Cases Of High-grade Intraepithelial Neoplasia Research Articles

Comparison of MBM and ESD in the Treatment of Single Early Esophageal Cancer and Precancerous Lesions.

Esophageal cancer is a disease with high morbidity and mortality, exploring effective treatment methods is the key to the treatment of this disease. This study aims to compare the clinical efficacy and safety of multi-band mucosectomy (MBM) and endoscopic submucosal dissection (ESD) in the treatment of single early esophageal cancer (EEC) and precancerous lesions, and whether MBM can achieve better clinical effect as an effective treatment method. The clinical data of 70 patients with EEC and precancerous lesions who were treated with MBM and ESD in the Fourth Affiliated Hospital of China Medical University from May 2021 to May 2023 and could be followed up were retrospectively analyzed. They were divided into two groups according to different treatment methods: MBM group (31 cases) and ESD group (39 cases). The general data, perioperative conditions, endoscopic treatment effect and pathological results of the two groups were compared. The duration of endoscopic treatment in MBM group was shorter than that in ESD group [36 (25~39) min vs 46 (41~57) min, p < 0.05], and there was no significant difference in the intraoperative bleeding rate between the two groups (12.90% vs 7.69%, p > 0.05). There was no significant difference in the rate of intraoperative perforation between the two groups (3.23% vs 7.69%, p > 0.05), and the hospitalization time in MBM group was shorter than that in ESD group [5 (4~7) days vs 8 (7~12) days, p < 0.05]. The hospitalization cost was less [2535 (2423~2786) dollars vs 4485 (3858~5794) dollars, p < 0.05]. No postoperative bleeding occurred in both groups. There was no statistically significant difference in postoperative stenosis rate between MBM group and ESD group (3.23% vs 12.82%, p > 0.05), and no statistically significant difference in postoperative local recurrence rate (12.90% vs 5.13%, p > 0.05). There was no significant difference in the rate of additional surgery (9.68% vs 2.56%, p > 0.05). The en bloc resection rate of MBM group was lower than that of ESD group (77.42% vs 97.44%, p < 0.05), but there was no significant difference in the complete resection rate between the two groups (87.10% vs 97.44%, p > 0.05). The postoperative pathological results of MBM group showed 13 cases of low-grade intraepithelial neoplasia (LGIN), 11 cases of high-grade intraepithelial neoplasia (HGIN), and 7 cases of canceration, while the postoperative pathological results of ESD group showed 10 cases of LGIN, 14 cases of HGIN, and 15 cases of canceration, with no statistical significance (p > 0.05). MBM and ESD are effective methods for the treatment of EEC and precancerous lesions. MBM has the advantages of short hospital stay, quick recovery and low cost. However, compared with MBM, ESD can improve the complete resection rate of the lesion, avoid the occurrence of positive incisal margin, and reduce the risk of secondary treatment and additional surgery.

Diagnostic Value of Serum Pepsinogen Ⅰ/Pepsinogen Ⅱ Combined with Tumor Markers for Helicobacter pylori-Positive Early-Stage Gastric Cancer

