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LOCAL EXCISION FOR STAGE I RECTAL CANCER Minetti AM., et al.

Controversies in local excision for stage I rectal cancer

Ángel M. Minetti

, Ignacio Pitaco

, Juan Pablo Santilli

, Ignacio Ramallo

, Facundo Carrasco

1 Encargado del Sector de Coloproctología, Servicio de Cirugía; Sanatorio Trinidad de Quilmes. Profesor Adjunto de Cirugía, Facultad de Medicina, UBA

2 Médico de planta, Servicio de Cirugía; Sanatorio Trinidad de Quilmes. Especialista Universitario en Coloproctología

3 Médico patólogo, Sanatorio Trinidad de Quilmes Médico de planta, Servicio de Cirugía;

4 Médico de planta, Servicio de Cirugía; Hospital Penna, Bahía Blanca y Hospital Naval Puerto Belgrano, Punta Alta. Especialista Universitario en Coloproctología

5 Médico cirujano. Cursista del Curso de Especialista en Coloproctología, Facultad de Medicina, UBA

ABSTRACT

Introduction: The standard treatment for rectal cancer is total

mesorectal excision and neoadjuvant treatment in Stage II and III.

However, it results in undesirable functional consequences. In T1

and T2 tumors without lymph node involvement, studies have

demonstrated that organ-preserving treatment is possible, with

similar outcome to radical treatment.

Aim: To present the results of a series of Stage I rectal cancer

patients treated by local excision (LE).

Material and methods: Thirteen Stage I rectal cancer patients

treated with LE between 2012 and 2021.

Results: Gender: 7 women, mean age: 63.1 years. Mean height of

the lesions was 4.07 (range 2-8) cm from the anal verge. Posterior

6, anterior 4, anterolateral 2 and posterolateral 1. Three patients

with T2 tumors received neoadjuvant treatment, and the histopatho-

logical report after LE was ypT1 in 2 and complete pathological

response in 1. In the remaining 10 patients, histopathology result

was T2: 3, T1 Sm1: 3 and T1 Sm3: 4. Lymphovascular invasion

was negative in 8 patients. Complications occurred in 2 (15.4%)

patients.

Two patients were re-operated, one due to insufficient margins and

another due to adverse histological features. With a mean follow-up

of 54.5 (range 12-120) months, 12 patients are free of local and

distant recurrence. One patient died at 8 months due to carcinoma-

tosis.

Conclusion: The strategies currently used in the conservative

treatment of rectal cancer are promising, so they should be offered

to patients in the setting of a clinical trial with rigorous and safe

registration. The quality of evidence to date is insufficient to replace

the current standard of care.

Key words: transanal endoscopic microsurgery, TAMIS, transanal

minimally invasive surgery, stage I rectal cancer

INTRODUCTION

The standard treatment for rectal cancer is resection with

total mesorectal excision (TME), accompanied by neoadju-

vant treatment in stages II and III. However, although long-

term oncologic results have improved, this treatment is

associated with functional disorders, which in patients who

develop a modern social life generate a significant degree of

dissatisfaction. For this reason, doctors and patients are

looking for new alternatives to avoid these undesirable

consequences.

Tumors that are limited to the muscularis propria, without

involving lymph nodes, have generated enthusiasm in the

surgical and oncological community with some studies

showing encouraging results through conservative treat-

ment. However, there are various controversies regarding

the strategy to use.

The objective of this study is to present the results of a

series of patients with stage I rectal cancer treated by local

excision (LE).

MATERIAL AND METHODS

Thirteen patients with stage I rectal cancer located up to 8

cm from the anal verge, who were treated by LE between

June 2012 and November 2021, were retrospectively select-

ed from a prospective database.

All patients, except those who initially presented as a villous

tumor, were staged locally preoperatively by physical

examination, rectosigmoidoscopy, colonoscopy, high-

resolution MRI, and/or endorectal ultrasound and interpreted

by a specialist with extensive rectal experience. CT scans of

the chest, abdomen and pelvis, routine laboratory tests and

tumor biomarkers were also performed. The height and

location of the tumor was established by digital examination

and/or rectosigmoidoscopy.

All patients were explained how the attempted organ-

preserving surgery would proceed and the possible variants;

as well as the need to extend the resection if histological risk

features for an adverse outcome were found in the definitive

pathological study.

Those who refused radical resection were included in this

series. Initially, patients with tumors preoperatively classi-

fied as T2 were prescribed neoadjuvant therapy and LE.

