Value of Size and Malignant Features of Lateral Lymph Nodes in Risk Stratification at Lateral Local Recurrence of Rectal Cancer: A National Cohort Study

Authors:
Eline G.M. van Geffen Department of Surgery, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Cancer Center Amsterdam, Treatment and Quality of Life, Imaging and Biomarkers, Amsterdam, the Netherlands

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Tania C. Sluckin Department of Surgery, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Cancer Center Amsterdam, Treatment and Quality of Life, Imaging and Biomarkers, Amsterdam, the Netherlands

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Sanne-Marije J.A. Hazen Department of Surgery, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Cancer Center Amsterdam, Treatment and Quality of Life, Imaging and Biomarkers, Amsterdam, the Netherlands

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Karin Horsthuis Cancer Center Amsterdam, Treatment and Quality of Life, Imaging and Biomarkers, Amsterdam, the Netherlands
Department of Radiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

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Regina G.H. Beets-Tan Department of Radiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
GROW School for Oncology and Developmental Biology, University of Maastricht, Maastricht, the Netherlands
Department of Radiology, Odense University Hospital, Odense, Denmark
Department of Clinical Research University of Southern Denmark, Odense, Denmark

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Susan van Dieren Department of Surgery, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

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Corrie A.M. Marijnen Department of Radiation Oncology, Leiden UMC, Leiden, the Netherlands
Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands

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Pieter J. Tanis Cancer Center Amsterdam, Treatment and Quality of Life, Imaging and Biomarkers, Amsterdam, the Netherlands
Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus Medical Center, Rotterdam, the Netherlands

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Miranda Kusters Department of Surgery, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Cancer Center Amsterdam, Treatment and Quality of Life, Imaging and Biomarkers, Amsterdam, the Netherlands

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Background: Patients with rectal cancer who have enlarged lateral lymph nodes (LLNs) have an increased risk of lateral local recurrence (LLR). However, little is known about prognostic implications of malignant features (internal heterogeneity, irregular margins, loss of fatty hilum, and round shape) on MRI and number of enlarged LLNs, in addition to LLN size. Methods: Of the 3,057 patients with rectal cancer included in this national, retrospective, cross-sectional cohort study, 284 with a cT3–4 tumor located ≤8 cm from the anorectal junction who received neoadjuvant treatment and who had visible LLNs on MRI were selected. Imaging was reassessed by trained radiologists. LLNs were categorized based on size. Influence of malignant features and the number of LLNs on LLR was investigated. Results: Of 284 patients with at least 1 visible LLN, 122 (43%) had an enlarged node (≥7.0 mm) and 157 (55%) had malignant features. Of the 122 patients with enlarged nodes, 25 had multiple (≥2). In patients with a single enlarged node (n=97), a single malignant feature was associated with a 4-year LLR rate of 0% and multiple malignant features was associated with a rate of 17% (P=.060). In the group with multiple malignant features, their disappearance on restaging was associated with an LLR rate of 13% compared with an LLR rate of 20% for persistent malignant features (P=.532). The presence of intermediate-size LLNs (5.0–6.9 mm) with at least 1 malignant feature was associated with a 4-year LLR rate of 8%; the 4-year LLR rate was 13% when the malignant features persisted on restaging MRI (P=.409). Patients with multiple enlarged LLNs had a 4-year LLR rate of 28% compared with 11% for those with a single enlarged LLN (P=.059). Conclusions: The presence of multiple enlarged LLNs (≥7.0 mm), as well as multiple malignant features in an enlarged node contribute to the risk of developing an LLR. These radiologic features can be used for clinical decision-making regarding the potential benefit of LLN dissection.

Background

Over the past few decades, treatment strategies for patients with advanced rectal cancer have developed rapidly, and now the combination of neoadjuvant (chemo)radiotherapy ([C]RT) and total mesorectal excision (TME) has become the cornerstone of Western curative therapy.1 This has resulted in a decrease in local recurrence (LR) rates but a proportional increase in lateral local recurrences (LLRs), now comprising half of all LRs.2 These LLRs are most likely caused by spread to lateral lymph nodes (LLNs) located beyond the TME plane.3 An LLN dissection (LLND) has been proven effective in reducing LLRs and is widely used in Asian countries.4,5 However, it is a technically difficult procedure and is associated with increased morbidity. Hence, it is important to accurately predict which LLNs would lead to increased LLR rates in order to carefully select patients who might benefit from LLND, while sparing others who are at less risk for LLR.

