Diagnostic and Therapeutic Management of Early Colorectal Cancer

Abstract

Background

Early colorectal cancer (eCRC) is defined as cancer that does not cross the submucosal layer of the colon or rectum, including carcinoma in situ (pTis), pT1a, and pT1b. Early carcinomas differ in their prognosis depending on the risk profile. The differentiation between low and high risk is essential. The low-risk group includes R0-resected, well (G1) or moderately (G2) differentiated tumors without lymphatic vessel invasion (L0), without blood vessel invasion (V0) and a tumor size ≤3 cm. In this constellation, the estimated risk of lymph node metastasis is around 1% or below. The high-risk group includes tumors with incomplete resection (Rx), poor (G3) or undifferentiated (G4) carcinomas, and/or lymphatic and blood vessel invasion (L1) and size ≥3 cm. In a “high-risk” situation, there is a risk for lymph node metastasis of up to 23%.

Summary

The incidence of eCRC is rising with a rate of 10% in all endoscopically removed lesions during colonoscopy. For a correct histological evaluation, all suspected lesions should be completely resected. In case of a pT1 lesion in the rectum, pelvic magnetic resonance imaging should be performed to evaluate for suspicious lymph nodes. The therapeutic approach for eCRC is based on histological assessment and ranges from endoscopic resection to radical oncological surgery. The advantages, disadvantages, and associated risks of the individual treatment strategy need to be carefully discussed on a tumor board and with the patient.

Key Messages

Treatment options for early colorectal cancer depend on the histological assessment. Poorly differentiated carcinomas, a Kudo ≥ SM2 classified lesion, and a Haggitt level 4 always represent a “high-risk” situation. It should also be mentioned that in rectal cancer, local surgical tumor excision (full-wall excision) is also sufficient for pT1 carcinomas with a “low-risk” constellation (G1/G2; L0, size <3 cm) and an R0 resection.

Introduction

Colorectal cancer (CRC) is one of the most common malignancies worldwide and the third leading cause of cancer-related death in Europe and the USA [1]. Over 90% of all CRC arise from the adenoma-carcinoma sequence [2, 3]. However, the risk of progression to cancer depends on the histopathological classification of the adenoma: an invasive carcinoma can be detected in up to 30% of villous adenomas and of tubular adenomas only in about 4% [4]. Sessile, pedunculated, non-protruding, and excavated lesions are morphologically distinguished. The malignant potential increases with the increasing size of the polyp [5, 6]. Fortunately, the implementation of national CRC screening programs has led to a significantly higher detection rate of CRC in its early stages (from 5% to 17%) [7, 8]. Early carcinomas are those tumors that are limited to mucosa and submucosa (pTis and pT1a/b category). The pretherapeutic assessment of the risk constellation (“low” vs. “high risk”) is extremely important. Approximately 10–15% of all pT1 CRC already have lymph node metastases at the time of initial diagnosis, herein pedunculated pT1 CRC have a lower risk (3–7%) in comparison to sessile ones (up to 28%) [9, 10, 11]. Therefore, the following information is mandatory for further treatment: grading, TNM category, the status of lymphatic vessel invasion, the status of blood vessel invasion, the status of perineural invasion, and the status of the resection margin. This review was performed to outline the current management of eCRC.

Diagnostic and Therapeutic Management

Endoscopic Risk Assessment

The rate of eCRC in endoscopically removed polyps is up to 10%. During endoscopy, the macroscopic appearance and size of a lesion allow an initial risk estimation and for the presence of invasive disease [12, 13]. Larger and non-polypous lesions are associated with a higher risk of malignancy [6, 14]. The structured polyp classification is performed according to the Paris classification [5, 6, 15], the Narrow Band Imaging (NBI) International Colorectal Endoscopic Classification (NICE) [16], or the Japanese NBI Expert Team classification (JNET) [17]. In the future, artificial intelligence in combination with endoscopic tools and software has a high potential to be supportive for risk assessment of colorectal lesions [18, 19].