Starting in 2015, it was modified to LE and adjuvant treat-

ment if the pathological result showed risk features and the

patient rejected radical surgery. Otherwise, resection with

TME was performed within 30 days after the first interven-

tion.

Neoadjuvant treatment was long course chemoradiotherapy

(CRT). Radiotherapy was performed with a total dose of

5040 cGy for a period of 5 weeks, divided into doses of 2

Gy per day. Chemotherapy was performed with 5-Fluoracil

(225 mg/m²/day) plus Leucovorin. Adjuvant treatment with

5-Fluoracil was performed for a period of 4 months, starting

4 to 12 weeks after surgery.

Surgery was performed between 8 and 12 weeks after

completing treatment. The technique was transanal endo-

scopic microsurgery (TEM) and the platform used was

Endorec® in the first period and Gel Point® later. The

patients were operated on in the jackknife, gynecological,

right or left lateral position, depending on the location of the

lesion, so that it was located below the position of the

instruments and the operator's eye. The laparoscopy equip-

ment used was Stryker®, composed of a high-resolution

LED camera and display, a 40lt high-flow insufflator and an

X8000.1 xenon light source.

In cases with doubtful or incomplete margins, a new LE was

indicated in T1, and resection with TME in T2. Those

patients in whom the specimen was fragmented were dis-

carded.

All surgical specimens were studied by one of the authors

(JPS), who evaluated the macroscopy by measuring the

surgical specimen, describing the appearance, consistency,

color and size of the tumors, and the distance to the lateral

and deep margins. Microscopy evaluated the degree of

differentiation, lymphovascular invasion, resection margin,

depth of invasion, and dedifferentiation/budding) (Figs. 1 y

2). To determine the presence or absence of lymphovascular

invasion, immunostaining was used to demonstrate vascular

endothelium (CD34, CD31, and/or D2-40) (Fig. 3). Differ-

entiation, lymphovascular invasion, deep invasion and

budding were considered risk features.

The authors declare no conflicts of interest. Angel M. Minetti: amminetti51@gmail.com

Received: June 15, 2023. Accepted: September 18, 2023.

Angel M. Minetti: https://orcid.org/0000-0003-1235-6904, Ignacio Pitaco: https://orcid.org/0000-0002-8450-0488, Juan Pablo Santilli: https://orcid.org/0000-0001-8165-2171,

Ignacio Ramallo: https://orcid.org/0000-0001-5139-3586, Facundo Carrasco: https://orcid.org/0000-0002-4193-9562.

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LOCAL EXCISION FOR STAGE I RECTAL CANCER Minetti AM., et al.

All patients were followed up by an interdisciplinary team.

Postoperative control was performed by physical examina-

tion, high-resolution MRI, computed tomography, and

tumor markers every 3 months. Colonoscopy was performed

one year after surgery.

RESULTS

Of the 13 patients, 6 were men and 7 women, the average

age was 63.1 (range 42-81) years. Lesions were located

between 2 and 8 (mean 4.07) cm from the anal verge. The

location was posterior: 6, anterior: 4, anterolateral: 2 and

posterolateral: 1.

Preoperative staging was performed in 7 patients, 4 were

T2N0 and 3 were T1N0. After the histopathological study, a

false negative was confirmed (T1 Sm3, in which two posi-

tive nodes were found in the surgical specimen after radical

resection).

In 6 patients with initial biopsy of villous adenoma, the final

pathological result was: T2N0 in 2, T1 sm3 in 1 and T1 sm1

in 3.

In 3 patients staged T2, neoadjuvant treatment was per-

formed, and the definitive pathological result was: yptT1 in

2 and complete pathological response in 1. In the remaining

10 patients who did not receive preoperative treatment, the

pathological result was: T2 in 3 (in 1 of them with positive

margins, an extended LE was performed), T1 Sm1 in 3 and

T1 Sm3 in 4 (1 with lymph node invasion, N1 final). In

relation to lymphovascular invasion, the remaining 8 were

negative. (Figs, 1, 2 and 3)

Figure 1. Histopathology. H&E (100X). Moderately differentiated

adenocarcinoma (ADC) with deep invasion of the submucosa (SM)

Sm3 (arrow). MP (muscularis propria).

Figure 2. Histopathology. H&E (400X). Neoplastic invasion of a

lymphatic vessel (arrow).

One patient had complications intraoperatively, with perfo-

ration of the cul-de-sac of Douglas, and two (15.4%) in the

postoperative period, with urethral perforation, and uncon-

trollable sacral pain.