The current American Society of Colon and Rectal Surgeons guidelines recommend an LLND for patients with suspicious LLNs,6 although the definition of “suspicious” remains controversial, with short-axis sizes of either >5.0 mm or ≥7.0 mm suggested as the cutoff.7,8 Conversely, for mesorectal lymph nodes, a clear definition of “suspicious” exists in the European Society of Gastrointestinal and Abdominal Radiology guideline based on a combination of size (<5 mm, 5–8 mm, and ≥9 mm) and malignant features (internal heterogeneity, irregular margins, and round shape), and the guideline recommends the same criteria be used for LLNs.9 However, multiple studies recently reported short-axis size (≥7.0 mm) to be the main predictor for LLR, which is associated with 5-year LLR rates up to 20% after (C)RT and TME only.911 This short-axis cutoff (≥7.0 mm) is implemented in the current Dutch guidelines, but other radiologic parameters, such as malignant features and the presence of multiple enlarged LLNs, have not yet been incorporated.1214

Only a few studies have previously investigated the presence of malignant features in LLNs. Ogura et al15 found no association between malignant features and LLR rates, whereas Kroon et al16 found an increased distant metastasis (DM) rate in the presence of malignant features. It is also unclear which malignant features are important; the study by Kroon et al16 used only irregular margins and internal heterogeneity, whereas other studies have also used loss of fatty hilum and round shape to describe potential malignant lymph nodes.12,17 Moreover, the focus of LLN research has thus far been on the largest LLN because it is thought to have the most malignant potential, but the potential impact of multiple enlarged LLNs has not yet been assessed.

We previously reported that the presence of any malignant feature was a predictor for LLR.11 The objective of this study was to perform an in-depth analysis of malignant features on primary or restaging MRI and the number of LLNs to determine their prognostic impact in addition to short-axis size.

Methods

The Snapshot Rectal Cancer 2016 study is a population-based, cross-sectional cohort study in which a detailed dataset of all patients treated for primary rectal cancer in 2016 in the Netherlands was gathered from the Dutch ColoRectal Audit (DCRA). The Snapshot Rectal Cancer 2016 study included 3,057 patients from 67 centers, and was extended with additional patient, diagnostic, and therapeutic variables between 2020 and 2022. Data collection was performed by local collaborative teams that included surgeons, residents, and abdominal radiologists. The study was approved by the Medical Research Ethics Committee of Amsterdam UMC in 2020, and local approval was obtained from local Institutional Review Boards. A more detailed description of the Snapshot Rectal Cancer 2016 study can be found in previous publications.11,18

Patient Selection

A subset of patients (those with stage ≥cT3 tumors ≤8 cm from the anorectal junction [ARJ]) underwent reassessment of the primary MRI scans, and if applicable, restaging MRI scans or MRI scans of recurrent rectal cancer was performed by 90 trained radiologists. These radiologists participated in a 2-hour dedicated training session regarding size, anatomic location, and malignant features of LLNs, as previously described.18 After training, significant improvements in assessments of size and location were reported.19 Patients with visible internal iliac and/or obturator LLNs on MRI reassessment who had received neoadjuvant (C)RT were selected (see Figure S1 in the supplementary materials, available online with this article). None underwent formal LLND.20 Oncologic outcomes for these patients versus those without LLNs or those who did not receive neoadjuvant therapy were previously published.11 Patients were excluded if they had synchronous DMs (within 3 months of surgery), were treated according to a watch-and-wait protocol (due to incomplete registration in the DCRA database), or had only external iliac or long-stretched obturator LLNs (short axis <5.0 mm, long axis:short axis ratio of ≥2:1, and no malignant features) because previous research showed they did not result in LLRs.11

Outcomes and Definitions

The main oncologic outcome was 4-year LLR rate, with 4-year LR and metachronous DM rates as secondary outcomes. Visible LLNs were categorized as small (<5.0 mm), intermediate (5.0–6.9 mm), or enlarged (≥7.0 mm) based on short-axis size. Analyses were performed per size category of the largest LLN. A recursive partitioning analysis was conducted to evaluate the prognostic value of the number of LLNs and the presence of malignant features (internal heterogeneity, irregular margins, loss of fatty hilum, and round shape) and their disappearance on restaging MRI scans, in addition to short-axis size. For analyses of multiple LLNs, the number of LLNs ipsilateral to the LLR or, in patients without an LLR, the largest number of LLNs (left or right side) was used. The influence of the number of malignant features on primary MRI and changes on restaging MRI for the largest LLN was analyzed in patients with only one enlarged LLN or intermediate LLN(s). For analyses of multiple intermediate LLNs, the malignant features on the largest LLN in patients who did not develop an LLR, or the malignant features on the largest LLN on the ipsilateral side of the LLR were used.