Endoscopic Resection

Requirements concerning endoscopic resection are complete removal of the lesion and a thorough benefit-risk assessment. The potential risk of malignancy increases with size, type of growth, and location of the lesion. It has also to be balanced against the risk profile of the patient and location including the likelihood of post-interventional bleeding and a more challenging procedure in the thin-walled proximal colon with a higher incidence of perforation during the endoscopic intervention [20, 21, 22, 23]. In the case of larger flat adenomas, called laterally spreading tumors [24], the malignant potential of the nongranular type is about 15% compared to 1–3% in LSTs with a granular growth pattern [25, 26, 27, 28].

Endoscopic Mucosal Resection

Snare polypectomy is the method of choice for removing pedunculated polyps [29]. After injecting fluid into the submucosa, sessile or flat lesions can also be lifted (“lifting sign”) and removed using a diathermic snare [30]. As a positive side effect, the submucosal fluid depot acts as thermal insulation during coagulation. In lesions with a diameter of >20 mm, the EMR is demanding, so in distinct cases, an ablation has to be carried out as piecemeal EMR, not as en bloc resection. The piecemeal technique is reserved for exceptional situations, as histopathological assessment of the resected material is limited [31, 32]. If a polyp cannot be safely removed, surgical resection must be considered.

Endoscopic Submucosal Dissection

Endoscopic submucosal dissection (ESD) enables interventional resection of larger and deeper lesions. In addition, lesions resected by this technique enable an accurate histopathological evaluation of the margins [33]. ESD instead of EMR should always be considered if the morphology of a polyp carries a risk of malignancy as pointed out by the following features: LST of the granular type with larger nodules, LST of the nongranular type, sunken lesions, and lesions with a suspicious surface or vascular architecture [34].

“Non-Lifting Sign”

The submucosal injection of saline as part of an EMR or an ESD can provide additional information for malignant risk assessment of the lesion. If a lesion after submucosal injection does not detach from the tunica muscularis propria (called “non-lifting sign”), it is highly suspicious of deeper invasion [35, 36, 37]. These lesions are highly likely more advanced than early invasive T1 carcinomas, making complete endoscopic removal (R0) impossible. In addition, it has been repeatedly shown that the primary assessment of the endoscopic “ablatability” of a polyp depends on the experience of the endoscopist and that most “non-ablative” polyps can be successfully ablated in centers [38, 39, 40, 41, 42, 43].

Complications

Post-interventional bleeding occurs after EMR and ESD in 2–11% depending on the study [31, 44]. The risk of perforation with snare polypectomy of pedunculated lesions is almost negligible at 0.05% [31]. In contrast, for EMR in flat lesions, a risk between 0.58 and 3.9% was reported [31, 45]. ESD is associated with a remarkably higher risk of perforation (14–18%) [31, 44]. Perforations in the context of endoscopic ablation do not usually require surgical treatment; adequate endoscopic closure using a clip is almost always possible. Interventions in the more muscular rectum and left hemicolon show low perforation rates; the risk in the thin-walled right hemicolon is significantly higher [46, 47]. In addition, there is an increased risk in the flexures and the areas of the descendo-sigmoid transition or rectosigmoid transition due to the technically often difficult accessibility and visibility.

Marking of the Resection Site

Before surgery, the resection site should be endoscopically marked (except for the cecum and rectum). Ideally, by submucosal ink injection (“tattooing”) or a metal clip, whereby ink marking is an advantage during laparoscopic resection [48]. As an alternative, an intraoperative colonoscopy can be performed.

Transanal Resection

Transanal Endoscopic Microsurgery

Transanal endoscopic microsurgery is a full-thickness excision with a safety margin of at least 0.1 cm by using a special surgical rectoscope [49, 50]. Direct grasping should be avoided, as the rule of a no-touch technique also applies. Postoperative urinary retention and postoperative bleeding are the most common complications after this procedure [51]. Infectious complications such as abscesses can usually be managed with endoluminal drainage and antibiosis. In exceptional situations, a protective loop ileostomy is necessary. Opening the peritoneum while resecting lesions in the upper third of the rectum is not per se an indication for a transabdominal procedure, provided that the defect can be closed transanally [51].

