Introduction
Local excision (LE) with or without chemoradiothera- py represents an alternative treatment to major radical surgery in small low rectal cancer. LE can be used in selected cases with the advantages of lower morbidity and mortality, maintaining at the same time a good functional result. On the other hand, from the litera- ture some concern emerges on the higher rate of recurrence and the possible compromise of the poten- tials of cure a radical rectal resection would offer. The key to a successful LE is certainly a reliable pre-opera- tive staging and the correct selection of patients. The criteria of eligibility for curative LE are still a matter of discussion and are not generally accepted. In this chapter more useful pre-operative staging tools are analysed in detail, some therapeutic strategies are pre- sented and finally, as to date no guideline has been fully agreed upon, current recommendations for cura- tive and palliative LE are discussed.
Pre-Operative Staging and Patient Selection
The staging system adopted in the present chapter refers to TNM classification [1]. Stage T1 has been
divided into three subgroups according to the Japan- ese classification (Fig. 1).
Only N0 tumours are amenable to undergo LE of low-lying rectal cancer because by definition satellite lymph nodes are left behind [2]. Considering this aspect, a correct and reliable pre-operative staging is of dramatic importance [3]. Besides, should LE fail, salvage rectal resection remains the only chance, al- though prognosis remains poor in these cases.
In order to assess nodal involvement, the following predictive factors have been analysed: tumour depth (T), age, lymphovascular invasion, unfavourable his- tology, grading, tumour morphology and size.
Tumour Depth
In the majority of studies, depth of tumour invasion through the rectal wall is considered the most impor- tant independent prognostic factor for nodal involvement. As a matter of fact the risk for N+ has been estimated from 0 to13% in T1, 12–28% in T2 and36–79% in T3 and T4 [2, 4, 5]. Kikuchi et al. [6]
have divided T1 tumours into 3 subgroups according to the level of submucosal invasion. T1sm1 stands for slight submucosal layer infiltration, T1sm2 for inter- mediate infiltration and T1sm3 for whole thickness submucosa involvement [6–8]. The T1sm3 subgroup bears a risk of lymph node metastasis estimated from 20 to 27%; this represents a contraindication to cura- tive LE.
Age
Although age is not an independent factor for nodal involvement, Sitzler et al., in a study on 805 patients all treated with radical rectal resection for rectal can- cer, compared groups with the same T staging but different age, showing that the risk of nodal involve- ment was much higher in the patient groups younger than45 years old (N+ being 33.3% in T1 subgroup) [9].
Diego Segre, Paola Sorba Casalegno, Herbert M. Dal Corso, Gian Gaetano Delaini, Felice Borghi
Fig. 1. Depth of invasion into the submucosa: sm1, upper- third; sm2, middle-third; sm3, lower-third (With permis- sion from [8])
sm1 sm2 sm3
Lymphovascular Invasion
The predictive value of lymphovascular invasion is still debated, although the majority of Authors con- sider this element as indicative of poorer outcome [10]. In a Japanese study on 182 patients lymphovas- cular invasion has been detected in 30% of T1sm1, though no one in this group showed lymph node invasion. The Authors concluded that the degree of infiltration through the rectal wall was by far a more reliable predictive factor than lymphovascular inva- sion [6]. Nivatvongs, reviewing 81 cases of degener- ated colorectal polyps, showed vascular and lym- phatic invasion in 37% and 20% of cases respective- ly, concluding that as far as it is carefully looked for, lymphovascular invasion seems a rather common finding in early rectal cancer [7]. On the other hand, Sengupta and Tjandra reporter a paper by Brodsky et al., which, although in a small group of 24 patients, showed that in T1 rectal cancer signs of lymphatic invasion imply a 33% of nodal involvement com- pared to 0% of N+ when no sign of lymphovascular invasion is present [2]. In a more recent study on 353 T1 rectal cancers, Nascimbeni et al. both in a univari- ate and a multivariate analysis concluded that lym- phovascular invasion is one of the three unique pre- dictive factors of nodal involvement, with a high grade of statistical significance (p=0.005) [8].
