The aim of this study was to analyze oncologic outcomes after transanal local excision (LE) to ensure adequate surveillance of recurrence in order to treat with curative intent.
Between January 2000 and June 2009, 102 patients who underwent transanal LE for rectal adenocarcinoma were retrospectively reviewed.
Of the 102 patients, 53 (52.0%) were male. The mean age was 57 ± 11 years. Postoperative pathologic examination revealed 93 cases (91.2%) of pathologic T stage (pT)1 and 9 cases (8.8%) of pT2. Forty-eight patients (47.1%) underwent adjuvant postoperative radiotherapy. The median follow-up interval was 60 months (range, 3 to 146 months). Seven (6.9%) out of 15 patients who suffered recurrence had locoregional recurrence, three (2.9%) had systemic recurrence and five (4.9%) had both systemic and locoregional recurrence. The latter five patients and two of the three patients with systemic recurrence died because of the disease recurrence. On the other hand, only one of the seven patients with locoregional recurrence died because of disease recurrence.
Systemic recurrence after transanal LE results in fatal consequences. Therefore, not only is it important to identify ideal candidates for LE, but intensive postoperative surveillance is important as well to identify curable recurrence as soon as possible.
Rectal neoplasms; Local excision
The standard treatment for patients with locally advanced rectal cancer is preoperative chemoradiotherapy followed by total mesorectal excision. This approach is supported by randomized trials, but there are still many unanswered questions about the multimodal management of rectal cancer. In surgical terms, these include the optimal time interval between completion of chemoradiotherapy and surgery; adequate distal resection margin and circumferential radial margin; sphincter preservation; laparoscopic surgery; and conservative management, including a 'wait and see' policy and local excision. This review considers these controversial issues in preoperative chemoradiotherapy.
Rectal cancer; Chemoradiotherapy; Surgical procedures
The objective of the current study was to identify the clinicopathological risk factors affecting recurrence after a curative resection for stage I colorectal cancer.
We retrospectively studied 434 patients who underwent a curative resection for stage I colorectal cancer between January 1999 and December 2004. Postoperative oral chemotherapy was performed in 189 patients (45.3%). The following prognostic factors were correlated with recurrence: age, gender, preoperative carcinoembryonic antigen level, location of tumor, T stage, size of tumor, histologic differentiation, growth pattern, and lymphovascular invasion. The median follow-up duration was 65 months.
The overall recurrence rate was 4.6% (20/434). The median time to recurrence was 33 months. Two-thirds of the recurrence occurred more than two years after surgery. Risk factors associated with recurrence were rectal cancer (P = 0.009), T2 stage (P = 0.010), and infiltrative growth pattern (P = 0.020). A Cox proportional hazards regression analysis demonstrated that the infiltrative growth pattern was an independent predictor for recurrence. Tumor cell budding was observed in all pathologic reviews with recurrence.
Long-term follow-up is necessary for stage I colorectal patients with high risk factors like rectal cancer, T2 stage, and infiltrative growth pattern.
Colorectal neoplasms; Recurrence; Risk factors
This current study examined the clinicopathologic characteristics of patients with splenic flexure (SF) colon cancer and the association with the surgical outcomes to find the optimal procedure to treat this malady.
Materials and Methods
A total of 167 operated patients with SF colon cancer were consecutively recruited between 1993 and 2003. The clinicopathological, operative and survival data was reviewed and analyzed.
For the SF colon cancer patients, the proportion of males was higher than that for the right-sided colon patients or the sigmoid-descending junction & sigmoid (SD & S) colon patients (p≤0.05, respectively) and the age at the time of diagnosis was younger (p≤0.05). Obstruction was more frequent in the patients with SF colon cancer than that for the patients with colon cancer at other sites (p≤0.001). The incidence of mucinous adenocarcinoma for the SF patients was similar to that for the patients with right-sided colon cancer, but it was higher than that for the patients with SD & S colon cancer (11.4% vs. 6.5%, p=0.248 or 2.5%, respectively, p=0.001). Disease-free and overall survival did not differ between the patients who underwent a left hemicolectomy and extended surgery such as combined splenectomy or subtotal colectomy. Multivariate analysis showed that old age (≥60 years) and a N1-2 and M1 status were the independent risk factors for overall survival.
