Risk factors for lymph node metastasis in T2 colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Lymph node metastasis (LNM) occurs in 20-25% of patients with T2 colorectal cancer (CRC). Identification of risk factors for LNM in T2 CRC may help identify patients who are at low risk and thereby potential candidates for endoscopic full-thickness resection. We examined risk factors for LNM in T2 CRC with the goal of establishing further criteria of the indications for endoscopic resection. METHODS: MEDLINE, CENTRAL, and EMBASE were systematically searched from inception to November 2023. Studies that investigated the association between the presence of LNM and the clinical and pathological factors of T2 CRC were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Certainty of evidence (CoE) was assessed using the GRADE approach. RESULTS: Fourteen studies (8349 patients) were included. Overall, the proportion of LNM was 22%. The meta-analysis revealed that the presence of lymphovascular invasion (OR, 5.5; 95% CI 3.7-8.3; high CoE), high-grade tumor budding (OR, 2.4; 95% CI 1.5-3.7; moderate CoE), poor differentiation (OR, 2.2; 95% CI 1.8-2.7; moderate CoE), and female sex (OR, 1.3; 95% CI 1.1-1.7; high CoE) were associated with LNM in T2 CRC. Lymphatic invasion (OR, 5.0; 95% CI 3.3-7.6) was a stronger predictor of LNM than vascular invasion (OR, 2.4; 95% CI 2.1-2.8). CONCLUSIONS: Lymphovascular invasion, high-grade tumor budding, poor differentiation, and female sex were risk factors for LNM in T2 CRC. Endoscopic resection of T2 CRC in patients with very low risk for LNM may become an alternative to conventional surgical resection. TRIAL REGISTRATION: PROSPERO, CRD42022316545.

Additional staining for lymphovascular invasion is associated with increased estimation of lymph node metastasis in patients with T1 colorectal cancer: Systematic review and meta-analysis.

OBJECTIVES: Lymphovascular invasion (LVI) is a critical risk factor for lymph node metastasis (LNM), which requires additional surgery after endoscopic resection of T1 colorectal cancer (CRC). However, the impact of additional staining on estimating LNM is unclear. This systematic review aimed to evaluate the impact of additional staining on determining LNM in T1 CRC. METHODS: We searched five electronic databases. Outcomes were diagnostic odds ratio (DOR), assessed using hierarchical summary receiver operating characteristic curves, and interobserver agreement among pathologists for positive LVI, assessed using Kappa coefficients (κ). We performed a subgroup analysis of studies that simultaneously included a multivariable analysis for other risk factors (deep submucosal invasion, poor differentiation, and tumor budding). RESULTS: Among the 64 studies (18,097 patients) identified, hematoxylin-eosin (HE) and additional staining for LVI had pooled sensitivities of 0.45 (95% confidence interval [CI] 0.32-0.58) and 0.68 (95% CI 0.44-0.86), specificities of 0.88 (95% CI 0.78-0.94) and 0.76 (95% CI 0.62-0.86), and DORs of 6.26 (95% CI 3.73-10.53) and 6.47 (95% CI 3.40-12.32) for determining LNM, respectively. In multivariable analysis, the DOR of additional staining for LNM (DOR 5.95; 95% CI 2.87-12.33) was higher than that of HE staining (DOR 1.89; 95% CI 1.13-3.16) (P = 0.01). Pooled κ values were 0.37 (95% CI 0.22-0.52) and 0.62 (95% CI 0.04-0.99) for HE and additional staining for LVI, respectively. CONCLUSION: Additional staining for LVI may increase the DOR for LNM and interobserver agreement for positive LVI among pathologists.

The effect of staple height and rectal-wall thickness on anastomotic leakage after laparoscopic low anterior resection.

