Extracapsular spread of nodal metastasis as a prognostic factor in rectal cancer

doi:10.1016/S0360-3016(03)01616-X

International Journal of Radiation OncologyBiologyPhysics

Volume 58, Issue 3, March 2004, Pages 773-778

https://doi.org/10.1016/S0360-3016(03)01616-X Get rights and content

Abstract

Purpose

To evaluate the prognostic value of lymph node metastasis with extracapsular extension (ECE) for local control and metastasis-free survival in rectal cancer.

Methods and materials

A total of 145 rectal cancer patients were treated with surgery and postoperative radiochemotherapy. Patients were grouped according to nodal status (node negative, n = 49; node positive without ECE, n = 64; node positive with ECE, n = 32). In addition, well-known prognostic factors such as International Union Against Cancer (UICC) stage, T and N stage, presence of lymphangiosis, and grade were assessed. The end points were analyzed by the Kaplan-Meier method, and prognostic factors were compared in a Cox regression model.

Results

Of the entire group, the actuarial 5-year local control and distant metastasis-free survival rate was 85% and 66%, respectively, after a median follow-up of 47 months (range, 14–104). Patients with ECE of lymph node metastasis had an impaired 5-year local control rate (58%) compared with node-negative (83%) and node-positive without extracapsular involvement patients (87%, p = 0.041). Metastasis-free survival also differed for the three groups, with a rate of 40% for those with extracapsular involvement, 54% for those without ECE, and 78% for node-negative patients (p <0.0001). The impact of ECE on local control was confirmed in the regression model (risk ratio [RR] 1.6, 95% confidence interval [CI] 1.01–2.7, p = 0.044). T stage was only of borderline significance (RR 2.4, 95% CI 1.0–5.7, p = 0.052). However, only UICC stage (RR 5.1, 95% CI 2.0–13.1, p <0.001) and the presence of lymphangiosis (RR 2.8, 95% CI 1.4–5.3, p = 0.002) were of independent prognostic value for distant metastasis.

Conclusion

ECE of node metastasis is connected with a substantial decline in local control. The frequency of distant metastasis is increased in this patient group as well, but stage and lymphangiosis are the independent factors for assessment of a patient's risk of systemic spread.

Introduction

Several randomized studies 1, 2, 3, 4, 5, 6 have shown a substantial benefit in local control, metastasis-free survival, and overall survival for rectal carcinoma patients with International Union Against Cancer (UICC) Stage II and III who receive postoperative radiochemotherapy compared with those receiving surgery alone or combined with single modality adjuvant treatment (i.e., chemotherapy or postoperative radiotherapy). Although the outcome for a small proportion of the treated patients obviously improves, most undergo a procedure with the potential for severe long-term morbidity 7, 8, 9, 10 but without any benefit in disease control. A better understanding of a patient's risk profile could allow individually adapted treatment decisions with the potential of toxicity sparing on the one hand and therapy intensification on the other.

Extracapsular extension (ECE) of lymph node metastasis is known to be of prognostic value in a variety of solid tumors, such as breast cancer 11, 12, vulvar carcinoma (13), head-and-neck cancers 14, 15, and cancer of an unknown primary (16). Although several studies have reported a major impact on local control, frequency of distant metastasis, and survival, only two histopathologic studies have provided data on the role of ECE in rectal carcinoma 17, 18.

We explored the hypothesis that ECE of lymph node metastasis in rectal cancer is connected with an increase in local and distant recurrence and compared its prognostic value with that of well-known factors such as UICC stage (25), T and N stage, grade, and the presence of lymphangiosis.

Section snippets

Inclusion criteria

All 145 patients who started simultaneous 5-fluorouracil–containing radiochemotherapy after surgery for Stage II and III rectal cancer in our department between January 1993 and December 2000 were included in the analysis. Preoperative staging for distant metastasis by abdominal ultrasonography or CT scan and chest X-ray was mandatory.

Clinical end points and follow-up

Three patient groups were analyzed for local control and freedom from distant spread: Node-negative patients and node-positive patients without and with ECE.

Results

The follow-up data of 145 patients were analyzed for the clinical end points of local control and distant metastasis-free survival. The median follow-up for the surviving patients was 47 months (range 14–104).