Transanal Full-Thickness Excision

In the case of lesions in the lower to the middle third of the rectum, the resection can also be performed surgically as a full-thickness transanal excision using an anal retractor. The risk of lymph node metastasis of lesions in the lower third of the rectum may be slightly higher than in the middle or upper rectum [8].

Histological Risk Assessment after Endoscopic Removal

To be able to determine further treatment, a standard classification of the resected specimen should be provided: “low-risk” (G1, G2, and no lymphatic invasion [L0] and size <3 cm [rectum]) or “high-risk” (G3, G4, and/or lymph vessel ruptures [L1] and/or size >3 cm [rectum]). This is extremely important as the risk of lymph node metastasis in the “low-risk” group is 1% or below [9, 52, 53, 54, 55, 56, 57, 58, 59, 60], in contrast to the high-risk group, which has a risk for lymph node metastasis of up to 23% [9, 58, 61, 62].

Histologic Grading

Histologic grading influences the prognosis of eCRC significantly. Most eCRCs show moderate differentiation (G2) [63]. Poorly and undifferentiated eCRCs (G3/G4), including all mucinous and signet ring cell carcinomas, are found in about 4–9% of all polyps and have an extremely unfavorable prognosis with a high risk of lymph node (up to 23%) and distant metastases (up to 10%) [55, 63, 64]. Poorly differentiated polyps are associated with recurrence rates of up to 38% after endoscopic removal [63, 65]. Furthermore, poor differentiation is often accompanied by other prognostically unfavorable histological characteristics, e.g., tumor cell budding or lymphovascular invasion [63].

Lymph and Blood Vessel Invasion (L-/V-Category)

Histologically, lymphovascular infiltration means the presence of tumor cells in submucosal lymph vessels (L1) or blood vessels (V1). The infiltration of tumor cells into submucosal lymphatic vessels (pL1) has long been regarded as one of the most important independent predictive parameters for the presence of lymph node metastases in eCRC and thus also for estimating the prognosis [9]. An L+ status is associated with a 20% N+ rate [66].

Tumor Cell Budding

Tumor cell budding is defined as a single tumor cell or tumor cell cluster consisting of five or fewer cells at the invasion front, most of which are poorly differentiated and have stem cell-like properties. The classification is as follows: grade 1 with 0–4 cells, grade 2 with 5–9, and grade 3 with >9 buddings or tumor cell clusters. Grade 2 or 3 tumor budding is an additional parameter for an increased risk of lymph node metastases in several studies [67, 68, 69, 70, 71]. The indication of tumor budding is not yet a standard in Germany, but it can be used in the risk assessment of pT1 carcinomas according to the current S3 guideline [72].

Submucosa Invasion

The Kudo classification describes tumor infiltration depending on the depth of penetration of the submucosa. Herein, Sm1 indicates infiltration into the upper third of the submucosal layer (submucosal invasion ≤1,000 μm), Sm2 (1,000–2,000 μm) in the middle third, and Sm3 (>3,000 μm) in the lower third [58]. Sm1 is associated with a low risk of lymph node metastasis (0–4%), Sm2 and Sm3 carcinomas have around a 20% high risk of lymph node metastasis and are generally an indication for adjuvant surgical resection [9, 29, 54, 58, 61, 73]. The Haggitt classification (Fig. 1) is difficult to use in practice [74, 75]. At Haggitt level 0, the invasion is limited to the mucosa; there is no invasion of the lamina muscularis mucosas (“carcinoma in situ”). At level 1, there is a submucosal invasion in the area of the polyp head. At level 2, the infiltration reaches up to the neck − the transition between head and stalk − and at level 3, it extends down to the stalk. If the infiltration reaches the submucosa of the colonic wall below the stalk of the polyp, the criteria for Haggitt level 4 are met. Early CRC in pedunculated polyps with Haggitt level 0–3 has a very low risk of synchronous lymph node metastasis; some of the rates are below 1%. Haggitt 4 lesions are associated with lymph node metastases in up to 27% [15, 76]. Poorly differentiated carcinomas, a Kudo ≥ SM2 classified lesion, and a Haggitt level 4 always represent a “high-risk” situation.