BACKGROUND: The aim of this study was to evaluate the effect of staple height and rectal wall thickness on the development of an anastomotic leak after laparoscopic low anterior resection performed with the double stapling technique. METHODS: One hundred ninety-nine patients treated from 2013 to 2021 were enrolled. Patients were divided into two groups: those who developed an anastomotic leak (AL (+)) and those who did not (AL (-)). Clinicopathological factors were compared between the groups. RESULTS: Anastomotic leaks were observed in 8/199 patients (4%). A 1.5 mm linear stapler was used for 35/199 patients (17%), 1.8 mm for 89 (45%), and 2 mm for 75 (38%). In the AL (+) group (n = 8), lower staple height (1.5 mm or 1.8 mm) was used more frequently than in the AL (-) group (n = 191). Rectal wall thickness and the rectal wall thickness to staple height ratio was significantly (p < .05) greater in the AL (+) group. However, rectal wall thickness was significantly (p < .05) greater in patients who received neoadjuvant treatment and those with advanced T stage (T3,4) lesions. CONCLUSION: Linear stapler staple height and rectal wall thickness are significantly associated with the development of an anastomotic leak after laparoscopic low anterior resection. Larger staples should be selected in patients with a thicker rectal wall due to neoadjuvant treatment or adjacent advanced rectal tumors.

Metachronous Krukenberg tumor from adenocarcinoma in a Meckel's diverticulum: a case report.

Adenocarcinoma in a Meckel's diverticulum is rare and difficult to diagnose preoperatively. We report the first case of a metachronous Krukenberg tumor from adenocarcinoma in a Meckel's diverticulum. A 45-year-old woman was admitted for recurrent abdominal pain. Computed tomography scan showed a lesion with contrast enhancement, and a Meckel's diverticulum-associated tumor was suspected. Double-ballon enteroscopy revealed intestinal stenosis and biopsy showed adenocarcinoma. Operative findings showed a Meckel's diverticulum with tumor. Histopathological evaluation revealed well-differentiated adenocarcinoma, interrupted by ectopic gastric mucosa, diagnosed as adenocarcinoma in a Meckel's diverticulum. Two years postoperatively, a multi-cystic mass with contrast enhancement was observed in the pelvis on imaging evaluation and oophorectomy performed. Histological examination of the resected ovary showed proliferation of atypical glandular ducts, consistent with metastatic adenocarcinoma. This case demonstrates that adenocarcinoma in a Meckel's diverticulum may result in distant metastases and requires appropriate follow-up.

Goblet cell carcinoid of the rectum: a case report.

BACKGROUND: Goblet cell carcinoid (GCC) is a neuroendocrine tumor usually found in the appendix. GCCs exhibit characteristic findings with mixed endocrine-exocrine features such as staining positive for neuroendocrine markers and producing mucin. The primary GCC of the rectum is exceedingly rare. CASE PRESENTATION: A 77-year-old Japanese male presented with hematochezia. Anal tenderness and a hard mass in the anal canal were found on the digital rectal examination, and colonoscopy was performed. Colonoscopy showed an irregularly shaped mass in the anal canal. Biopsy showed mixed features including adenocarcinoma in situ, well-differentiated adenocarcinoma, and mucinous carcinoma with invasive proliferation. No metastatic lesions were found on the computed tomography scan. Pelvic magnetic resonance imaging scan showed extramural growth of a tumor on the ventral side of the rectum without invasion to the prostate. Laparoscopic abdominoperineal resection was performed. The final diagnosis was well-differentiated adenocarcinoma in the mucosa and goblet cell carcinoid from the submucosa to the adventitia of the rectum. The patient was discharged from the hospital on postoperative day 16. Six months after resection, a computed tomography scan revealed multiple metastatic lesions in the liver. Several chemotherapy regimens were given, and the patient has stable disease 27 months after surgery. CONCLUSION: We present a patient with rectal GCC with metachronous liver metastases. Since GCC grows intramurally and is biologically aggressive compared to typical carcinoid lesions, the disease is usually diagnosed at an advanced stage. The development of optimal adjuvant chemotherapy is needed for those patients.

Four-directional approach to the meso-transverse attachment combined with preoperative radiological vascular simulation facilitates short-term surgical outcomes in laparoscopic transverse colon cancer surgery.

