Up to now, surgery is still the most effective means of treating rectal cancer. However, anastomotic recurrence is one of the important reasons for surgical failure, with a recurrence rate of about 5%～15％［1］. The causes of anastomotic recurrence are multifaceted, but insufficient resection length of the distal bowel segment is a widely recognized fact. The optimal resection length of the distal bowel segment in cancer has always been a focus of scholars' attention, but there is still no conclusion to date.
Part One: Reasons for Anastomotic Recurrence Caused by Insufficient Resection Length of Distal Bowel Segment
There are mainly two reasons for anastomotic recurrence caused by insufficient resection length of the distal bowel segment: one is the distal spread of rectal cancer ［2］, including intraluminal and extraluminal spread ［3］. During surgery, the distal bowel segment infiltrated by cancer cells is not completely resected, leading to the proliferation of residual cancer foci and anastomotic recurrence; the second reason is that the transitional mucosa of the distal bowel segment in rectal cancer has already undergone significant changes at the molecular level in terms of histochemistry, cell proliferation kinetics, oncogenes, and tumor suppressor genes, which differ from normal colonic mucosa ［4］. It has already been considered as precancerous lesion status. Moreover, patients with colorectal cancer themselves have a predisposition to tumors. When these transitional mucosa are stimulated by surgery and carcinogenic factors, they easily transform into new cancers ［2］.
Part Two: Issues Related to Distal Spread of Rectal Cancer
Mode of Spread and Influencing Factors: The distal spread of rectal cancer refers to cancer cells infiltrating the distal bowel through direct extension along lymphatic vessels, blood vessels, and nerves. The incidence of intramural spread is approximately 65％～26％［3］, with direct extension being the main mode of spread. Intramural spread can occur throughout the entire intestinal wall layer, but it is most common in the submucosal layer ［5］. Generally, the poorer the differentiation of tumor tissue and the later the Dukes stage, the more likely it is to develop distal intramural spread and the larger the spread range. Lazorthes ［6］ believed that the presence or absence of distal intramural spread and its extent were positively correlated with the presence or absence of lymph node involvement and their number.
Distal Spread Range and Safe Distal Margin: Handly and Cole proposed based on the distance of distal spread of rectal cancer that the safe distal margin for rectal cancer should be 5 cm, which was considered the classic "5 cm rule"; Williams ［7］ studied 50 patients undergoing abdominoperineal resection for rectal cancer, showing that 12 cases had distal intramural metastasis, among which 7 cases had a spread ≤1 cm, and 5 cases had a spread >1 cm. These 5 cases were all poorly differentiated Dukes C stage patients. Implementing the 5 cm rule did not improve efficacy, as patients died of distant metastasis rather than local recurrence. Therefore, Williams believed that cutting off the bowel 25 cm away from the distal end of the tumor could allow 94％ of patients to achieve safe distal bowel resection. Kazuo ［3］ retrospectively studied 610 specimens of rectal cancer resection, where 61 cases had distal intramural metastasis, with most cases having metastasis 3 cm, and for infiltrative type should be >5 cm.
As mentioned above, domestic and foreign scholars have varying opinions on the standard for the safe distal margin of rectal cancer, but all their common bases are built on the basis of cancer cell infiltration. However, many studies have confirmed that even if no cancer cell infiltration is seen at the distal bowel margin, there have already been changes at the molecular level in terms of histochemistry, cell proliferation kinetics, oncogenes, and tumor suppressor genes. Under the influence of multiple factors, these changes may develop into new cancers, similarly leading to surgical failure.
Part Three: Issues Related to Peritumoral Transitional Mucosa (TM) in Rectal Cancer
Definition of Peritumoral TM: Filipe ［11］ found that there exists a transitional mucosal tissue between colorectal adenocarcinoma and normal intestinal mucosa. Its histochemical characteristics are manifested by an increase in sialomucin content and a decrease or disappearance of sulfomucin content in the goblet cells of the mucosal epithelium, while the histological examination appears normal, referred to as peritumoral transitional mucosa (TM), indicating that the derivation of TM stems from the histochemical characteristics of peritumoral mucosa, specifically the change in mucins.
Frequency, Length, and Influencing Factors of TM: Previously, the measurement standard for the length of peritumoral TM was based on the observation of acidic mucin histochemical changes using high-iron diamine-Alcian blue staining. Greaves ［12］ reported that out of 95 specimens of colorectal cancer, 93 cases showed characteristic changes in TM mucins, with the length of peritumoral TM ranging from 0 to 195 cm, averaging 34 cm; Wang Qiang et al. ［13］ studied 72 specimens of rectosigmoid cancer undergoing anterior resection, discovering that all cases had peritumoral TM, with the distal peritumoral TM range being from 0.3 to 9.6 cm, averaging cm. The distribution trend of the range was relatively dispersed, without any concentrated distribution around the mean. There was no significant correlation between the length of peritumoral TM and tumor size, Dukes staging, or degree of differentiation.
Relationship Between Peritumoral TM and Anastomotic Recurrence: Deng Guosan et al. ［14］ compared the mucin staining of the two margins of the bowel in 28 recurrent colorectal cancer cases and 32 colorectal cancer cases surviving 5 years without recurrence after radical surgery, finding that the mucosal sialomucin content at the surgical margins of the recurrent group was significantly higher than that of the non-recurrent group patients. This suggests that the residual transitional mucosa after radical surgery for colorectal cancer is one of the important factors related to anastomotic recurrence after colorectal cancer surgery. Wang Qiang et al. ［15］ clinically and pathologically examined 26 cases of anastomotic cancer recurrence out of 89 cases treated with anterior resection for mid-upper rectal cancer, analyzing the related factors affecting cancer recurrence using the Cox regression model. The results showed that the histochemical changes in mucins at the bowel margins, Dukes staging, and tumor histological type were successively the main factors significantly influencing cancer recurrence after anterior resection of rectal cancer, revealing that cancer recurrence after anterior resection was closely related to the residual peritumoral TM around the anastomosis.