After LE, TME was performed in two patients; one initially

had a villous adenoma that turned out to be a T2 adenocar-

cinoma with involved margins, (finally T2 N0). He under-

went radical resection 20 days after LE, and died 8 months

later due to pelvic carcinomatosis. Another patient had a T1

tumor with risk factors, (lymphovascular invasion and foci

of intermediate dedifferentiation), and the final pathological

report was T1N1 (Fig.4). This patient received adyuvant

treatment with FOLFOX.

Figure 3. Histopathology ( 400X). Immunohistochemistry for CD34

to label endothelium. Neoplastic vascular invasion is observed.

Figure 4. Histopathology. H&E (100X). Lymph node metastasis in a

T1 Sm3 adenocarcinoma (ADC), with dedifferentiation and

lymphovascular invasion. Intranodal neoplasia without capsular

rupture (arrow) can be seen. Preoperative staging by MRI and

endorectal ultrasound had been T1N0.

The remaining 12 patients have no evidence of local or

distant disease with an average follow-up of 54.5 (range 12-

120) months (Fig. 5).

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Figure 5. Long-term outcome.

DISCUSSION

The treatment of low rectal cancer is very well established

and includes TME and the addition of neoadjuvant treatment

in stages II and III. Although oncological results in terms of

local recurrence and survival have improved, the impact of

this treatment in quality of life is still high.

The classic LE described by Sir Alan Parks has shown that it

is possible to treat tumors confined to the mucosa and

submucosa with good results when they present favorable

histological factors. However, it is a technically-demanding

procedure and, consequently, the specimens resected are

frequently fractionated or with incomplete or doubtful

margins.

3,4

The development of TEM, as a variant approach, has re-

vealed better results with a lower rate of recurrence and

complications.

4,5

The good results of local resection in T1 tumors and the

notable response to radio and chemotherapy in advanced

tumors have led to the proposal of organ-preserving treat-

ment in lesions with muscular propria invasion.

6,7

Local resection in T2 tumors has shown local recurrence

rates of around 20% when no treatment is added. The use of

neoadjuvant therapy reduces these rates to around 5% to

12%, with a pathological complete response of 20% to 40%

and disease-free and overall survival rates comparable to

patients treated with TME.

8-10

When neoadjuvant therapy is used, staging notably loses

certainty, since the effect of CRT significantly distorts the

initial histological structure, regarding parietal invasion and

lymph nodes.

The accuracy of preoperative staging of

stage I rectal cancer has not been as high as desired. En-

dorectal ultrasound and high-resolution magnetic resonance

imaging (MRI) are commonly used alone or in combination.

The main difficulties encountered are that both procedures

are highly dependent on the operator and when it comes to

submucosal invasion close to the muscularis propria, con-

troversial interpretations are generated given the tenuous

changes that occur. Regarding the presence of pathologic

lymph nodes close to the tumor, MRI with or without diffu-

sion is presented as the best option based on the anatomical,

structural and diffusion changes. None of these characteris-

tics alone or in combination is a guarantee of neoplastic

involvement.

For these reasons, the results mentioned in

relation to T have a sensitivity and specificity of 87 and

75%, respectively, while for the involved lymph nodes it is

77 and 71%.

13-16

After neoadjuvant treatment, all nodes decrease in size and

approximately 44% disappear. MRI with the addition of

diffusion may improve outcomes. However, even in highly

trained hands the margin of error is 11%.

Most research regarding local resection in T2 tumors has

been developed with the use of neoadjuvant therapy. Some

series include conventional LE, TEM, and combined resec-

tions.

18-20

If initial imaging staging is not accurate and neo-

adjuvant treatment radically changes the pathologic find-

ings, then oncologic outcomes relative to the true initial

staging will be affected by these distortions.

The advantage of initially performing the resection is ob-

taining a virgin specimen that can be accurately staged by

histopathology which enables more precise decision-making

(adjuvant treatment, radical resection) in the presence of risk

factors.

Nodal invasion in rectal cancer has been widely studied.

Global analyzes indicate that when there is submucosal or

muscular involvement, the risk of metastasis is 12 and 23%,

respectively. In recent years, various authors have dedicated

themselves to investigate in detail the risk factors for lymph

node involvement.

Initially, Kikuchi et al.,

in 1995 described the importance

of the depth of submucosal invasion for lymph node metas-

tases in T1 carcinoma. The authors subcategorized accord-

ing to the depth of the submucosal invasion, into upper,

middle and lower third (Sm1, Sm2 and Sm3) invasion. The

series of 182 patients, operated on between 1982 and 1989

with a 5-year follow-up, included local, endoscopic or

surgical excision of the colon and rectum. Intestinal resec-

tions were performed in 108, and lymphatic metastases were

found in 13 (14.4%), 4 in Sm2, and 9 in Sm3. Of these, 9

had lymphatic invasion and 4 had vascular invasion. During

follow-up, 2 developed distant metastases.