To investigate the diagnostic value of serum pepsinogen (PG) Ⅰ/PGⅡ combined with tumor markers for Helicobacter pylori ( Hp)-positive early-stage gastric cancer. A retrospective study was conducted with the clinical data of 109 patients with gastric cancer (the gastric cancer group), 115 patients with chronic atrophic gastritis (the benign group), 112 cases of low-grade intraepithelial neoplasia (the low grade group), 109 cases of high-grade intraepithelial neoplasia (the high grade group), and 104 healthy subjects who underwent the relevant screening tests as part of their general physical examination (the healthy group). All the subjects were admitted to or received care at our hospital between May 2018 and April 2021. The levels of serum PGⅠ, PGⅡ, carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and carbohydrate antigen 724 (CA724), and Hp infection status were examined. The findings for these indicators were compared among the groups, and the differences in serum indicators in Hp-positive and Hp-negative patients were compared. The diagnostic value of serum PGⅠ/PGⅡ combined with tumor markers for Hp-positive early-stage gastric cancer was assessed with receiver operating characteristic (ROC) curve. The serum levels of PGⅠ and PGⅠ/PGⅡ decreased in successive order in the healthy group, the benign group, the low grade group, the high grade group, and the gastric cancer group ( P<0.05). The serum levels of PGⅡ, CEA, CA199, and CA724 in the gastric cancer group, the high grade group, and the low grade group were all higher than those in the healthy group and the benign group ( P<0.05). The Hp-positive rates of the gastric cancer group, the high grade group, the low grade group and the benign group were higher than that of the healthy group ( P<0.01). The levels of serum PGⅠ, PGⅡ, CEA, CA199, and CA724 of the Hp-positive subjects of the healthy group, the benign group, the low grade group, the high grade group, and the gastric cancer group were higher than those of the Hp-negative subjects ( P<0.05), while their PGⅠ/PGⅡ levels were always lower than those of the Hp-negative persons ( P<0.05). The specificity and area under the curve ( AUC) of serum PGⅠ/PGⅡ, CEA, CA199, and CA724 in the combined diagnosis of Hp-positive early-stage gastric cancer were higher than those of each indicator used alone in diagnosis ( P<0.05). In the gastric cancer group, the proportion of patients with PGⅠ/PGⅡ>2.32 was lower in the Hp-positive patients than that in the Hp-negative patients ( P<0.05), while the proportions of patients with CEA>66.99 ng/mL, CA199>110.35 U/mL, and CA724>44.20 U/mL were higher in the Hp-positive patients than those in the Hp-negative patients ( P<0.05). Testing PGⅠ/PGⅡ in combination with CEA, CA199, and CA724 results in better diagnostic value for Hp-positive early-stage gastric cancer.

Clinicopathological features of differentiated-type dysplasia of the esophagus

Objective: To investigate the clinicopathological features of differentiated-type (squamous) dysplasia of the esophagus. Methods: A total of 184 cases of esophageal differentiated-type dysplasia were collected retrospectively at People's Liberation Army Joint Logistics Support Force 989 Hospital (formerly 152 Hospital), and Beijing Chaoyang Hospital, Capital Medical University, China from 2016 to 2019. Their histological characteristics and immunophenotypes were analyzed, and related literature was reviewed. Results: The median age of the 184 patients was 65 years (range 39-83 years), while the ratio of men to women was 1.7∶1.0. There were 17 cases in the upper esophagus, 143 in the middle esophagus and 24 in the lower esophagus. The median diameter of the dysplasia was 15 mm (range 2-50 mm). According to the Paris classification, 2 cases were 0-Ⅰ, 25 cases were 0-Ⅱa, 70 cases were 0-Ⅱb, 74 cases were 0-Ⅱb and 0-Ⅱc and 13 cases were 0-Ⅱc. Macroscopically, the lesional mucosa was reddish with rough surface and white moss; capillary abnormality was found on narrow-band imaging. Histologically, dysplastic cells had distinct features of squamous epithelium, with abundant eosinophilic cytoplasm, round to irregular nuclei, coarse chromatin, obvious nucleolus, and conspicuous mitoses. The cellularity was increased, the arrangement of cells was disordered, and the polarity of cells in basal layer was lost. When the dysplasia did not completely spread to the whole layer of squamous epithelium, a clear boundary was often formed between the dysplasia and the normal epithelium above it. The neoplastic epithelial protrusions often grew toward the lamina propria and were accompanied by conspicuous inflammatory cell reaction at its frontal edge. Sometimes, abnormal mature single epithelial cells or cell clusters infiltrated into the lamina propria. There were high-grade dysplasia of the common type and superficial invasive squamous cell carcinoma in 98 cases of differentiated-type dysplasia. Immunohistochemical staining showed that the mutation rate of TP53 was 47.7% (53/111). The median of Ki-67 labeling index was 50.0% (range 10%-80%), while that of basal tumor cells was 12/HPF (range 3-65/HPF). The abnormal distribution pattern of Ki-67 was seen in 111 (100%) cases. According to the initial pathological diagnosis, there were 16 cases of low-grade intraepithelial neoplasia, 37 cases of atypical epithelial cells and 131 cases of high-grade intraepithelial neoplasia and superficial invasive squamous cell carcinoma. Conclusions: The morphology of differentiated-type dysplasia of the esophagus is unique. Characteristics of highly differentiated dysplastic cells suggest that they may represent a differentiated type in the morphological lineage of esophageal squamous (high-grade) dysplasia. When the knowledge of the lesion is insufficient, it is easy to be misdiagnosed or missed in pathologic examination.