INTRODUCTION: Transverse colon resection is one of the most difficult laparoscopic procedures because of anatomic hazards such as variations in the mesenteric vascular anatomy and the complex structure of organs and surrounding membranes. METHODS: We evaluated the short-term surgical outcomes of laparoscopic transverse colon resection using a creative approach. This approach included preoperative surgical simulation using virtual surgical anatomy by CT, a four-directional approach to the mesentery, and 3-D imaging during laparoscopic surgery. RESULTS: A total of 45 consecutive patients who underwent laparoscopic resection for transverse colon cancer from June 2013 to December 2017 were enrolled in this study. All procedures were completed safely, with minor postoperative complications, including two patients with anastomotic stenosis, two with intra-abdominal phlegmon, one with delayed gastric emptying, and one with pneumonia, all treated non-operatively. There were no conversions to open resection. Operation time was 203 min (range, 125-322 min), and the estimated blood loss during surgery was 5 mL (range, 0-370 mL). The mean postoperative hospital stay was 10 days (range, 7-21 days), and no patients required readmission. CONCLUSION: Short-term surgical outcomes after laparoscopic transverse colon resection demonstrated that this creative approach was safe and feasible. The four-directional approach to the meso-transverse attachment combined with preoperative radiological simulation can facilitate laparoscopic transverse colon surgery.

Utility of preoperative 3-D simulation of laparoscopic lateral pelvic lymph node dissection for advanced rectal cancer: Surgical outcomes of 10 initial cases.

INTRODUCTION: Laparoscopic lateral pelvic lymph node dissection (LPLD) is technically challenging because of the complicated anatomy of the pelvic wall. To overcome this difficulty, we introduced preoperative 3-D simulation. The aim of the study is to investigate the usefulness of preoperative 3-D simulation for the safe conduct of laparoscopic LPLD for rectal cancer. METHODS: After undergoing colonoscopy, patients were brought to the radiology suite where multi-detector row CT was performed. Three-dimensional images were constructed at a workstation and showed branches of the iliac artery and vein, ureter, urinary bladder, and enlarged lymph nodes. All members of the surgical team participated in preoperative simulation using the 3-D images. RESULTS: A total of 10 patients with advanced lower rectal cancer and enlarged lateral pelvic lymph nodes underwent laparoscopic unilateral LPLD after total mesorectal excision, tumor-specific mesorectal excision, or total proctocolectomy. Four of the 10 patients (40%) had variations in pelvic vascular anatomy. The median operative time for unilateral LPLD was 91 min (range, 66-142 min) and gradually declined, suggesting a good learning curve. The median number of lateral pelvic lymph nodes harvested was nine (range, 3-16). The median estimated blood loss was 13 mL (range, 10-160 mL). No conversion to open surgery or intraoperative complications occurred. No patient had major postoperative complications. CONCLUSION: Preoperative 3-D simulation may be useful for the safe conduct of laparoscopic LPLD, especially for surgeons with limited prior experience.

Metachronous solitary metacarpal bone metastasis from rectal cancer.

Metachronous solitary metacarpal bone metastasis from rectal cancer has not been reported previously. Here, we describe a 54-year-old woman who underwent abdominoperineal resection for rectal cancer following neoadjuvant chemoradiotherapy. The resected specimen contained adenocarcinoma with no lymph node metastases (Stage II, T3N0M0); no adjuvant chemotherapy was administered. Fifteen months after surgery, the patient presented with pain and swelling of the right thumb. Radiography revealed metacarpal bone destruction, and fluorine-18 fluorodeoxyglucose positron emission tomography showed uptake only in the metacarpal bone. Open biopsy revealed an adenocarcinoma, and a right thumb resection was performed. Histological examination indicated features of adenocarcinoma similar to the findings of a rectal lesion, leading to a diagnosis of metachronous solitary metacarpal bone metastasis from rectal cancer. The patient remains free of disease after 6 years of follow-up. Our findings suggest that surgical resection may lead to favorable outcomes in patients with resectable solitary bone metastases.

Sigmoid colon carcinoma with focal neuroendocrine differentiation associated with ulcerative colitis: A case report.