Fig. 1.

Haggitt classification.

Resection Status (R Category)

Sessile (flat) lesions should be evaluated on the lateral and basal margins. The situation is different with piecemeal ablation, where only the basal margins can be reliably assessed histologically. However, an early (2–6 month) endoscopic-bioptic control is required in this case.

Management of pT1 Carcinoma

A possible treatment algorithm is shown in Figure 2. If an endoscopically ablated polyp presents as a pT1 carcinoma and is R0 removed on the final histopathologic workup, oncologic resection should not be performed if the situation is “low-risk.” It should also be mentioned that in rectal cancer, local surgical tumor excision (full-wall excision) is also sufficient for pT1 carcinomas with a “low-risk” constellation (G1/G2; L0, size <3 cm) and an R0 resection. In the “high-risk” situation, radical oncologic resection should be performed even if the lesion has been completely removed. If incomplete ablation of a “low-risk” pT1 carcinoma is achieved, local surgical or complete endoscopic excision should be performed [72]. Early CRC associated with inflammatory bowel disease plays a special role. Here, deep infiltration is often difficult to assess, so that a generous indication for radical resection is given [77]. As in all oncological diseases, a therapeutic strategy should be discussed in an interdisciplinary tumor board.

Fig. 2.

Algorithm for the management of early colorectal cancer.

Staging

A CT scan of the thorax and abdomen should be performed. In the evaluation of lymph nodes, sensitivity (55–73%) and specificity (74–78%) of magnetic resonance imaging and endoscopic ultrasound are currently unsatisfactory [78, 79]. For this reason, the indication for neoadjuvant therapy should be made very cautiously if it is based on the description of suspicious lymph nodes in pretherapeutic imaging. For local staging of rectal carcinoma, magnetic resonance imaging and an endoscopic ultrasound should be performed [80, 81].

Follow-Up

After radical oncologic resection of a “high-risk” eCRC, regular oncologic follow-up is performed according to the current S3 guideline [72]. This includes regular imaging with abdominal ultrasonography or CT, chest X-ray, blood CEA level, as well as regular colonoscopies. For locally removed “low-risk” eCRC, the S3 guideline recommends an endoscopic control after 6 months. A complete colonoscopy should be performed after 3 years. If the removal was performed using the piecemeal technique and resulted in a basal R0 situation, an early (2–6 months) endoscopic biopsy of the local R0 situation is required (Table 1).

Table 1.

Follow-up after endoscopic or surgical removal of early CRC

Months	Low risk	High risk
6	Endoscopy (+/− biopsy)	CEA, endoscopy, abdominal ultrasound
12		CEA, endoscopy, abdominal ultrasound, chest X-ray
18		CEA, abdominal ultrasound
24		CEA, abdominal ultrasound, chest X-ray
36	Endoscopy	CEA, abdominal ultrasound, chest X-ray
48		CEA, abdominal ultrasound, chest X-ray
60		CEA, abdominal ultrasound, chest X-ray

Conclusion

The assessment of the risk constellation (“low” vs. “high risk”) is critical for defining the treatment strategy. In particular, the risk of lymph node metastases and local recurrence must be estimated accordingly. Based on the histological evaluation of the lesion, the therapeutic options for eCRC range from endoscopic resection to radical oncological surgery.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding was received for the present article.

Author Contributions

Mathilda Knoblauch, Florian Kühn, Viktor von Ehrlich-Treuenstätt, and Bernhard Willibald Renz wrote the manuscript. Jens Werner critically revised the manuscript. All the authors revised and approved the manuscript for publication.

Funding Statement

No funding was received for the present article.