The Application of Core Needle Biopsy Through the Trocar Hole in the Surgical Operation of Endoscopically Unresectable Giant Colon Polyps: A Systematic Review Study.

The study aimed to investigate the application of core needle biopsy through the trocar hole during surgery on endoscopically unresectable giant colon polyps. The clinical data of 51 patients with endoscopically unresectable giant colon polyps from May 2016 to May 2020 were retrospectively analyzed. The primary observational outcomes were two comparative analyses of pathologic results, using the kappa index: comparison of the pathologic results from the preoperative colonoscopy and the postoperative pathologic results and comparison of the intraoperative pathologic results from core needle biopsy of the intestinal wall and the postoperative pathologic results. The secondary observational outcomes were duration of needle biopsy, operation duration, volume of intraoperative hemorrhage, rate of postoperative wound infection, rate of abdominal cavity infection, length of stay, and number and positivity of lymph node dissections after laparoscopic radical resection of colon cancer. Poor consistency was found between the preoperative (colonoscopy) and postoperative pathologic results, with kappa = 0.222 (i.e., kappa < 0.4), P < 0.05. However, good consistency was found between the intraoperative (core needle biopsy) and postoperative pathologic results, with kappa = 0.923 (i.e., kappa ≥ 0.75), P < 0.05. The postoperative pathologic results were as follows: 7 cases of adenomatous polyps of the colon, 12 cases of low-grade intraepithelial neoplasia, 12 cases of high-grade intraepithelial neoplasia, and 25 cases of invasive colon cancer. There was no incision infection, no abdominal cavity infection or formation of an abdominal abscess, no anastomotic leakage, and no death for any of the 51 patients. Postoperative complications occurred in two cases (3.92%). Biopsy through the trocar hole during laparoscopic surgery produced highly accurate pathologic results and was a fast, safe, and effective diagnostic method. Pathologic results from intraoperative biopsy could accurately determine the nature of colon polyps and provide a basis for choosing an appropriate surgical scheme.

Clinicopathological features of basal cell layer type high-grade squamous dysplasia of the esophagus

Objective: To investigate the clinicopathological features of basal cell layer type high-grade squamous dysplasia of the esophagus. Methods: Fifty-two cases of basal cell layer type high-grade squamous dysplasia of the esophagus were collected at PLA Joint Logistics Support Force 989 Hospital (34 cases) and Beijing Chaoyang Hospital (18 cases) from 2009 to 2019. The clinical, histological and immunohistochemical features were characterized. Related literature was also reviewed. Results: The median age of the 52 patients was 64 years (range 43-72 years). There were 35 men and 17 women, with a male to female ratio of 2.1∶1.0. There were 8 cases in the upper esophagus, 41 in the middle esophagus and 3 in the lower esophagus. According to the Paris Classification, 24 cases were 0-Ⅱb and 28 cases were 0-Ⅱc. Endoscopic examination showed that the color of the lesions was red and the edge was irregular. The narrow band imaging showed that the lesions were brown, and the microvascular abnormalities on the mucosal surface were observed with high magnification. Iodine staining of the lesions showed no or light staining and irregular border. Histologically, the basal layer of squamous epithelium was hypercellular, with large and hyperchromatic nuclei, and disordered cell arrangement. A high proportion of the cases showed a down-growth pattern and associated invasive squamous cell carcinoma. The immunohistochemical staining of 37 cases showed that the mutation rate of p53 was 48.6% (18/37), the median of Ki-67 labeling index was 60% (range 20%-90%), the median of Ki-67 labeling index of the basal tumor cells was 26/HPF (range 5-70/HPF), and the rate of abnormal Ki-67 distribution pattern was 37(100.0%). According to the initial pathological diagnosis, there were 8 cases of low-grade intraepithelial neoplasia, 2 cases of atypical epithelial cells and 42 cases of high-grade intraepithelial neoplasia. Conclusions: The basal cell layer type high-grade squamous dysplasia of the esophagus has a unique morphology. The dysplasia is mainly limited to the lower half part of the squamous epithelium. With marked cytological atypia and prominent invasiveness pattern, it is likely to develop into invasive squamous cell carcinoma at an early stage of the disease. The rate of pathologic misdiagnosis (such as low-grade lesion) is high. The p53 mutation and Ki-67 abnormal distribution pattern are helpful features for confirming the diagnosis of such high-grade dysplasia.