For the entire group, the actuarial 5-year survival rate was 64%, with a survival rate of 77% for patients with Stage II and 58% for those with Stage III disease. Of the 145 patients, 85% were free of local failure and 66% were free of distant metastasis after 5 years, resulting in a

Discussion

The overall and disease-free survival rates for our patients are in the range of results reported from large multicenter trials 20, 21, 22. Gunderson et al.(21) analyzed the treatment results of 2551 patients, most of whom underwent postoperative radiochemotherapy in three different randomized trials. According to their data, the 5-year survival rate of Stage II patients is expected to be between 65% and 74%, with a rate of 81% for Stage IIIA patients, 33–61% for Stage IIIB patients, and 38–48%

Conclusion

ECE of lymph node metastasis has a strong negative impact on local control independent of other prognostic factors. Furthermore, tumors with ECE have a high frequency of distant metastasis, but stage and lymphangiosis are the independent factors for the assessment of an individual patient's risk of systemic spread.

References (32)

L. Lundby et al.
Long-term colorectal function after postoperative radiotherapy for colorectal cancer
Lancet
(1997)
B.J. Fisher et al.
Extracapsular axillary node extension in patients receiving adjuvant systemic therapyAn indication for radiotherapy?
Int J Radiat Oncol Biol Phys
(1997)
J.A. Woolgar et al.
Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection
Oral Oncol
(1999)
J.R. Coster et al.
Cervical nodal metastasis of squamous cell carcinoma of unknown originIndications for withholding radiation therapy
Int J Radiat Oncol Biol Phys
(1992)
L.L. Gunderson et al.
Impact of T and N substage on survival and disease relapse in adjuvant rectal cancerA pooled analysis
Int J Radiat Oncol Biol Phys
(2002)
S.J. Cawthorn et al.
Extent of mesorectal spread and involvement of lateral resection margin as prognostic factors after surgery for rectal cancer
Lancet
(1990)
G.R. Jatzko et al.
Long-term results of radical surgery for rectal cancerMultivariate analysis of prognostic factors influencing survival and local recurrence
Eur J Surg Oncol
(1999)
Prolongation of the disease-free interval in surgically treated rectal carcinoma
N Engl J Med
(1985)
Survival after postoperative combination treatment of rectal carcinoma
N Engl J Med
(1986)
J.E. Krook et al.
Effective surgical adjuvant therapy for high-risk rectal carcinoma
N Engl J Med
(1991)

M.J. O'Connell et al.

Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery

N Engl J Med

(1994)

K.M. Tveit et al.

Randomized controlled trial of postoperative radiotherapy and short-term time-scheduled 5-fluorouracil against surgery alone in the treatment of Dukes B and C rectal cancer

Br J Surg

(1997)

Wolmark N, Wieand HS, Hyams DM, et al. Randomized trial of postoperative adjuvant chemotherapy with or without...

C.F. Kollmorgen et al.

The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function

Ann Surg

(1994)

B.S. Ooi et al.

Morbidities of adjuvant chemotherapy and radiotherapy for resectable rectal cancer

Dis Colon Rectum

(1999)

D. Hayne et al.

Anorectal injury following pelvic radiotherapy

Br J Surg

(2001)

Cited by (39)