The SF colon cancers exhibited exclusively different characteristics as compared to colon cancers at other site colon cancers. It appears that left hemicolectomy was generally sufficient for a satisfactory oncological outcome, obviating concurrent splenectomy.
Colonic neoplasms; Left colic flexure; Colectomy; Splenectomy
AIM: To investigate alternative or subordinate pathways involved in colorectal tumorigenesis and tumor growth, possibly determining at-risk populations and predicting responses to treatment.
METHODS: Using microarray gene-expression analysis, we analyzed patterns of gene expression relative to canonical molecular changes and clinicopathological features in 84 sporadic colorectal cancer patients, standardized by tumor location. Subsets of differentially expressed genes were confirmed by real-time reverse-transcript polymerase chain reaction (RT-PCR).
RESULTS: The largest number of genes identified as being differentially expressed was by tumor location, and the next largest number by lymphovascular or neural invasion of tumor cells and by mismatch repair (MMR) defects. Amongst biological processes, the immune response was significantly implicated in entire molecular changes observed during colorectal tumorigenesis (P < 0.001). Amongst 47 differentially expressed genes, seven (PISD, NIBP, BAI2, STOML1, MRPL21, MRPL16, and MKKS) were newly found to correlate with tumorigenesis and tumor growth. Most location-associated molecular changes had distinct effects on gene expression, but the effects of the latter were sometimes contradictory.
CONCLUSION: We show that several differentially expressed genes were associated with canonical molecular changes in sporadic colorectal cancers, possibly constituting alternative or subordinate pathways of tumorigenesis. As tumor location was the dominant factor influencing differential gene expression, location-specific analysis may identify location-associated pathways and enhance the accuracy of class prediction.
Colorectal adenocarcinomas; Sporadic; Gene expression; Profiling; Tumorigenesis
To determine whether family history of cancer may be a risk factor for the mutator phenotype in colorectal cancer, we recruited 143 consecutive colorectal cancer patients with a family history of accompanying cancers not meeting the Amsterdam criteria. Microsatellite instability (MSI) at 5 markers, hMLH1-promoter methylation, and expression of mismatch repair (MMR) proteins (hMLH1, hMSH2, hMSH6, hMPS1, and hPMS2) were determined. Among the relatives of familial colorectal cancer patients, colorectal cancer was the most common tumor type. Of the proband colorectal cancers, 26 (18.2%) showed high-level MSI (MSI-H); 47 additional tumors with mutator phenotype (32.9%) were identified by hMLH1-promoter methylation and/or loss of MMR protein expression. Mutator phenotype was associated with right-sided colon cancer and the type of accompanying cancer. Family history, which was differentially quantified according to the degree of relatives and the type of accompanying cancers, effectively discriminated MSI-H from microsatellite stable (MSS) and low-level microsatellite instability (MSI-L) and mutator phenotypes. Our findings indicate that familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers and that family history could be correlated with microsatellite instability.
Familial Colorectal Cancer; Family History; Mutator Phenotype; Ncrosatellite Instability
To assess the incidence and factors predictive of early postoperative complications in Korean patients who undergo surgery for Crohn's disease (CD).
We retrospectively assessed 350 patients (246 males, 104 females; mean age, 30 ± 9 years) who underwent surgery for primary or recurrent CD at Asan Medical Center between January 1991 and May 2010. The incidence and predictive factors of early postoperative complications were analyzed by both univariate and multivariate analyses.
Of the 350 patients, 81 patients (23.1%) developed postoperative complications, the most common being septic complications (54 patients), including 19 cases of wound infection. Thirty patients (8.6%) required re-operations, and only one patient died. Multivariate analysis showed that four factors were independently associated with a high risk of early postoperative complications; preoperative moderate to severe anemia (hematocrit concentration <30%; odds ratio [OR], 3.1; 95% confidence interval [CI], 1.6 to 5.9), hypoalbuminemia (serum albumin level <3.0 g/dL; OR, 2.6; 95% CI, 1.4 to 4.7), emergency surgery (OR, 4.0; 95% CI, 1.5 to 10.6), and covering stoma (OR, 2.6; 95% CI, 1.3 to 5.4). Correction of preoperative moderate to severe anemia and hypoalbuminemia decreased the incidence of postoperative complications. Mean hospital stay was significantly longer in patients with than without postoperative complications (31.3 ± 27.2 days vs. 10.3 ± 3.8 days, P < 0.001).