Cost-effectiveness and cost-benefit analysis of upper gastrointestinal cancer screening in Yangzhong City, Jiangsu Province, from 2009 to 2015

Objective: To evaluate the effectiveness and benefit of the upper gastrointestinal cancer screening in Yangzhong city, Jiangsu province, from 2009 to 2015. Methods: From 2009 to 2015, 31 natural villages with high-incidence of upper gastrointestinal cancer were selected from Baqiao town, Youfang town and Xinglong sub-district in Yangzhong city. 13 776 residents aged 40 to 69 years old were recruited and screened for upper gastrointestinal cancer by using endoscopic examination and pathological diagnosis. Two economic evaluation methods, cost-effectiveness analysis and cost-benefit analysis, were performed to evaluate the current screening schemes. Results: The mean age of all respondents were (53.60±8.14) years old and the males accounted for 43.64% (6 012). A total of 502 cases of upper gastrointestinal tract lesions were detected, including 100 cases of cancer (62 cases of esophagus, gastric/cardiac early stage cancer, 38 cases of advanced stage cancer), 38 cases of severe esophageal hyperplasia/carcinoma in situ, and 15 cases of high-grade intraepithelial neoplasia in stomach/cardia, the detection rate was 0.73%, 0.28% and 0.11%, respectively; the early diagnosis rate was 75.16% (115/153). The cost of a precancerous lesion, a case diagnosed at the early stage and a positive case identified through the upper gastrointestinal cancer screening in Yangzhong City was 10 037.17, 30 460.64 and 22 895.25 RMB, respectively. The early detection cost index from 2009 to 2015 was 0.52, 0.56, 0.48, 0.48, 0.21, 0.30, and 0.26, respectively. The effectiveness-cost ratio from 2009 to 2015 was 3.41, 2.77, 2.66, 2.58, 4.99, 3.12, and 3.48, respectively. Conclusions: The project of early diagnosis and treatment of upper gastrointestinal tract cancer in Yangzhong city has achieved good results and benefits.

Analysis of risk factors for non-curative resection after endoscopic submucosal dissection in early esophageal cancer and high-grade intraepithelial neoplasia

Objective To investigate the risk factors for non-curative resection after endoscopic submucosal dissection (ESD) for early esophageal cancer and high-grade intraepithelial neoplasia. Methods The clinicopathological data of 427 cases of early esophageal cancer and high-grade intraepithelial neoplasia who underwent ESD was performed from January 2013 to December 2016 in the Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed. According to the results of postoperative pathology and immunohistochemistry, 339 patients were defined as curative resection group and 88 patients were defined as non-curative resection group. Chi-square test, univariate analysis and multivariate logistic regression analysis were used for statistical analysis. Results A total of 427 patients were enrolled in this study, with an average age of (63.2±7.7) years, including 96 cases of early esophageal cancer and 331 cases of high-grade intraepithelial neoplasia. The enbloc resection rate of ESD was 94.8%(405/427), 88 of them were non-curative resected, and the non-curative resection rate was 20.6%. Univariate analysis showed that early esophageal cancer (odds ratio (OR)=3.682, 95% confidence interval (CI) 2.216 to 6.118, P<0.01), submucosal infiltration (OR=10.220, 95%CI4.861 to 21.481, P<0.01), ESD indications (OR=6.005, 95%CI3.545 to 10.172, P<0.01) and lifting sign after injecting at the base of lesions (OR=2.508, 95%CI1.005 to 6.255, P=0.042) were statistically significant between non-curative resection group and curative resection group. Multivariate unconditional logistic regression analysis revealed that submucosal infiltration (OR=4.329, 95%CI1.758 to 10.661, P=0.001), not absolute indications of ESD (OR=6.484, 95%CI2.205 to 19.068, P=0.001) and negative lifting sign (OR=3.182, 95%CI1.171 to 8.651, P=0.023) were independent risk factors for non-curative resection. Conclusions Patients with early esophageal cancer, submucosal infiltration, not absolute indications for ESD and negative lifting signs are prone to non-curative resection. Moreover, submucosal infiltration, not absolute indications for ESD, and negative lifting signs are the independent risk factors for non-curative resection. Key words: Endoscopic submucosal dissection; Early esophageal cancer; Precancerous lesions; Non-curative resection

