Clinical Management of pT1 Colorectal Cancer: Comparison
Please note this is a comparison between Version 1 by Diana Zaffalon and Version 2 by Rita Xu.

Implementation of population-based colorectal cancer screening programs has led to increases in the incidence of pT1 colorectal cancer. These incipient invasive cancers have a very good prognosis and can be treated locally, but more than half of these cases are treated with surgery due to the presence of histological high-risk criteria. These high-risk criteria are suboptimal, with no consensus among clinical guidelines, heterogeneity in definitions and assessment, and poor concordance in evaluation, and recent evidence suggests that some of these criteria considered high risk might not necessarily affect individual prognosis.

  • pT1 CRC
  • colorectal cancer
  • polyp
  • colonoscopy
  • polypectomy

1. Introduction

Colorectal cancer (CRC) is the third most common cancer in Western countries and the second most frequent cause of cancer death for both sexes in Spain [1]. Endoscopic resection of CRC precursor lesions (polypectomy) decreases CRC incidence and mortality [2]. pT1 CRC is a tumor that generally grows inside a polyp and invades the muscularis mucosae but not beyond the submucosal layer. It represents the earliest stage of CRC. The incidence of T1 CRC is increasing due to screening programs, and 40% of all screen-detected cancers are stage T1 [3][4][3,4].
Polyps with intramucosal carcinoma do not metastasize because there are no lymphatic vessels above the muscularis mucosa. They are thus curable with endoscopic polypectomy. When the malignant cells penetrate the muscularis mucosa, the risk of lymphatic invasion and, therefore, of metastasis is believed to progressively increase as the tumor penetrates deeper into the submucosal layer. The optimal treatment for this type of lesion is controversial. Characteristically, the submucosa of the colon has few lymphatic vessels on the surface, which means that some incipient invasive cancers have a very good prognosis and can be treated locally. Thus, endoscopic resection of pT1 CRCs is an attractive option because it is more conservative in terms of organ preservation and is associated with lower morbidity, mortality, and costs than surgery. However, from an oncological point of view, this approach does not include the resection of the locoregional lymph nodes, and this would be a suboptimal treatment in patients with a significant probability of lymph node metastasis (LNM). Therefore, more than half of all cases of this early-stage cancer, potentially curable with endoscopic treatment, are treated with surgery in clinical practice, even though this is the treatment applied to the most advanced stages of CRC [3].
The ultimate decision on whether to proceed with additional surgery after primary endoscopic treatment for pT1 CRC is primarily based on histology. Current histological risk criteria for pT1 CRC are suboptimal, with no consensus among clinical guidelines. Moreover, recent evidence suggests that some of these criteria deemed high risk may not necessarily affect prognosis on their own. NTo our knowledge, no clinical trials have compared a wait-and-see strategy and secondary surgery after endoscopic resection. It must be taken into account that screening programs include healthy individuals and that the disease-free survival of patients with early-stage CRC is excellent, above 90% [5][6][7][5,6,7]. Using the current criteria, most patients are classified as high-risk, which leads to additional surgical treatment. This may reduce locoregional recurrence, lymphatic spread, and cancer-related death but also entails an increased risk of morbidity, mortality, and functional loss and added treatment-related costs that should be considered in the clinical scenario of early-stage cancer with a good prognosis.

2. Suboptimal Histological Criteria Lead to Overtreatment

The final treatment decision for pT1 CRC, namely, if additional surgery is required or not after primary endoscopic treatment, is primarily based on histology. The so-called histological high-risk factors are believed to confer an increased risk of LNM that ranges from 0.7% to 36.4% [8]. The factors associated with the presence of LNM vary among clinical guidelines. Currently, pT1 CRC with any of the following histological findings is considered high risk for LNM and is indicated for additional surgery: lymphovascular invasion (LVI), poorly differentiated histology (PD), presence of tumor budding (TB), positive vertical margin, or deep submucosal invasion (DSI). There is consensus in the guidelines for three factors: PD, TB, and LVI. The other risk factors, DSI and positive vertical margin, are described in the guidelines, but recent evidence suggests that they should not be considered independent high-risk factors. The histological risk criteria according to the main clinical practice guidelines are summarized in Table 1 [9][10][11][12][13][9,10,11,12,13].
Table 1. Risk factors for lymph node metastasis according to international guidelines.
]. Also, TB and tumor grade are different concepts, and there is no consensus in the guidelines on the grade of TB that confers a worse prognosis.

