a large nodule or depression and nongranular type LSTs should be endoscopically removed en bloc.

Short-Term Outcomes of Colorectal Endoscopic Submucosal Dissection Performed by Trainees

Background: Colorectal endoscopic submucosal dissection (ESD) is a relatively new therapy that has been accepted as the most effective treatment procedure for superficial colorectal neoplasms. Given the increasing acceptance and use of this procedure worldwide, the outcomes of colorectal ESD performed by trainees should be understood from a practical perspective and for developing strategies to introduce ESD to trainees. This study aimed to evaluate the clinical outcomes of ESD when conducted by less-experienced endoscopists. Summary: We retrospectively reviewed the clinical outcomes of 164 patients with 164 colorectal neoplasms who underwent ESD carried out by 20 trainees performing their first colorectal ESDs between April 2005 and March 2012. For each operator, clinical data were collected between the first and 30th cases. For evaluating the technical aspects of the ESD procedure, the endoscopic characteristics of the lesions, procedure time, en bloc resection rate, R0 resection rate, invasion depth and complications were evaluated. The median procedure time was 95 min; about 75% of the lesions were resected within 120 min. Apparent perforation or electric damage in the muscularis propria was seen in 4% of lesions. In terms of factors with the potential to effect procedure time, lesion size and pathological invasion depth were significantly different between shorter and longer treatment times for granular-type laterally spreading tumors (LST). Key Messages: A granular-type LST of <40 mm is a good lesion for introducing colorectal ESD to trainees. Trainees should have a strong ability to make a depth diagnosis before starting ESD.

Morphological change of a laterally spreading rectal tumor over a short period

BackgroundLaterally spreading tumors (LSTs) are generally defined as superficial lesions ≥10 mm in diameter that typically extend laterally rather than vertically along the colonic wall. LSTs are usually categorized into 2 subtypes: granular type and nongranular type. Large nodules or depressed areas in granular-type LSTs (LST-Gs) are endoscopic findings of a cancerous component and sometimes represent submucosal invasion. However, the lateral growth and development of LST-Gs remains unclear.Case presentationThis case report describes a case of 79-year-old woman who underwent total colonoscopy due to a positive fecal occult blood test and was detected a LST-G, about 30 mm in diameter in the lower rectum. The lesion consisted of not only aggregated small and large nodules typically seen in LST-Gs but also the hardly elevated flat parts. In the flat part, there were dilated round pits and no evident capillary vessels. Three months later, the flat part increased in height, the dilated round pits were partly replaced by type IIIL pits, and capillary vessels were evident. The lesion was removed by endoscopic submucosal dissection, and diagnosed pathologically as tubular adenoma. We performed the sequence analyses on KRAS, BRAF, NRAS and PIK3CA genes in flat part and nodular part separately, and a mutation of KRAS gene at codon 146 was observed at only nodular part, suggesting probable that nodular part be a precancerous lesion.ConclusionThis is a unique and suggestive case, providing information on progression of LST-Gs at the very early stage to carcinogenesis.

The Cooperative Italian FLIN Study Group: prevalence and clinico-pathological features of colorectal laterally spreading tumors

Laterally spreading tumors (LSTs) are increasingly recognized as important precursors of colorectal carcinoma. The clinical behavior of these large nonpolypoid lesions is still uncertain. The aim of the present study was to assess prevalence and clinico-pathological features of LSTs in a large Italian cohort of patients. The study was a subgroup analysis of a large database of patients undergoing total colonoscopy. The database originated from a multicenter cross-sectional observational study involving 80 centers throughout Italy. Data from 27,400 total colonoscopies were analyzed. Precancerous lesions were detected in 5609 patients. Of these, LSTs were identified in 254 patients (4.5%; 95% confidence interval [CI] 3.5-6.2). Granular-type LSTs (G-LSTs) accounted for 83% of the cases (211/254). LSTs were predominant in the proximal colon (154, 60.6%). A total 231 lesions were endoscopically removed, with histology being available for 242. Neoplasia was confirmed in 225 lesions (93.4%) (143 low grade adenoma, 76 high grade adenoma, and six submucosal cancer). The six cases of submucosally invasive carcinoma were diagnosed in five G-LST and one nongranular LST (NG-LST). The risk of containing advanced histology was not increased in G-LST compared with NG-LST (odds ratio [OR] 1.55, 95%CI 0.73-3.27); it was significantly higher in lesions with large nodules (OR 3.09, 95%CI 1.05-9.04; P = 0.041) or depressed surface (OR 4.27, 95%CI 1.24-14.61; P = 0.021). LSTs represent approximately 5% of all precancerous colorectal lesions in the Italian population and are prevalent in the proximal colon. These lesions are no more likely to harbor advanced histology than similar-sized polypoid lesions. Large nodularity or depressed surface are risk factors for advanced histology.