Unfavourable Histology
The presence of budding (islets of focal dedifferenti- ated cancer) at the invasive front or signs of signet- ring-cell adenocarcinoma, or both elements, are histopathologic findings referred to as unfavourable histology, bearing a higher risk of nodal involvement and ultimately of adverse outcome, as evidenced in some recent Japanese works [11–13]. Masaki et al.
reported unfavourable histology to be the only prog- nostic factor significantly related to lymph node metastasis in T1 and T2 rectal carcinoma undergoing LE or radical surgery [13].
Grading
The predictive value of grading relevant to nodal invasion is controversial. Although a less differenti- ated cancer theoretically metastasises more easily to regional lymph node and distant organs compared to a well differentiated one, statistically significant data supporting this concept have been observed in uni- variate analysis only [8]. Hase et al. [14] showed how the risk of nodal metastasis increased in those can- cers with evidence of undifferentiated histology at
the front margin compared to those in which an undifferentiated component was detected within the neoplastic mass. In his paper Kikuchi notes that among 64 patients with T1sm1 no one developed local recurrence or lymph node metastasis although 12.5% of cases have been diagnosed a poorly differ- entiated lesion [6].
Tumour Morphology and Size
Many studies demonstrated that both morphology and size of the lesion do not represent independent prognostic factors for nodal involvement [9, 10]. The diameter of the lesion is nevertheless important when considering LE, as lesions wider than 3–4 cm leave a wide defect in the rectal wall that might lead to rectal stenosis [2, 15].
Pre-Operative Local Staging Assessment
An accurate pre-operative staging of rectal cancer is of dramatic importance for successful local treat- ment. Digital examination, endorectal ultrasonogra- phy (EUS), magnetic resonance imaging (MRI) and computed tomographic scanning (CT) are all valu- able tools that play an important role in the staging process of rectal malignancies, and basically help identifying those patients who should be treated by radical resection, those amenable to LE, and those in whom neoadjuvant radiation and chemotherapy should be recommended first.
Digital Examination
Until recently, digital examination was the most important and useful tool in assessing a rectal cancer.
It allows precise information on the location of the lesion, size and fixity that, where present, suggests a locally advanced tumour [16, 17]. The diagnostic accuracy of digital examination for T-stage has been estimated around 62–83% when carried out by an experienced surgeon [2, 17, 18] and somewhere around 44–78% for less experienced ones. Digital examination is definitely less accurate for the assess- ment of N-stage, with figures that do not exceed 67%
in experienced hands [2].
EUS
During the last decade EUS has been increasingly used to evaluate lesions lying in the last 10–12 cm of rectum from the anal verge. Basically it is a morpho- logic study of the rectal wall with its mucosal, submu-
cosal and muscular layers, visualised as a classic 5- layer echoic pattern (or a 7-layer pattern if a 10-MHz probe is used). Cancer usually appears as a hypoe- choic lesion invading one or more echoic layers through the rectal wall. Accuracy for T-stage has been reported in the literature from 67 to 95%, with a sen- sitivity of 83–98%, specificity 75–87%, ppv 89 and npv 95 [10, 16, 17, 19]. Pitfalls involve the operator’s expe- rience, the degree of tumour infiltration and some technical issues such as artefacts, peritumoral inflam- mation and post-biopsy alteration of the echoic pat- tern. Artefacts are generated by the presence of air bubbles between the rectal wall and the probe, caus- ing a complete loss of signal or by the position of the probe with respect to the bowel wall or lesion. If not visualised at right angles, layers of different echogenic property appear thicker at their interface until a mir- ror image is generated. Peritumoral inflammation appears as a hypoechoic band at the infiltration mar- gin that can be easily confused with the true level of infiltration, negatively impacting T-stage. Peritu- moral inflammation is the main cause of overstaging, especially in T2 cancers [20]. EUS is rather inaccurate for N-staging mainly because morphologic and echogenic characteristics of lymph nodes alone are not sufficient to clearly assess possible lymph node positivity and also because lymph nodes other than those located in the mesorectum are out of the reach of the rigid probe [16]. As a matter of fact accuracy figures varying from 61 to 83% [10, 17] are reported in the literature, with a sensitivity as low as 33%, and a specificity of 82% [3]. N-stage accuracy can be increased by echo-guided lymph node needle biopsy performed during the examination [21], but further works are necessary to address the benefits and pit- falls of this promising technique.