Preoperative anemia, low albumin level, emergency surgery, and covering stoma significantly increased the risk of early postoperative complications in patients with CD. Correcting preoperatively deficient nutritional factors may reduce postoperative morbidities.
Crohn disease; Surgery; Korea; Risk factors; Postoperative complications
Identification of subgroups of patients who differ in their response to treatment could help to establish which of the best available chemotherapeutic options are best, based on biological activity. In metastatic colorectal cancer (CRC), novel molecular-targeted agents that act on pathways that regulate cell growth, the cell cycle, apoptosis, angiogenesis, and invasion are being developed. Here, we employed an in vitro chemosensitivity assay to evaluate the biological efficacy of conventional monotherapies and combination chemotherapy with targeted drugs.
The chemosensitivities of 12 CRC cell lines to the established regimens FOLFOX (5-fluorouracil [5-FU] + leucovorin + oxaliplatin) and FOLFIRI (5-FU + leucovorin + irinotecan) and to therapy with these regimens in combination with the biologically targeted drugs bevacizumab or cetuximab were comparatively evaluated for their effects on apoptotic and autophagic cell death processes, angiogenesis, and invasion.
Each of the chemotherapeutic regimens promoted apoptotic cell death and invasion. All drug regimens caused significantly greater apoptotic cell death with activation of caspase-3 in SW480 cells compared to other cells, effects that were associated with a remarkable reduction in matrix metalloproteinase-9 activity. The FOLFOX regimen more effectively promoted apoptotic cell death, angiogenesis, and invasion than the FOLFIRI regimen. Combination therapy with FOLFOX/FOLFIRI regimen and bevacizumab produced a moderate angiogenesis-blocking effect in most cell lines.
The results validate our in vitro chemosensitivity assay, and suggest that it may be applied to help determine adequate regimens in individual CRC patients based on the biological characteristics of their tumors.
Colorectal neoplasms; Chemotherapy; Pharmacological biomarkers
To evaluate the safety and effectiveness of a 20-mm diameter dual-design expandable colorectal stent for malignant colorectal obstruction.
Materials and Methods
The study series included 34 patients with malignant colorectal obstruction who underwent implantation of a 20-mm dual-design expandable colorectal stent in our department between March 2009 and June 2010. The 20-mm dual-design expandable colorectal stent was placed by using a 3.8-mm delivery system that had 28-mm diameter proximal and distal ends. Among the 34 patients, stent placement for palliation was performed in 20 patients, while stent placement for bridge to surgery was performed in 14 patients.
A 97% (33 of 34) success rate was achieved for the stent placement. The perforation rate in the bridge to surgery group was 7% (1 of 14), compared to 0% (0 of 19) in palliative group. Migration occurred in one of 33 patients (3%) at 30 days after stent placement.
The placement of a 20-mm diameter dual-design stent appears to be clinically safe and effective for the management of colorectal obstruction, with low perforation and migration rates.
Colorectal cancer; Stent; Dual-design; Expandable
The aim of this study was to evaluate outcomes of a total colectomy with ileorectal anastomosis in patients with slow transit constipation.
A retrospective review of 37 consecutive patients with slow transit constipation who underwent a total colectomy between 1994 and 2008 was undertaken. Preoperative and postoperative Wexner's constipation scores were collected and used to evaluate the outcomes after surgical treatment. Also patients' postoperative satisfaction scores were collected using a 4-point scale.
The 37 patients consisted of 31 women and 6 men, with a median age of 41 years (range, 17 to 71 years). Pre- and post-operative Wexner's scores were collected from 33 patients (89.1%), and the mean preoperative Wexner's score was 19.3 (range, 11 to 24), which decreased to an average post-operative score of 2.3 (range, 0 to 8). Neither intraoperative complications nor postoperative mortalities were noted. Five patients (13.5%) had early postoperative complications, and the most common complication was postoperative ileus (10.8%). Seven patients (18.9%) had late postoperative complications, and postoperative ileus (10.8%) was also the most common. Twenty seven of 33 patients were satisfied with their surgical outcome (81.8%).