2.2. Risk Factors without Consensus

Deep submucosal invasion: Recent evidence calls into question whether DSI confers a risk, given that it seems to not be an independent risk factor for LNM. A recent meta-analysis published by a Dutch T1 CRC group [24] that included 67 studies (21,238 patients) showed that DSI, as a solitary risk factor, only has an absolute risk of LNM of 2.6% and was not a significant predictor of LNM in a multivariable meta-analysis (odds ratio [OR], 1.73; 95% confidence interval [CI], 0.96–3.12), in contrast to a significant association of LNM with PD (OR, 2.14; 95% CI, 1.39–3.28), high-grade TB (OR, 2.83; 95% CI, 2.06–3.88), and LVI (OR, 3.16; 95% CI, 1.88–5.33) (24). The authors concluded that DSI should be reconsidered as a strong indicator for oncological surgery;
Resection margin: A positive margin (R1) is considered a risk factor in most guidelines, although the definition of this item is controversial. The different definitions of an R1 margin include cancer that is within the diathermy margin, ≤0.1 mm from the margin, ≤1 mm from the margin, and ≤2 mm from the margin [22]. In addition, the definition of a positive margin may depend on the morphology (sessile or pedunculated polyp) [11][12][13][11,12,13]. The most common definition for R1 is <1 mm, based on studies showing a risk of residual disease of 6.1–21% [25], but recent evidence questions this suggestion, as it shows similar risk for residual disease in patients with resection margins between 0.1 mm (2.9%; 95% CI, 1.0–6.7%) and 1 mm (0.6%; 95% CI, 0.1–2.1%), in the absence of other histological risk factors [26].
Regarding the endoscopic resection technique, the risk of residual disease may be more strongly related to incomplete resection than margin status. Table 2 shows the risk of residual disease in patients with pT1 CRC treated by endoscopy with subsequent rescue treatment (surgery or local). Studies that report residual disease above 15% often have high rates of incomplete endoscopic resections (over 10%). Conversely, studies with lower residual disease values (0.6–8.2%) mostly exclude cases of incomplete resection. Additionally, the evaluation of the resection margin is influenced by the technique. Conventional polypectomy is usually confined to the superficial or middle submucosal layer and is usually fragmented when the polyp is greater than 20 mm. An indeterminate margin (Rx) is usually reported in fragmented resections, even if it is a complete resection. An Rx margin can be mistaken for an incomplete resection, with an indication for salvage surgery. A more conservative strategy would be close endoscopic surveillance, instead of additional surgery, in cases of a doubtful margin, but only if the endoscopic resection is considered complete and there are no other high-risk factors. Suboptimal histological criteria have repercussions in clinical practice. By using the current clinicopathological criteria, 60–70% of pT1 CRC patients are classified as high risk, but the post-surgical pathological results show that only 2–10.5% have LNM and that residual tumor is present in less than 20% [6][27][28][29][30][31][32][6,27,28,29,30,31,32], which leads to overtreatment in more than 80% of cases. Associations between histological risk factors and the presence of LNM have been reported in several meta-analyses, with the limitation that they were based on retrospective studies with different definitions of histological risk factors [15][33][15,33]. Additionally, these factors can appear simultaneously, and it is, therefore, difficult to know the real weight of each individual one. Current histopathological criteria have important limitations regarding their definitions, assessment, poor concordance, and lack of reproducibility. Davenport et al. reported a significant variation in the assessment of important prognostic parameters in pT1 CRC by four expert gastroenterology pathologists in the UK CRC screening program, with kappas ranging from 0.07 for tumoral differentiation to 0.15 for the Haggitt level, and 0.35 for LVI (poor to fair agreement) [19]. In the Dutch CRC screening cohort, a panel of experts reviewed pT1 CRC patients; discrepancies were identified in 53.0% of cases and could have led to alternative treatment approaches in 30.1% [17].
Table 2. Risk of residual disease in patients with pT1 CRC treated with secondary surgery after endoscopic treatment. Retrospective study series.