EUS is at present the most accurate technique for pre-operative local staging of rectal cancer, as con- firmed in a recent meta-analysis [22] that compared EUS with MRI and TC (Table 1).
MRI
The increasing interest in the circumferential resec- tion margin (CRM) (Fig. 2), whose prognostic value is considered by some Authors to be superior to T- stage [16, 23], and the introduction of more powerful coils up to 1.5 Tesla, have drawn new attention to MRI.
Average figures of accuracy are around 66–82%
for T-stage and 60–72% for N-stage and do not differ much from those obtained with EUS, but as evi- denced by Bipat et al. [22], MRI allows an accurate evaluation of the CRM. For when N-stage is con- cerned, the recent introduction of new contrast agents such as utrasmall superparamagnetic iron oxide (USPIO) seems promising for the diagnosis of positive lymph nodes. This agent is captured by macrophage cells in the reticulo-endothelial system of normal lymph nodes, while metastatic lymph nodes are incapable of taking USPIO as the reticulo-
Table 1.EUS, CT and MRI: pre-operative staging accuracy for rectal cancer (Modified from [22])
Stage Imaging modality Sensitivity (%) Specificity (%)
Muscularis propria invasion EUS 94 86
CT NA NA
MR 94 69
Perirectal tissue invasion EUS 90 75
CT 79 78
MR 82 76
Adjacent organ invasion EUS 70 97
CT 72 96
MR 74 96
Lymph node involvement EUS 67 78
CT 55 74
MR 66 76
Fig. 2.The circumferential resection margin (CRM) (with permission from [23])
Ves Seminalis
Mesorectal fascia Ves. Sem.
T4
T3o
T3o
T1 T2
endothelial system is altered to some extent [23].
Although promising, this new technique needs fur- ther validation.
CT Scan
Since the introduction of EUS that shows all the lay- ers of the rectal wall, the role of CT scan in local stag- ing has been limited. It remains the most important exam for the detection of distant metastasis.
Therapeutic Strategies
Once local and general staging have been completed, the decision to proceed with a curative LE should be taken after evaluating other important aspects (Fig. 3)
such as the size of the lesion, its position in the rec- tum, the functional status of the anal sphincters, and the route the surgeon intends to follow: either trans- sacral, trans-sphincteric or transanal. The advantage of LE over other local treatments is that the lesion can be retrieved at the end of the operation for thor- ough histological examination, allowing for further treatments should any adverse factor come up [10].
In the literature, local recurrence after curative LE is reported from 0 to 18% in T1 cancers and from 11 to 47% in T2, compared to 4–30% local recurrence after radical rectal resection [2, 5, 10]. Mellgren et al., com- paring the results of LE with respect to radical rectal resection showed 18% of local recurrence in T1 patients and survival rate significantly reduced in T2 after LE compared to radical surgery (65 vs. 81%), con- cluding that curative LE is contraindicated for T2 can- cers, while in T1 there is a high risk of recurrence [5].