A total colectomy with ileorectal anastomosis might be an effective surgical procedure with acceptable morbidity to treat medically intractable slow transit constipation.
Colonic inertia; Colectomy; Treatment outcome; Postoperative complication
To evaluate the comparative therapeutic efficacy of radiofrequency ablation (RFA) and hepatic resection for the treatment of colorectal liver metastasis (CRLM).
Between 1996 and 2008, 177 patients underwent RFA, 278 underwent hepatic resection and 27 underwent combination therapy for CRLM. Comparative analysis of clinical outcomes was performed including number of liver metastases, tumor size, and time of CRLM.
Based on multivariate analysis, overall survival (OS) correlated with the number of liver metastases and the use of combined chemotherapy (P < 0.001, respectively). Disease-free survival (DFS) also correlated with the number of liver metastases (P < 0.001). In the 226 patients with solitary CRLM < 3 cm, OS and DFS rates did not differ between the RFA group and the resection group (P = 0.962 and P = 0.980). In the 70 patients with solitary CRLM ≥ 3 cm, DFS was significantly lower in the RFA group as compared with the resection group (P = 0.015).
The results indicate that RFA may be a safe alternative treatment for solitary CRLM less than 3 cm, with outcomes equivalent to those achieved with hepatic resection. A randomized controlled study comparing RFA and resection for patients with single small metastasis would help to determine the most efficient treatment modalities for CRLM.
Radiofrequency ablation; Hepatectomy; Colorectal neoplasms; Liver metastasis
Hereditary colorectal cancer develops through a series of well-defined genetic and histological changes. However, elucidation of the canonical pathway based on hereditary colorectal cancer has not provided a clear explanation of the molecular mechanisms of sporadic colorectal cancer. To identify the alterative pathways involved in sporadic colorectal tumorigenesis, we performed gene expression analysis in patients with sporadic colorectal tumors. A comparison analysis of gene expression profiles revealed a pattern of upregulation of small proline rich repeat protein 3 (SPRR3) in tumor samples. SPRR3 has previously been reported to be downregulated in esophageal cancer. However, in the present study, we observed that SPRR3 was strongly upregulated in 31 of 35 samples of sporadic colorectal tumors (88%). We also determined that overexpression of SPRR3 not only accelerates colorectal cancer cell proliferation but also is associated with lymphovascular invasion in colorectal cancer. Moreover, AKT was activated and p53 levels were decreased in cells that overexpressed SPRR3. In contrast to the pattern seen in esophageal cancer, these results suggest that increased expression of SPRR3 is involved in colorectal tumorigenesis.
Integrative genetic changes were examined in relation to tumor growth and progression of sporadic colorectal cancers. Ninety-two sporadic colorectal cancer patients and 12 human colorectal cancer cell lines were evaluated. Genetic changes in representative steps of colorectal tumorigenesis were determined. Biological characteristics, i.e., clinicopathologic parameters, expression of invasion-associated molecules, and in vitro invasion and migration, in association with these changes were further analyzed. Adenomatous polyposis coli (APC) and/or Wnt-activated alterations occurred in 66% patients, whereas mismatch repair (MMR) defects and/or RAF-mediated alterations were identified in 47% patients. The crossover rate between these two alterations was 26%. Differential mRNA expression of ARK5 was closely associated with that of MMP2, MMP9, and S100A4 (P≤0.044-0.001). Additionally, enhanced ARK5 mRNA expression was more frequent in tumors displaying RAF-mediated alterations and crossover pathways (P=0.01 and 0.03, respectively). Upregulation of CEA mRNA was more common in the advanced stages (P=0.034), while VEGF expression was greater in poorly differentiated or mucinous tumors (P=0.042). The high expressions of MMP2 and MMP9 were closely associated with invasion and migration of colorectal tumors and cell lines. Our results conclusively show that specific pathways of colorectal tumorigenesis are closely associated with characteristic tumor growth and invasion.