Recently Ushigome et al.,

from the International Cancer

Institute of Osaka, published a study that investigated the

risk factors for lymph node metastasis in T2 rectal tumors

located below 10 cm from the anal verge, with radical

resections without prior treatment. Over a period of 10 years

(2008-2018), 95 patients were analyzed and lymphatic

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LOCAL EXCISION FOR STAGE I RECTAL CANCER Minetti AM., et al.

invasion was confirmed in 26 (27%), including 2 (2%) with

lateral pelvic invasion. Univariate analysis indicated that

lymphovascular invasion (p=0.008), tumor budding

(p=0.012), and dedifferentiation (p=0.08) were associated

with lymph node invasion. Multivariate analysis revealed

that lymphovascular invasion (p=0.03) was the only inde-

pendent risk factor. No lymph node metastases were found

in 8 cases that did not present any histological risk factor.

Invasion of the muscular layer ≥2 mm was not a risk factor

(p=0.854). They conclude that lymphovascular invasion,

budding and histological type may be risk factors for lymph

node invasion in low T2 rectal tumors.

Similar results were found by Rasheed et al.,

in a study of

55 T1 and 248 T2 patients. The incidence of involved lymph

nodes was 12.7 and 19%, respectively. There was no signif-

icant difference in the number of patients with involved

nodes according to the depth of tumor invasion Sm1-3, or

T2. In the multivariate analysis, the presence of extramural

vascular invasion (odds ratio = 10) and degree of tumor

differentiation (odds ratio for poorly vs. well differentiated =

11.7) were independent predictors of lymph node metastasis.

In this short series, 8 patients without lymphatic or vascular

invasion, regardless of the depth of tumor invasion, did not

receive neoadjuvant treatment and were free of local recur-

rence during follow-up.

Regarding the strategy to use in the presence of risk factors,

the debate that arises is whether to use adjuvant therapy

(chemotherapy, radiotherapy or both), adjuvant therapy and

surgery, or add total excision of the mesorectum only.

After LE, radical surgery performed in a short period of time

does not seem to affect the final outcome. This has been

demonstrated by Hahnloser et al.

After comparing 3

groups: 1) 52 patients treated with LE and TME within 30

days due to risk factors, 2) 78 patients who underwent

primary radical surgery, and 3) 77 patients treated only with

LE, they found no differences in survival and local recur-

rence at 5 or more years.

In our series, a patient with a T1 tumor with risk factors

(dedifferentiation and lymphovascular invasion) underwent

radical resection within 40 days and two 4-mm positive

lymph nodes were found in the surgical specimen. Chemo-

therapy was added and there was no evidence of local or

distant recurrence at 4 years of follow-up.

When, after LE, there are histological risk features, the

addition of adjuvant treatment is a valid alternative, with

long-term outcome similar to radical resection.

Sasaki et al.,

in 2017 reported the long-term results of a

multi-institutional phase II study in 53 patients with low T1

and T2 rectal cancers with adverse histological features that

underwent adjuvant treatment after LE. Follow-up at an

average of 7.3 years showed a 5-year disease-free survival

and overall survival of 94% and 75%, respectively.

In 2020, Kang Xu et al.

published a study comparing the

results of 62 patients with high-risk T1 or T2 tumors treated

by TEM with and without adjuvant treatment (20 and 42,

respectively). Follow-up was 52.5 months and showed a 3-

year overall survival of 93.3% for those treated with adju-

vant treatment vs. 66.6% for those treated with LE alone

(p=0.022). Local recurrence was 5 and 31%, respectively

(p=0.025). In the multivariate analysis, the only independent

prognostic factor was adjuvant treatment.

CONCLUSIONS

Local resection in stage I rectal cancer is feasible. The study

of the surgical specimen allows an exact pathological stag-

ing, defining the risk factors with certainty.

Subsequent treatment will depend on the histopathology of

the tumor and the surgical risk compared to a major resec-

tion.

The final decision must be agreed upon with the patient after

a deep and thoughtful understanding of the treatment pro-

posal.

When radical surgery is waived, follow-up at frequent

intervals that includes clinical monitoring, endoscopy, and

imaging studies is recommended.

The strategies currently used in the conservative treatment

of rectal cancer are promising, so they should be offered to

patients within the framework of a clinical trial with rigor-

ous and safe registration.

The quality of evidence to date is insufficient to replace the

current standard of care.

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