Laterally Spreading Type of Colorectal Adenoma Exhibits a Unique Methylation Phenotype and K-ras Mutations

Laterally spreading tumors (LST), characterized by superficial extension along the colonic lumen, have recently been detected by colonoscopy. However, genetic and epigenetic characteristics of these tumors were scarcely reported. A total of 205 sporadic colorectal adenoma tissues (157 protruded-type, 23 granular-type LST (G-LST), 12 flat-type LST (F-LST), and 13 flat-type smaller than 1 cm) were collected. CpG island methylator phenotype (CIMP) was determined by examination of methylation status at p16, methylated in tumor (MINT) 1, 2, 12, and 31 loci. K-ras codon 12 and 13 point mutations were also examined. The relationship between macroscopic appearance and CIMP status or K-ras mutations was analyzed. Among adenomas larger than 1 cm, CpG island methylation involving 2 or more loci (CIMP-high) was more likely to be observed in G-LST (14/23, 61%) than in protruded-type adenomas (18/73, 25%) (P = .002). The prevalence of K-ras mutations in G-LST (18/23, 78%) was significantly higher than that in protruded-type adenomas (18/73, 25%) (P < .0001). Moreover, the prevalence of CIMP-high and K-ras mutations in G-LST located in the proximal colon was much higher (11/13, 85%; and 12/13, 92%, respectively). In contrast, F-LST exhibited low prevalence of CIMP-high (1/12, 8%) and K-ras mutations (2/12, 16%). High prevalence of CIMP-high and K-ras mutations in G-LST, especially in the proximal colon, could strongly suggest that G-LST appearance is associated with a unique carcinogenic pathway.

MUC1 Expression in Intramucosal Colorectal Neoplasms

Purpose: The mucin core peptide MUC1 often is detectable in colorectal carcinoma (CRC) tissue and cell lines. However, whether MUC1 in CRC correlates with tumor histogenesis and progression is unclear. We studied the relationship between MUC1 expression in intramucosal CRC and clinicopathologic features, expression of Ki-67, and p53 protein, and apoptosis. Methods: The intramucosal CRC we studied included 140 endoscopically or surgically resected lesions, including 106 low-grade carcinomas and 34 high-grade carcinomas. De novo carcinoma, defined as carcinoma with no adenomatous component, represented 9 of 140 tumors. Three macroscopic types were identified: 57 lesions were polypoid, 55 were superficial and flat, and 28 were granular-type laterally spreading tumors (G-LST). MUC1, Ki-67, and p53 expression were examined immunohistochemically. Apoptotic cells were identified by in situ DNA nick end labeling. Results: MUC1 expression in high-grade carcinomas was significantly more frequent (p < 0.01) than in low-grade carcinomas; expression in adenomas was almost nil. MUC1 expression in polypoid carcinomas was significantly more frequent (p < 0.05) than in superficial carcinomas or G-LST. MUC1 expression in carcinomas with p53 expression was significantly more frequent (p < 0.01) than in carcinomas not expressing p53. No significant correlation was found between expression of MUC1 and Ki-67 labeling index. MUC1 was expressed more frequently in carcinomas with relatively high apoptotic index (p < 0.01). MUC1 expression did not differ between de novo carcinomas and those developing from adenomas. Conclusions: The results suggest that MUC1 is likely to be expressed in the course of colorectal carcinoma development when p53 protein is overexpressed and apoptosis is prominent.