Colorectal Neoplasms; Sporadic; Tumorigenesis; Molecular; Growth; Invasion
To determine the role of methylation in colorectal cancer patients with a family history, we enrolled 25 colorectal cancer patients with a family history of colorectal cancer but without a mutation in the hMLH1 and hMSH2 genes. Thirty patients with sporadic colorectal cancer were included as control. The methylation status of COX2, MGMT, hMLH1, TIMP3, p16, and MINT2 in normal mucosa and tumor were assessed using methylation-specific PCR. In patients with a family history, the methylation frequency ranged from 4.0% for TIMP3 to 44.4% for MGMT, whereas, in patients with sporadic colorectal cancer, it ranged from 6.7% for TIMP3 to 50.0% for p16. Nine of the 25 patients with family history (36.0%) were classified as methylation-prone, and nine of the 30 patients with sporadic cancers (30.0%) were as methylation-prone, making their methylation indices 0.19 and 0.16, respectively (p=0.522). As for the individual genes, the methylation rate of MGMT was higher in colorectal cancer patients with family history (44.0% vs. 13.0%, p=0.016), whereas the methylation rate of p16 was higher in sporadic colorectal cancers (50.0% vs. 8.7%, p=0.046). While CpG island methylation of tumor suppressor genes may play a role in colorectal carcinogenesis, the genes involved may be different between tumors of patients with and without a family history of colorectal cancer.
Colorectal Neoplasms; Familial; Carcinogenesis; Methylation; Microsatellite Instability
Granulocytic sarcoma is an extramedullary tumor composed of immature granulocytic cells. These tumors usually occur simultaneously with or follow after the onset of acute myeloid leukemia (AML) or other myeloproliferative disorders. Rarely, it is the first manifestation of AML which appears several months before the onset of leukemia. We report a case of a 48-year-old man presenting with symptoms of small bowel obstruction. Laparotomy and open biopsy were performed. Immunohistochemical studies showed that the neoplastic cells were of myeloid lineage positive for myeloperoxidase and leukocyte common antigen, but negative for CD3, 20, 56, 79a, and cytokeratin. Initially, there was no evidence of blood or bone marrow involvement suggesting acute leukemia or other myeloproliferative disorders. The findings were consistent with the diagnostic findings of solitary granulocytic sarcoma (preleukemic). However, one month later, bone marrow biopsy revealed 57% myeloblasts. Sequentially, the patient developed FAB M2 acute myeloid leukemia. Induction chemotherapy including cytarabine and idarubicine was done which led to complete remission. Allograft bone marrow transplantation was performed later, and there is no evidence of recurrence till present.
Granulocytic sarcoma; Acute myeloid leukemia; Small bowel obstruction
Colonic hamartomas are rare polypoid lesions. We report an unusual case of multiple colonic hamartomatous polyps, including a giant hamartoma, unrelated to hereditary or familial polyposis syndromes, in a 48-year-old man. The diameter of the largest polyp was 9.5 cm, and endoscopy revealed that the lesion caused colonic obstruction. The clinical, endoscopic and histological aspects of this case are discussed.
Hamartoma; giant hamartoma
Capecitabine is an oral fluoropyrimidine carbamate and it is known as an effective radiosensitizer. Capecitabine and its metabolite reach their peak concentration in the plasma at 1~2 hours after a single oral administration of capecitabine and the levels fall rapidly thereafter. To verify the radiosensitizing effect of capecitabine that is based on such pharmacokinetic characteristics, we performed a retrospective analysis on the optimal timing of capecitabine administration with performing preoperative chemoradiation for locally advanced rectal cancer.
Materials and Methods
Among 171 patients who were treated with preoperative radiotherapy and concurrent capecitabine administration for rectal cancer, 56 patients were administered capecitabine at 1~2 hours before radiotherapy (group A), and at other time in the other 115 patients (group B). Total mesorectal excision was done at 4 to 6 weeks after the completion of chemoradiation. The radiosensitizing effect of capecitabine was evaluated on the basis of the pathological response.
Complete pathological regression of the primary tumor was observed in 12 patients (21.4%) for group A and in 11 patients (9.6%) for group B (p=0.031). Residual disease less than 0.5 cm (a good response) was observed in 19 patients (33.9%) for group A and in 23 patients (20.0%) for group B (p=0.038). On multivariate analysis, the capecitabine ingestion time showed marginal significance.