Extracapsular extension and tumor implants in lymph nodes with canine mammary carcinoma metastasis: Study of the impact on survival
2021, Research in Veterinary Science
Citation Excerpt :
Among the impairments observed in the lymph node, we can highlight extracapsular extension (ECE), which is characterized by progression of the metastatic focus to the adjacent tissue by the lymph node capsule (Palamba et al., 2001; Altinyollar et al., 2007; Nottegar et al., 2016). ECE is known to have prognostic value in several human neoplasms, such as breast cancer (Bucci et al., 2001; Ilknur et al., 2004; Neri et al., 2005; Altinyollar et al., 2007; Geng et al., 2013; Nottegar et al., 2016), head and neck cancer (Leemans et al., 1993; Woolgar et al., 1999), tongue tumors (Zhou et al., 2006) and rectal cancer (Heide et al., 2004). Another change that may be found in lymph nodes with metastasis is the tumor implant (TI), represented by the presence of tumor cells in adjacent adipose tissue without nodal capsule involvement (Nottegar et al., 2016; Matta et al., 2017).
Regional lymph node status impacts survival in dogs with malignant mammary tumors. However, few studies have evaluated extracapsular extension and tumor implants in regional lymph node metastases in dogs with mammary carcinoma. Therefore, 84 cases of mammary carcinomas with metastases in inguinal and/or axillary lymph nodes from female dogs of different breeds and a total of 139 metastatic lymph nodes were evaluated by routine histological staining. Clinical and pathological characteristics of primary tumors as well as the presence of extracapsular extension and tumor implants in the lymph nodes were analyzed, in addition to survival. One to 5 lymph nodes were evaluated in each case. Extracapsular extension and tumor implants were present in 17.9% and 39.3% of cases, respectively. The simultaneous presence of extracapsular extension and tumor implants were associated with an increased risk of death (hazard ratio 10.46). In addition, “special type carcinomas”, high histological grade (grade III), and presence of extracapsular extension associated with tumor implants were related to a worse prognosis and shorter survival times (p < 0.05). Based on these results, we highlight the importance of identifying extracapsular extension and tumor implants in dogs with metastatic mammary carcinomas, as they are associated with a higher risk of death and shorter survival.
Prognostic Impact of Extranodal Extension in Rectal Cancer Patients Undergoing Radical Resection After Preoperative Chemoradiotherapy
2021, Clinical Colorectal Cancer
Citation Excerpt :
Furthermore, ENE positivity and recurrence patterns observed in this study were different from those reported in studies of ENE in CRC, excluding PCRT. In this study, 25.2% of the patients had ENE-positive pathology; this rate is around half the rate reported in studies excluding PCRT (33.3%-56%).19,23,24 The difference is expected to be the result of chemoradiotherapy effects.
Extranodal extension (ENE) of nodal metastasis has emerged as an important prognostic factor in many malignancies, including rectal cancer. However, its significance in patients with rectal cancer receiving preoperative chemoradiotherapy (PCRT) has not been extensively investigated. We therefore assessed ENE and its prognostic impact in a large series of consecutive rectal cancer patients with lymph node metastasis after PCRT and curative resection.
Between January 2000 and December 2014, a total of 1925 patients with rectal cancer underwent surgical resection after PCRT. Medical records of 469 patients with pathologic node positivity were retrospectively reviewed.
Of the 469 patients, 118 (25.2%) presented with ENE. ENE was observed more frequently in those with advanced tumor stage (higher ypT, ypN, and ypStage), lymphovascular invasion, and perineural invasion. Five-year disease-free survival rate was lower in patients with ENE-positive tumors than those with ENE-negative tumors (36.1% vs. 52.3%, P = .003). Similarly, 5-year overall survival rate was lower in patients with ENE-positive tumors than those with ENE-negative tumors (60.2% vs. 70.6%, P < .001). Multivariate analysis revealed that the presence of ENE was an independent poor prognostic factor for disease-free survival (hazard ratio = 1.412; 95% confidence interval, 1.074-1.857; P = .013) and overall survival (hazard ratio = 1.531; 95% confidence interval 1.149-2.039; P = .004).
The presence of ENE in patients with rectal cancer undergoing PCRT is a negative prognostic factor, reflecting poor survival outcome.
Prognostic impact and implications of extracapsular lymph node involvement in colorectal cancer: A systematic review with meta-analysis
2016, Annals of Oncology
The extranodal extension (ENE) of nodal metastasis (i.e. the extension of tumor cells through the nodal capsule into the perinodal adipose tissue) has recently emerged as an important prognostic factor in different types of malignancies. However, the tumor–node–metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a systematic review and meta-analysis to determine the prognostic role of ENE in patients with lymph node-positive colorectal cancer.
Two independent authors searched PubMed and SCOPUS until 7 January 2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with the presence of ENE (ENE+) versus only intranodal extension (ENE-) were eligible. Data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) together with 95% confidence intervals (CIs) for time-dependent risk related to ENE+, adjusted for potential confounders.