2.1. Risk Factors with Consensus

Lymphatic and/or vascular invasion: LVI is the risk factor most strongly correlated with LNM and poor outcome [14][15][16][14,15,16] but is also known for high interobserver variability [17]. LVI can be assessed using hematoxylin and eosin staining with or without immunohistochemistry. A meta-analysis reported a clear benefit of using immunohistochemistry for predicting LMN, with an increase in the detection of LVI from 14.3% to 35.7%, but it is used only in doubtful cases in clinical practice [18];
Poorly differentiated histology: Similar to LVI, PD is an established risk factor, with recent evidence suggesting that it is an independent risk factor associated with poor prognosis [16]. As with LVI, PD has high interobserver variability, with the lowest value of kappa (0.07) in a concordance study of histological assessment in pT1 CRC [19]. Due to highly variable reporting of the tumor grade according to the three-tiered system (G1–G3), the latest version of the WHO classification [20] recommends a two-tiered system, where G1 and G2 are combined as low grade and G3 is considered high grade. This change is based on the similar prognosis for G1 and G2 tumors and improved reproducibility. However, variability remains in how this new system is applied in clinical practice [21][22][21,22];
Tumor budding: Defined as a single tumor cell or cell cluster of four tumor cells or less extending at the invasive margin of the cancer. TB is an established predictor of LNM in pT1 CRC according to the guidelines [23]. Nevertheless, it is reported in less than 50% of published studies [22
The integration of digital pathology into clinical practice represents an opportunity to enhance histological risk assessment. By incorporating artificial intelligence (AI) for automated analysis, pathologist subjectivity could be reduced, leading to more objective results. Predictive models could also be a useful resource for individualized risk estimation. For example, Kudo et al. [34] developed a predictive model using machine learning that incorporates clinical, endoscopic, and histological variables. The model was found to more accurately predict the presence of LNM compared to traditional clinical guidelines. Another group from the US developed a predictive model that uses a microRNA signature in conjunction with histological criteria. This model enabled the reclassification of a high-risk cohort identified by conventional histological criteria, resulting in a reduction of truly high-risk patients from 100% to only 25%. This approach could have prevented overtreatment (additional surgery) in 92% of cases, reducing the need for only 18% of cases [35]. Both of these predictive models need to be validated in prospective cohorts.

3. Conclusions and Future Directions

Future research efforts should focus on improving the quality of the histological evaluation of pT1 CRC, given that it is such an important part of the decision-making process regarding additional treatments. Histological risk factors could be redefined, based on recent evidence, particularly regarding submucosal invasion not being an independent risk factor and the consideration of a margin >0.1 as a free (R0) margin. Moreover, it is essential to improve concordance in histological evaluations, and AI may play a pivotal role in achieving this goal. Due to the uncertainty regarding the protective benefits of surgery for high-risk patients, it is crucial to thoroughly assess the need for this treatment as a primary or additional measure on a case-by-case basis. In particular, it may be worth considering closer monitoring after endoscopic treatment in high-risk patients rather than opting for additional surgery in elderly patients with considerable comorbidities or for pT1 CRC located in the rectum, where local excision techniques may be a safer alternative with a lower risk of AEs. Advanced local endoscopic techniques are now available that represent organ-preserving procedures and permit complete resection while allowing better histological assessment. These techniques may offer a greater chance of achieving a curative R0 resection and reducing the risk of AEs in the future. To advance the management of pT1 CRC, it is imperative to conduct long-term prospective follow-up studies with large sample sizes to resolve the existing dilemmas, especially randomized controlled trials that can compare the treatment strategies, such as surgery versus endoscopic treatment in high-risk patients, as well as evaluate the safety and oncological outcomes of the new endoscopic treatments. RWesearchers must acknowledge the limitations of histology and take a comprehensive approach by additionally considering demographic, clinical, endoscopic, and molecular factors when estimating the risk of pT1 CRC. To improve the management of the many clinical dilemmas of pT1 CRC, a multidisciplinary approach should be adopted for decision making. The incorporation of predictive models could further optimize the decision-making process in clinical settings.    
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