Oncogenes, Tumor Suppressor Genes, and Their Protein Expression in TM:
1. Oncogenes, Tumor Suppressor Genes, and Their Protein Expression and Significance: The carcinogenesis process of colorectal cancer is a multi-gene, multi-step interaction process. The activation of proto-oncogenes, the inactivation of tumor suppressor genes, the overexpression of their encoded products, and defects in the DNA damage repair system all play important roles in the malignant transformation and proliferative dysfunction of tumor cells. Many studies have confirmed that peritumoral mucosa is in a precancerous lesion state, with mutations in ki-ras and P53 genes and overexpression of their protein products. Ki-ras gene mutation points are fixed at codons 12, 13, and 61, with the most common being codon 12 mutation. Due to the substitution, loss, or insertion of other amino acids between glycine and alanine at the mutated site, the cellular transmission process is altered, giving cells selective growth advantages. About 50％ of colorectal cancers possess the ki-ras-encoded P21 protein, which belongs to the G protein family. There is only a trace amount of P21 protein in normal tissues, maintaining normal cell differentiation. After ki-ras mutation activation, it can lead to the overexpression of P21 protein, which can be detected by routine immunohistochemical methods ［16］. P53 is an important tumor suppressor gene. In colorectal cancer, P53 mutations most commonly occur in exons 5, 6, 7, and 8, and are mostly missense mutations. Normal wild-type P53 protein regulates the Cipl gene, which encodes a protein with a molecular weight of 21KD, inhibiting the activity of enzymes that promote the cell cycle entering mitosis. When cells undergo DNA damage due to radiation or certain drugs, cell division stops at the G1/S phase. On one hand, this allows cells to have enough time to repair the damage and return to normal state; on the other hand, if the damage cannot be repaired, wild-type P53 initiates cell apoptosis. Mutant P53 loses its normal physiological function against clonal expansion or gene mutations, thereby causing excessive growth and degeneration of uncontrolled proliferating cells caused by oncogene ras, promoting tumor occurrence.
2. Frequency and Range of Appearance of ki-ras Gene, P53 Gene, and Their Protein Products in Peritumoral TM: Gan Yuebo ［17］ used polymerase chain reaction-restriction fragment length polymorphism analysis to detect ki-ras gene mutations in 13 cases of colorectal cancer and adjacent mucosa, finding that both cancer tissue and adjacent mucosa had ki-ras mutations in 2 cases, only cancer tissue had mutations in 2 cases, and only adjacent mucosa had mutations in 1 case. This result indicates that part of the adjacent mucosa has already undergone ki-ras gene mutation, further confirming that ki-ras gene mutation can occur in the early stages of development of colorectal cancer, and there is no necessary connection between the genetic changes in adjacent mucosa and those in adjacent cancer tissue. Peng Dunfa et al. ［18］ used immunohistochemical S-P method to detect P53 expression in 53 cases of peritumoral mucosa of colorectal cancer, finding P53 expression in 7 cases. Feng Maohui et al. ［19］ used histochemical and immunohistochemical methods to observe the expression of P53, P21 proteins and their relationship with mucin changes in the peritumoral mucosa of 34 cases of rectal cancer, resulting in HIP-AB indicating that the peritumoral TM was directly continuous, with a range not exceeding 4 cm distal bowel segment, and no transitional changes were observed in the normal control mucosa. P53 in peritumoral TM had a range not exceeding 4 cm distal bowel segment, and was weakly positive in the 3-4 cm bowel segment; P21 positive range did not exceed 2 cm bowel segment; the appearance of P53, P21 positive mucosa were all transitional change mucosa, and P53, P21 were negative in normal control mucosa. There was no correlation between P53, P21 expression in rectal adenocarcinoma and peritumoral TM. It was believed that peritumoral TM significantly differs from normal mucosa at the molecular genetic level, and easily develops into tumor hyperplasia, and it was found that the range of abnormal mucin and molecular genetic abnormalities occurring in the distal bowel segment of rectal cancer was within 4 cm, and this zone of mucosa should be resected during radical surgery.
Conclusion:
Insufficient resection length of the distal bowel segment in rectal cancer is an important cause of anastomotic recurrence. How to define the appropriate resection length of the distal bowel segment to prevent anastomotic recurrence can be considered from two aspects: one is to determine the distance of distal spread of rectal cancer and completely resect the distal bowel segment infiltrated by cancer cells during surgery, removing residual lesions. Foreign scholars suggest that resecting 1-2 cm is sufficient, while domestic scholars still believe that resecting ≥3 cm distally is safer; the second aspect is to define the length of peritumoral transitional mucosa at the distal end from the perspective of histochemical mucin changes, oncogenes, tumor suppressor genes, and their protein content changes at the molecular pathological level, and completely resect this segment of peritumoral transitional mucosa during surgery. To date, there is still no definitive conclusion on the appropriate range of resection of the distal bowel segment, requiring further research on the correlation between the distal spread distance of rectal cancer and peritumoral transitional mucosa, the relationship between oncogene ki-ras, tumor suppressor gene P53, and protein expression in peritumoral transitional mucosa and anastomotic recurrence, and further comparison of the relationship between distal spread distance, mucin changes in peritumoral transitional mucosa, and molecular pathological changes with anastomotic recurrence, selecting the best indicator to define the safe distal margin of rectal cancer to prevent postoperative anastomotic recurrence and improve survival rates. References omitted.