Thirteen studies including 1336 patients were identified with a median follow-up of 4.7 years. ENE was associated with a higher T stage and tumor grading. In addition, ENE was associated with a significantly increased risk of all-cause mortality (RR = 1.75; 95% CI 1.42–2.16, P < 0.0001, I² = 60%; HR = 1.69, 95% CI 1.32–2.17, P < 0.0001, I² = 46%) and of recurrence of disease (RR = 2.07, 95% CI 1.65–2.61, P < 0.0001, I² = 47%; HR = 2.31, 95% CI 1.54–3.44, P < 0.0001, I² = 48%).
Based of these results, in colorectal cancer, ENE should be considered from the gross sampling to the pathology report, as well as in future oncologic staging systems.
Prognostic factors affecting short-term outcome of curative rectal cancer resection
2013, Tzu Chi Medical Journal
The aim of this study was retrospectively to identify tumor characteristics or any other prognostic factors that influence disease survival after curative rectal cancer resection.
The records of 95 patients with Stages I, II, or III rectal cancer (TNM system) seen from August 2008 to June 2012 in one institution were reviewed. The patients underwent radical surgery (abdominoperineal resection or laparoanterior resection with lymph node dissection) as definitive therapy and then adjuvant treatment if pathology indicated T3 or T4 lesions, lymph node involvement, or positive margins. Radiation therapy (54 Gy) was delivered to the gross tumor volume and 45–50 Gy to the nodal region. The chemotherapy protocol consisted of 12 biweekly courses of oxaliplatin (85 mg/m²), 5-fluorouracil (FU) (400 mg/m²), and leucovorin (400 mg/m²) on Day 1, followed by continuous infusion of 5-FU (2400 mg/m²) for 48 hours.
The 3-year cumulative overall survival rates for Stages I, II, and III rectal cancer were 100%, 100%, and 75%, respectively. Univariate analysis for all 91 patients indicated that pN classification, stage, surgical margin ≤ 10 mm, and extracapsular spread (ECS) were significantly associated with overall survival. The pN classification and stage also significantly affected the disease-free survival and distant metastasis-free survival. Furthermore, univariate analysis indicated vascular permeation, neural invasion, and surgical margin ≤ 10 mm were significantly associated with disease-free survival. Vascular permeation also significantly affected distant metastasis-free survival. On multivariate analysis for all patients, pN classification and close surgical margin significantly affected disease-free survival.
The presence of lymph node involvement and close margins was associated with lower disease-free survival. More aggressive postoperative therapy is suggested for patients if these factors exist.
Incidence of small lymph node metastases with evidence of extracapsular extension: Clinical implications in patients with head and neck squamous cell carcinoma
2010, International Journal of Radiation Oncology Biology Physics
Small lymph nodes (LN) show evidence of extracapsular extension (ECE) in a significant number of patients. This study was performed to determine the impact of ECE in LN ≤7 mm as compared with ECE in larger LN.
All tumor-positive LN of 74 head and neck squamous cell carcinoma (HNSCC) patients with at least one ECE positive LN were analyzed retrospectively for the LN diameter and the extent of ECE. Clinical endpoints were regional relapse-free survival, distant metastasis-free survival, and overall survival. The median follow-up for the surviving patients was 2.1 years (range, 0.3–9.2 years).
Forty-four of 74 patients (60%) had at least one ECE positive LN ≤10 mm. These small ECE positive LN had a median diameter of 7 mm, which was used as a cutoff. Thirty patients (41%) had at least one ECE positive LN ≤7 mm. In both univariate and multivariate Cox regression analyses, the incidence of at least one ECE positive LN ≤7 mm was a statistically significant prognostic factor for decreased regional relapse-free survival (adjusted hazard ratio [HR]: 2.7, p = 0.03, 95% confidence interval [CI]: 1.1–6.4), distant metastasis-free survival (HR: 2.6, p = 0.04, 95% CI: 1.0-6.6), and overall survival (HR: 2.5, p = 0.03, 95% CI: 1.1–5.8).
The incidence of small ECE positive LN metastases is a significant prognostic factor in HNSCC patients. Small ECE positive LN may represent more invasive tumor biology and could be used as prognostic markers.
T2WI-based MRI radiomics for the prediction of preoperative extranodal extension and prognosis in resectable rectal cancer
2024, Insights into Imaging

View all citing articles on Scopus

View full text

Clinical investigationExtracapsular spread of nodal metastasis as a prognostic factor in rectal cancer

Abstract

Purpose

Methods and materials

Results

Conclusion

Introduction

Section snippets

Inclusion criteria

Clinical end points and follow-up

Results

Discussion

Conclusion

Lancet

Int J Radiat Oncol Biol Phys

Oral Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lancet

Eur J Surg Oncol

Prolongation of the disease-free interval in surgically treated rectal carcinoma

N Engl J Med

Survival after postoperative combination treatment of rectal carcinoma

N Engl J Med

Effective surgical adjuvant therapy for high-risk rectal carcinoma

N Engl J Med

Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery

N Engl J Med

Randomized controlled trial of postoperative radiotherapy and short-term time-scheduled 5-fluorouracil against surgery alone in the treatment of Dukes B and C rectal cancer

Br J Surg

The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function

Ann Surg

Morbidities of adjuvant chemotherapy and radiotherapy for resectable rectal cancer

Dis Colon Rectum

Anorectal injury following pelvic radiotherapy

Br J Surg

Clinical investigation
Extracapsular spread of nodal metastasis as a prognostic factor in rectal cancer