When performing preoperative chemoradiation for locally advanced rectal cancer, the radiosensitizing effect of capecitabine was enhanced when it was administered 1 hour before radiotherapy.
Rectal neoplasms; Combined modality therapy; Capecitabine
Serum carcinoembryonic antigen (s-CEA) is used to detect recurrence and predict prognosis in colorectal cancer. However, the cutoff values of s-CEA for prognosis have not been determined. We therefore tried to determine the preoperative s-CEA levels predictive of survivals in colorectal cancer patients. We retrospectively analyzed the medical records of 989 patients who underwent curative resection for colorectal cancer between July 1990 and December 1997, with a mean follow-up of 46 months (range, 3-129 months). When patients were divided into four subgroups with the cutoff values of s-CEA at 3,6, and 17 ng/mL, their 5-yr disease-free survival rates were 85.3% (<3.0 ng/mL), 70.0% (3-6 ng/mL), 64.2% (6-17 ng/mL), and 55.2% (>17 ng/mL) (p<0.001). Multivariate analysis showed that factors predictive of survival included age (p=0.028), tumor stage (p<0.001), cell differentiation (p=0.016), and gross type (p=0.007), location (p=0.003) and preoperative s-CEA (p<0.001). Using the above-described cutoff levels, a significant difference in survival was observed only in patients with stage III tumors (p=0.007) when analyses were performed by stage. We can suggest the new cutoff values of s-CEA used in the present study.
Carcinoembryonic Antigen; Prognosis; Colonic Neoplasm
Lymph node involvement is the most important prognostic factor of rectal cancer. Cancer originating from sites other than the rectum rarely metastasizes to the mesorectal lymph node. We report a rectal cancer patient with a synchronous metastatic prostatic carcinoma to the mesorectal lymph node.
Mesorectal; Lymph node; Prostatic carcinoma
Capecitabine is an attractive oral chemotherapeutic agent that has a radiosensitizing effect and tumor-selectivity. This study was performed to evaluate the efficacy and toxicity of preoperative chemoradiation therapy, when used with oral capecitabine, for locally advanced rectal cancer.
Materials and Methods
A prospective phase II trial of preoperative chemoradiation for locally advanced adenocarcinomas of the lower two-thirds of the rectum was conducted. A radiation dose of 50 Gy over five weeks and a daily dose of 1650 mg/m2 capecitabine in two potions was administered during the entire course of radiation therapy. Surgery was performed with standardized total mesorectal excision four to six weeks after completion of the chemoradiation.
Between January 2002 and September 2003, 61 patients were enrolled onto this prospective phase II trial. The pretreatment clinical stages were T3 in 64% (n=39), T4 in 36% (n=22) and N1-2 in 82% (n=50) of these patients. Fifty-six (92%) patients completed the chemoradiation as initially planned and a complete resection performed in 58 (95%). Down-staging was observed in 45 patients (74%) and a pathologic complete response in 6 (10%). Among the 37 patients with tumors located within 5 cm from the anal verge on colonoscopy, 27 (73%) underwent a sphincter-preserving procedure. No grade 3 and 4 proctitis or hematological toxicities were observed.
Preoperative chemoradiation therapy with capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation, with a low toxicity profile. This combined modality can be regarded as a safe and effective treatment for locally advanced rectal cancer.
Rectal cancer; Preoperative; Chemoradiotherapy; Capecitabine
Isolated diaphragmatic metastasis arising from colorectal cancer has been reported only one case in the literature presently. Here, we presented a new case and discussed the possible pathogenesis and the treatment options. A 42-year-old male patient had received anterior resection for sigmoid colon cancer. Although the increased serum CEA level was detected 20 months after the surgery, metastatic lesion could not be detected by repeated colonoscopy, CT scan, bone scan or PET scan for 35 months. We could detect a suspicious metastatic lesion on the liver by CT scan at 56 month after the surgery. During a second-look operation, we found a solitary metastasis on the diaphragm and removed it along with the 1 cm tumor-free resection margin. Although the prognosis associated with skeletal metastasis is poor, the complete resection of isolated diaphragmatic metastasis and subsequent appropriate adjuvant chemotherapy may achieve a cure the disease provided that other metastatic lesions are absent.