Endoscopic follow-up of gastric low-grade intraepithelial neoplasia and influencing factors for outcome

Objective To study the influencing factors for outcomes of gastric low-grade intraepithelial neoplasia (LGIN) for better LGIN treatment regimen. Methods Using magnifying endoscopy combined with narrow-band imaging (ME-NBI) follow-up strategy, the endoscopic features of 47 cases of LGIN in Fujian Provincial Hospital, including location, size, surface situation, demarcation line, microvascular pattern and microsurface pattern, were prospectively observed, then the factors influencing the outcome were analyzed. Results Among the 47 cases of LGIN, there were 35 cases in stable condition, whose results of biopsy and ME-NBI had no changes (stable LGIN), and the mean follow-up time was 20.7±6.9 months. The remaining 12 patients had progressive dysplasia (progressive LGIN), including 4 cases of high-grade intraepithelial neoplasia, and 8 cases of moderate dysplasia. The mean follow-up time was 16.3±11.8 months. There were no significant differences between the two groups in gender (P=0.33), mean age (P=0.13), lesion distribution (P=0.70), and lesion morphology (P=0.97). The lesion size was less than 20 mm in the stable group (71.4%, 25/35), and over 20 mm in the progressive group (66.7%, 8/12), and the difference was statistically significant (P=0.02). The proportion of the lesion surface heterogeneity in the progressive group was significantly higher than that in the stable group[75.0% (9/12) VS 34.3% (12/35), P=0.01]. The proportion of positive manifestations under ME-NBI in the progressive group was also significantly higher than that in the stable group[83.3% (10/12) VS 8.6% (3/35), P=0.00]. Conclusion The size of lesions over 20 mm, the uneven surface and positive ME-NBI are the important factors influencing the outcome of LGIN, which are of significance for the diagnosis and treatment of LGIN. Key words: Follow-up study; Magnifying endoscopy combined with narrow-band imaging; Low-grade intraepithelial neoplasia; Early gastric cancer

P63 is more sensitive and specific than 34βE12 to differentiate adenocarcinoma of prostate from cancer mimickers.

Prostate cancer is the world's leading cause of cancer and the second cause of cancer-related death in men after lung cancer. Differentiation of prostate adenocarcinoma from benign prostate lesions and hyperplasia sometimes cannot be done on the basis of morphologic findings. Considering the fact that in the prostate adenocarcinoma there is no basal cell layer, basal cell markers can help to differentiate prostate adenocarcinoma from cancer mimickers. We studied 98 prostate biopsy blocks (40 adenocarcinoma and 58 benign lesions) for basal cell marker expression. p63 and 34βE12 were negative in all prostate adenocarcinoma specimens, but all benign prostate hyperplasia and high grade intraepithelial neoplasia cases expressed them. Basal cell markers can help to distinguish prostate adenocarcinoma from cancer mimickers.