DRE + proctoscopy:
- size
- circumferential involvement (%) - site
- distance from anal verge - sphincteric function - mobility - morphology
Colonoscopy:
- synchronous lesions exclusion - synchronous polyps excision
Pedunculate lesion Sessile lesion
Endoscopic polypectomy EUS
Benign polyp Invasive lesion
Complete staging:
- clinical history - clinical evaluation - haematologic evaluation - thorax-abdomen TC scan
Favourable features:
curative LE
Distant mts:
palliative LE
Radical surgery refuse:
curative or palliative LE
Risk factors-comorbidity:
curative or palliative LE Fig. 3. Clinical evaluation flow- chart
Both short- and long-term results seem unsatis- factory when surgical margins are involved, in cases of poor histology and when lymphovascular infiltra- tion is present. In these cases the majority of Authors suggest an immediate radical rectal resection, with long-term results substantially similar to those after primary rectal resection. On the contrary, long-term results after salvage surgery, carried out only after the recurrence has occurred, are very poor. In fact, 5- year disease-free survival after immediate radical surgery is 94.1% vs. 55.5% after salvage surgery [2, 5, 24, 25]. The biological behaviour of the recurrence is probably different after LE and after rectal resection because in the former case the recurrence is related to the bowel wall, while in the latter it is related to the pelvis. As a matter of fact salvage surgery for recur- rence after LE is higher with respect to salvage sur- gery after abdomino-perineal resection or anterior rectal resection [2]. Hershman et al. in a recent study on long-term results after LE [26], sustain that local recurrence rates are unacceptably high, with mortal- ity rates that worsen with time as evidenced in 10- years, follow up, and advise against LE as a curative procedure.
Current Recommendations
On the basis of what has been presented before, cur- ative LE should be considered in very select cases. In Table2 the selection criteria for LE of rectal cancer are summarised [10].
In patients undergoing excision of a malignant polyp level 1, 2 or 3 according to Haggitt’s classifica- tion [27], with a disease-free margin of a least 2 mm, the risk of local recurrence is probably less than 1%,
even if lymphovascular infiltration or low-grade dif- ferentiation have been detected. In these cases a major surgical procedure is not justified. For T1 can- cers, Haggitt’s level 4, the risk of residual cancer or lymph node metastasis depends on the level of sub- mucosal infiltration. In T1sm1 with favourable his- tology the risk does not exceed 1–2%, a figure equiv- alent to perioperative mortality after anterior resec- tion in low-risk patients. In these cases LE can be considered an adequate procedure. For T1sm2 with favourable histology the risk of residual cancer or nodal invasion grows to 2–10%, so if the patient has a low operative risk an anterior rectal resection would probably be the best choice, leaving LE for patients in a poor general condition or with moder- ate–high operative risk. In cases of T1sm2 with unfavourable histology, anterior rectal resection should be considered, or alternatively an adjuvant therapy if LE has already been carried out.
LE is not indicated in T1sm3. In T2 where the patient’s general condition does not allow a radical resection, neoadjuvant radiotherapy followed by LE Table 2. Selection criteria for rectal cancers suitable for local treatment (Modified with permission from [10])
• Accessible
• Amenable to complete excision
• Haggitt levels 1, 2 or 3 in pedunculate polyps (clear margin≥ 2 mm)
• Haggitt level 4 (pedunculate or sessile T1 cancer) with sm1 invasion
• Haggitt level 4 (pedunculate or sessile T1 cancer) with sm2 invasion
well or moderately differentiated no lymphovascular invasion
Local excision:
histopathologic evaluation
pT1:
- clear margins - favourable histology
pT2:
complete excision
pT2 with incomplete excision-pT3
Follow-up
pT1:
- incomplete excision - unfavourable histology
Adjuvant RT-CT
Follow-up Surgery after local failure
Adjuvant RT-CT
Follow-up Surgery after local failure
Radical surgery Radical surgery
Fig. 4. Flow-chart on deci- sion making after local excision
can be considered, together with other adjuvant ther- apies [10].
Finally, LE can be offered to patients not eligible for major surgery or who refuse to undergo a major operation. In these cases a multimodal approach with neoadjuvant or adjuvant radiochemotherapy is usually adopted [28] (Fig. 4).
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