Colorectal neoplasm; Metastasis; Diaphragm; Carcinoembryonic antigen
The high-frequency microsatellite instability (MSI-H) phenotype, frequently identified in hereditary nonpolyposis colorectal cancer (HNPCC), also accounts for approximately 15% of sporadic colorectal cancers. Microsatellite instability (MSI) occurs from the mutational inactivation of the DNA mismatch repair genes, i.e. hMSH2 and hMLH1 in HNPCC, as well as from epigenetic inactivation of hMLH1 in sporadic colorectal tumors. The mutator pathway including microsatellite instability, hMLH1 promoter methylation, and hMSH2 and hMLH1 mutation patterns were identified in 21 sporadic colorectal adenocarcinoma patients younger than 30 yr excluding HNPCC. More than half of tumors showed MSI, with five MSI-H and six MSI-L (low-frequency microsatellite instability). Three of six MSI-H tumors showed the hMLH1 promoter methylation and did not express the hMLH1 protein. On the other hand, all MSI-L and all MSS (microsatellite stable) tumors expressed both hMSH2 and hMLH1 proteins. Two novel mutations, i.e. a missense mutation in hMLH1 and a splice-site alteration in hMSH2, were identified in two patients respectively. Although mutator pathway was implicated in younger-age-onset colorectal carcinogenesis, many tumors appeared to evolve from different genetic events other than hMSH2 and hMLH1 mutations frequently identified in HNPCC.
Colorectal signet-ring cell carcinoma (SRCC) is a rare type of adenocarcinoma and presents with distinctive clinicopathological features. This study was performed to assess the biological characteristics of colorectal SRCC regarding the E-cadherin expression. Seventeen patients with primary colorectal SRCC were identified and their clinicopathological characteristics were analyzed. The mean age of the 17 patients was 45.3 yr (14-68). Immunohistochemical staining of E-cadherin and beta-catenin were performed in ten colorectal SRCCs and in 30 ordinary colorectal adenocarcinomas as control. Primary colorectal SRCC occurred in 0.7% of 2,388 colorectal adenocarcinomas. Most patients had advanced stage tumor at surgery (stage III and IV, AJCC: 82%). Five-year survival rate was 16%. Peritoneal seeding was the most common recurrence pattern (41%) and liver metastasis was not identified. All SRCCs showed a markedly reduced or absent expression of E-cadherin on immunohistochemical staining, whereas seven (23.3%) of ordinary carcinomas showed reduced expression, thereby indicating a significant difference between the two groups (p<0.005). In immunohistochemical staining for beta-catenin, eight of ten SRCCs showed reduced membrane expression that did not attain statistical significance compared to ordinary adenocarcinomas. It is suggested that aberrant E-cadherin expression may explain the distinct clinicopathological features in primary colorectal SRCC.
Autophagy has paradoxical and complex functions in cancer development, and autophagy-related genes (ATG) are key regulators in autophagy. Until now, more than 30 different ATG proteins have been identified in yeast, and their mammalian counterparts also have been reported. Although the roles of a few ATG proteins in cancer have been characterized, the role of ATG10 is almost completely unknown.
To investigate the clinicopathological role of ATG10 in colorectal cancer, we analyzed ATG10 expression in colorectal cancer tissues and cell lines. Protein expression analysis showed that ATG10 is highly increased in colorectal cancer (tissue - 18/37 cases, 48%; cell line –8/12 cell lines, 66%). Immunohistochemical analysis with clinicopathological features indicated a strong association of the up-regulation of ATG10 with tumor lymph node metastasis (p = 0.005) and invasion (p<0.001). Moreover, both 5-year disease free survival and overall survival rates of patients bearing tumors that did not express ATG10 were significantly higher than those of patients bearing ATG10-expressing tumors (p = 0.012).
Increased expression of ATG10 in colorectal cancer is associated with lymphovascular invasion and lymph node metastasis indicating that ATG10 may be a potential prognostic maker in colorectal cancer.