INTRODUCTION: Neuroendocrine tumors of the colon and rectum are relatively rare compared to sporadic colorectal carcinoma. There are few reports of neuroendocrine tumors of the colon and rectum in patients with ulcerative colitis. PRESENTATION OF CASE: A patient with sigmoid colon carcinoma with focal neuroendocrine features is presented. A 32-year-old man, who had been followed for ulcerative colitis for 14 years, was found to have carcinoma of the sigmoid colon on routine annual colonoscopy, and he underwent laparoscopic total colectomy. Pathologic examination showed sigmoid colon adenocarcinoma with focal neuroendocrine features. DISCUSSION: Most colorectal carcinomas associated with inflammatory bowel disease are histologically similar to the sporadic type, and tumors with neuroendocrine features are very unusual. CONCLUSION: Very rare case of sigmoid colon carcinoma with neuroendocrine features arising in a patient with UC was described.

Synchronous metastatic squamous cell carcinoma to the colon and cervical lymph nodes from a carcinoma of unknown primary site: A case report.

Metastatic squamous cell carcinoma (SCC) from an unknown primary site to the colon has not been reported previously. A 75-year-old woman presented with a mass in the left submandibular region. Biopsy revealed a Class V lesion, but the histologic type was undetermined. Surgical resection of the left submandibular gland with cervical lymph node dissection was performed. However, SCC was seen in the lymph nodes only, with no tumor in the submandibular gland. Three months after surgery, computed tomography revealed that the preoperatively diagnosed lesion in the transverse colon had grown considerably. A laparoscopic right hemicolectomy was performed. Histological examination showed features of SCC, similar to the findings in the cervical lymph nodes. We report a rare case of synchronous metastatic SCC to the colon and cervical lymph nodes from a carcinoma of unknown primary site.

Haplotype defined by the MLH1-93G/A polymorphism is associated with MLH1 promoter hypermethylation in sporadic colorectal cancers.

BACKGROUND: Methylation of the MLH1 promoter region has been suggested to be a major mechanism of gene inactivation in sporadic microsatellite instability-positive (MSI-H) colorectal cancers (CRCs). Recently, single-nucleotide polymorphism (SNP) in the MLH1 promoter region (MLH1-93G/A; rs1800734) has been proposed to be associated with MLH1 promoter methylation, loss of MLH1 protein expression and MSI-H tumors. We examined the association of MLH1-93G/A and six other SNPs surrounding MLH1-93G/A with the methylation status in 210 consecutive sporadic CRCs in Japanese patients. METHODS: Methylation of the MLH1 promoter region was evaluated by Na-bisulfite polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis. The genotype frequencies of SNPs located in the 54-kb region surrounding the MLH1-93G/A SNP were examined by SSCP analysis. RESULTS: Methylation of the MLH1 promoter region was observed in 28.6% (60/210) of sporadic CRCs. The proportions of MLH1-93G/A genotypes A/A, A/G and G/G were 26% (n=54), 51% (n=108) and 23% (n=48), respectively, and they were significantly associated with the methylation status (p=0.01). There were no significant associations between genotype frequency of the six other SNPs and methylation status. The A-allele of MLH1-93G/A was more common in cases with methylation than the G-allele (p=0.0094), especially in females (p=0.0067). In logistic regression, the A/A genotype of the MLH1-93G/A SNP was shown to be the most significant risk factor for methylation of the MLH1 promoter region (odds ratio 2.82, p=0.003). Furthermore, a haplotype of the A-allele of rs2276807 located -47 kb upstream from the MLH1-93G/A SNP and the A-allele of MLH1-93G/A SNP was significantly associated with MLH1 promoter methylation. CONCLUSIONS: These results indicate that individuals, and particularly females, carrying the A-allele at the MLH1-93G/A SNP, especially in association with the A-allele of rs2276807, may harbor an increased risk of methylation of the MLH1 promoter region.

The use of Olaparib (AZD2281) potentiates SN-38 cytotoxicity in colon cancer cells by indirect inhibition of Rad51-mediated repair of DNA double-strand breaks.