P0067 Basal cell markers for differentiation of prostate adenocarcinoma from cancer mimickers

<h3>Background</h3> Prostate cancer is the leading cause of cancer and the second cause of cancer-related death in men after lung cancer in the world. Differentiation of prostate adenocarcinoma from benign prostate lesions and hyperplasia sometimes cannot be done on the basis of morphological findings. As there is no basal cell layer in prostate adenocarcinoma, basal cell markers could help to differentiate prostate adenocarcioma from cancer mimickers. <h3>Methods</h3> We studied 98 prostate biopsies (40 adenocarcinoma and 58 benign lesions) for expression of basal cell markers. <h3>Findings</h3> P63 and 34<i>β</i>E12 were negative in all prostate adenocarcinoma specimens, but all benign prostate hyperplasia and high grade intraepithelial neoplasia cases expressed them. <h3>Interpretation</h3> Basal cell markers can help to distinguish prostate adenocarcioma from cancer mimickers.

Comparison of two gastric cancer screening schemes in a high-risk population

To evaluate the effects of two gastric cancer screening schemes for early detection of gastric cancer in a high-risk population. A cluster random sampling method was used to select local residents aged 40-69 years from Linqu County, Shandong Province. "Serum pepsinogen initial screening combined with further endoscopic examination (PG scheme)" and "direct endoscopic examination (endoscopy scheme)" were conducted. The associations between screening schemes and detection rates of gastric cancer, and early gastric cancer/high-grade intraepithelial neoplasia were evaluated by unconditional logistic regression analysis. Overall, 3654 and 2290 participants completed PG and endoscopy schemes, respectively. A total of 11 (0.30%) cases of gastric cancer and 10 (0.27%) cases of high-grade intraepithelial neoplasia were detected by PG scheme, of which 7 (0.19%) cases were early gastric cancer. While, 19 (0.83%) cases of gastric cancer and 10 (0.44%) cases of high-grade intraepithelial neoplasia were detected by endoscopy scheme, with 12 (0.52%) cases of early gastric cancer. Compared with the PG scheme, the endoscopy scheme had a significantly higher detection rates of gastric cancer (OR = 2.83, 95%CI 1.34-5.98), and early gastric cancer/high-grade intraepithelial neoplasia (OR = 2.12, 95%CI 1.12-4.02). The endoscopy scheme is more effective in the detection of gastric cancer in a high-risk population, particularly for early gastric cancer/high-grade intraepithelial neoplasia than the PG scheme.

Pathological features of gastro-esophageal high-grade intraepithelial neoplasia： a pre- and post-procedure comparative study

Objective To investigate the pathological features of gastro-esophageal high-grade intraepithelial neoplasia （HGIEN） confirmed by biopsy and to compare the differences of its diagnosis after endoscopic resection. Methods Data of 147 patients with gastro-esophageal HGIEN confirmed by biopsy, who underwent EMR or ESD in recent 4 years were analyzed for the pathological findings of pre- and post- procedures. Results Among 147 cases of HGIEN diagnosed by endoscopic biopsy, 106 lesions were in esophagus and 41 in stomach. After endoscopic resection, intraepithelial neoplasia was confirmed in 97 （66%）, and cancer was diagnosed in 50 （34%）, of which submucosal layer was involved in 11. There were 34 cases of adenocarcinoma and 16 squamous cell carcinomas, in which 22 cases （44%） were poorly or moderately differentiated. Conclusion More than one third cases of biopsy diagnosed HGIEN are confirmed to be carcinoma after endoscopic resection, which needs active therapeutic measures. Key words: High-grade intraepithelial neoplasia; Endoscopic surgical procedures; Biopsy; Clinical pathology

Expression of Skp2 in cervical squamous cell carcinoma and precancerous lesions and its correlation with HPV16/18 infection

To study the expression of Skp2 in cervical squamous cell carcinoma (SCC) and its precancerous lesions, and to investigate its relationship with human papillomavirus (HPV) infection. The expression of Skp2 protein and HPV16/18 DNA was determined using immunohistochemistry and in-situ hybridization in 30 cases of normal cervical squamous epithelium, 29 cases of low-grade intraepithelial neoplasia, 31 cases of high-grade intraepithelial neoplasia and 31 cases of cervical SCC. Skp2 expression was not detected in normal cervical squamous epithelium and no significant difference was obtained statistically on Skp2 expression between normal cervical squamous epithelium and low-grade intraepithelial neoplasia (P > 0.05). However, the expression of Skp2 gradually increased with elevation of epithelial lesion grading in an order from low to high grade and to cervical SCC (P < 0.01). The positive rate of HPV16/18 DNA in cases of normal cervical squamous epithelium, low-grade, high-grade intraepithelial neoplasia and cervical SCC was significantly different (P < 0.01), although both high-grade intraepithelial neoplasia and cervical SCC had a similar high HPV infection rate up to 96.8%. There was no correlation obtained between Skp2 expression and HPV16/18 infection in low-grade intraepithelial neoplasia. In contrast, expression of Skp2 and HPV infection were significantly correlated in both high-grade intraepithelial neoplasia and cervical SCC (gammaH = 0.373, gammaC = 0.416, P < 0.05). Abnormal expression of Skp2 is present mainly in high-grade cervical intraepithelial neoplasia and invasive carcinoma, which may be considered as a surrogate marker for the high-grade lesions. Skp2 may play a key role in the development of cervical squamous carcinoma induced by HPV16/18 infection, through E7-Skp2-Rb signaling pathway.

Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma

Activation of the Raf/MEK/ERK (MAPK) signal transduction cascade by RAS mutations has been found in a variety of human cancers. Mutations of BRAF provide an alternative route for activation of this signalling pathway. To determine the role of mutations in BRAF and KRAS2 in the neoplastic progression of Barrett's adenocarcinoma, we analysed both genes for common mutations. After microdissection, DNA of 19 Barrett's adenocarcinomas, 56 Barrett's intraepithelial neoplasias (n=29 low-grade intraepithelial neoplasia (LGIN) and n=27 high-grade intraepithelial neoplasia (HGIN)), 30 Barrett's mucosa without neoplasia and normal squamous, as well as gastric epithelium, were analysed for BRAF and KRAS2 mutation. Activating BRAF mutations were identified in 2/19 Barrett's adenocarcinomas (11%) and in 1/27 HGIN (4%). KRAS2 mutations were found in four out of 19 (21%) Barrett's adenocarcinomas examined and in three cases of HGIN (11%). In LGIN as well as in normal gastric or oesophageal mucosa, neither BRAF nor KRAS2 mutations were detected. All lesions with KRAS2 mutations had an intact BRAF gene. The status of mismatch-repair proteins was neither related to BRAF nor KRAS2 mutations. These data indicate that RAS or BRAF mutations are detected in about 32% of all Barrett's adenocarcinomas. We conclude that the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett's adenocarcinoma.

MHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma.

Colorectal tumorigenesis has been associated with the progressive acquisition of a variety of genetic alterations. These include mutations of the Ki-ras proto-oncogene in codons 12 and 13, which account for 85% of genetic changes in colorectal cancer. In murine in vitro models of oncogenic transformation, an association between ras-mediated transformation and downregulation of different components of the MHC class I antigen processing machinery (APM) has been described. In order to investigate whether this association also exists in human tumors, 10 cases of high-grade intraepithelial neoplasia (HIN), as well as primary tumors and autologous lymph node metastases from 42 patients with colorectal carcinoma, were monitored by allele-specific restriction analysis for Ki-ras mutations. In parallel, APM component expression and tumor cell proliferation were analyzed by immunohistochemistry. In comparison to autologous colorectal mucosa, TAP1, LMP2 and tapasin loss was found in 68%, 67% and 80% of HIN, respectively. In contrast, impaired TAP1, LMP2 and tapasin expression was found in 42%, 42% and 63% of primary adenocarcinomas of stage III disease and in 63%, 47% and 79% of the matched lymph node metastases, respectively. More than 60% of colorectal tumor lesions with TAP1, LMP2 and/or tapasin defects displayed Ki-ras mutations. The frequency of TAP1, LMP2 and tapasin loss varied between 33% of primary adenocarcinomas, 40% of HIN to approximately 67% of metastases. These data suggest that i) APM component deficiencies occur more frequently in Ki-ras-mutated colorectal carcinoma lesions and ii) APM abnormalities in conjunction with Ki-ras mutations appear to be associated with disease stage. These findings support the hypothesis that Ki-ras mutations may contribute to immune escape mechanisms of tumors by downregulating the MHC class I APM component expression.