Potent application of topoisomerase I inhibitor plus PARP inhibitor has been suggested to be an effective strategy for cancer therapy. Reportedly, mismatch repair (MMR)-deficient colon cancer cells are sensitive to topoisomerase I inhibitor, presumably due to microsatellite instability (MSI) of the MRE11 locus. We examined the synergy of SN-38, an active metabolite of irinotecan, in combination with the PARP inhibitor olaparib in colon cancer cells showing different MMR status, such as MSI or microsatellite stable (MSS) phenotype. Treatment with SN-38 and olaparib in combination almost halved the IC50 of SN-38 for a broad spectrum of colon cancer cells independent of the MMR status. Furthermore, olaparib potentiated S-phase-specific double-strand DNA breaks (DSB) induced by SN-38, which is followed by Rad51 recruitment. siRNA-mediated knockdown of Rad51, but not Mre11 or Rad50, increased the sensitivity to olaparib and/or SN-38 treatment in colon cancer cells. In vivo study using mouse xenograft demonstrated that olaparib was effective to potentiate the antitumor effect of irinotecan. In conclusion, olaparib shows a synergistic effect in colon cancer cells in combination with SN-38 or irinotecan, potentiated by the Rad51-mediated HR pathway, irrespective of the Mre11-mediated failure of the MRN complex. These results may contribute to future clinical trials using PARP inhibitor plus topoisomerase I inhibitor in combination. Furthermore, the synergistic effect comprising topoisomerase I-mediated DNA breakage-reunion reaction, PARP and Rad51-mediated HR pathway suggests the triple synthetic lethal pathways contribute to this event and are applicable as a potential target for future chemotherapy.

Partial duplication of MSH2 spanning exons 7 through 14 in Lynch syndrome.

BACKGROUND: Lynch syndrome, also referred to as hereditary nonpolyposis colorectal cancer, is the most common form of hereditary colorectal cancer, and is associated with a high incidence of multiple primary neoplasms in various organs. METHODS: A 79-year-old woman (patient 1) diagnosed with ascending colon cancer had a history of previous carcinomas of the uterus, stomach, uroepithelial tract, and colon. One year later, she developed a brain tumor (glioblastoma). A 54-year-old female (patient 2) was diagnosed with endometrial cancer and sigmoid colon cancer. Both patients underwent genetic evaluations independently. RESULTS: No mutations were found in an exon-by-exon analysis of genomic DNA by polymerase chain reaction (PCR) and reverse transcription (RT)-PCR. However, multiplex ligation-dependent probe amplification (MLPA) identified genomic duplication spanning from exon 7 to exon 14 of the MSH2 gene in both patients. Due to the presence of this characteristic gene duplication, their pedigrees were investigated further, and these showed that they are paternal half-sisters, consistent with paternal inheritance. CONCLUSION: Large genomic duplication from intron 6 through intron 14 in MSH2 is a very rare cause of Lynch syndrome and is difficult to identify with conventional methods. MLPA may be an alternative approach for detecting large-scale genomic rearrangements.

Cell diameter measurements obtained with a handheld cell counter could be used as a surrogate marker of G2/M arrest and apoptosis in colon cancer cell lines exposed to SN-38.

In vitro assessment of chemosensitivity are important for experiments evaluating cancer therapies. The Scepter 2.0 cell counter, an automated handheld device based on the Coulter principle of impedance-based particle detection, enables the accurate discrimination of cell populations according to cell size and volume. In this study, the effects of SN-38, the active metabolite of irinotecan, on the colon cancer cell lines HCT116 and HT29 were evaluated using this device. The cell count data obtained with the Scepter counter were compared with those obtained with the (3)H-thymidine uptake assay, which has been used to measure cell proliferation in many previous studies. In addition, we examined whether the changes in the size distributions of these cells reflected alterations in the frequency of cell cycle arrest and/or apoptosis induced by SN-38 treatment. In our experiments using the Scepter 2.0 cell counter, the cell counts were demonstrated to be accurate and reproducible measure and alterations of cell diameter reflected G2/M cell cycle arrest and apoptosis. Our data show that easy-to-use cell counting tools can be utilized to evaluate the cell-killing effects of novel treatments on cancer cells in vitro.