Statistics

SPSS Statistics, version 28 (IBM Corp) was used for analyses. Baseline characteristics were presented as numbers with percentages for categorical data, and as means with standard deviations for normally distributed continuous data. Subgroups were compared using independent t tests or chi-square tests. Oncologic outcomes (LLR, LR, DM) after surgical resection were assessed with Kaplan-Meier survival analyses and compared using log-rank tests. After testing Cox proportional hazard assumption in a log-minus-log plot, a Cox proportional hazards regression analysis was performed. Variables with a P value <.10 in univariate analyses were selected and eliminated backwards. It was not possible to conduct a multivariate analysis for (L)LR rate due to low event numbers. A P value <.05 was considered statistically significant.

Results

The 284 included patients had a median follow-up of 49 months (IQR, 33–55 months). Enlarged LLNs were associated with tumors located closer to the ARJ (mean distance, 2.2 vs 3.3 cm; P=.010), a higher cT stage (T4, 30% vs 10%; P=.014), and positive resection margins (15% vs 4% R1; P=.043) compared with smaller LLNs (Table 1).

Table 1.

Baseline Patient Characteristics

article image

Bold indicates statistically significant P value.

Abbreviations: ARJ, anorectal junction; ASA, American Society of Anesthesiologists; LLN, lateral lymph node; LOREC, English Low Rectal Cancer National Development Program; mrEMVI, MRI-detected extramural venous invasion; MRF, mesorectal fascia.

One missing value.

Lower border of the tumor is located beneath the insertion of the musculus levator ani as seen on coronal plane.

25 × 2 Gy or 28 × 1.8 Gy combined with chemotherapy.

Malignant features were present in 157 (55%) patients, and the number of malignant features increased with node size: 22% of the small, 47% of the intermediate, and 80% of the enlarged LLNs had ≥1 malignant features (P<.001). In small LLNs, round shape was the most frequently present malignant feature (7/21; 33%), whereas in enlarged LLNs, this feature was often present in combination with other features (see Supplementary Figure S2).

Types of Malignant Features of the Largest LLN

Among the 157 patients with malignant features in their largest node, 76% demonstrated internal heterogeneity, 66% demonstrated round shape, 59% demonstrated loss of fatty hilum, and 49% demonstrated irregular margins. When the presence of each separate malignant feature was compared with its absence, the association with increased (L)LR was found for internal heterogeneity, irregular margins, and loss of fatty hilum (Figure 1 and Supplementary Table S2). Only the presence of round shape was associated with decreased LLR risk compared with its absence (4-year LLR, 10% vs 18%; LR, 16% vs 27%). However, this association was not present in a subanalysis of enlarged LLNs.

Figure 1.
Figure 1.

Oncologic outcomes for patients with malignant features in their largest LLN; in patients with malignant features, the presence of each feature (heterogeneity, irregular margins, loss of fatty hilum, and round shape) is compared with absence of this feature in the largest LLN. Charts show 4-year (A) LR and (B) LLR rates for the whole cohort, and 4-year (C) LR and (D) LLR rates for patients with enlarged (≥7.0 mm) LLNs.

Abbreviations: LLN, lateral lymph node; LLR, lateral local recurrence; LR, local recurrence.

Citation: Journal of the National Comprehensive Cancer Network 22, 1; 10.6004/jnccn.2023.7081

Multiple Unilateral LLNs

Of 71 patients with a small LLN as their largest node, 21 had multiple unilateral LLNs, which did not lead to any LLRs; all 3 LLRs in this group occurred in patients with a single small LLN. In the intermediate LLN group, 12 of 91 patients had multiple intermediate unilateral LLNs, 1 of whom developed an LLR compared with 4 of 79 who had a single intermediate node.

Of 122 patients, 25 had multiple enlarged unilateral LLNs, which increased the 4-year LLR risk to 28%, compared with 11% in patients with 1 enlarged LLN per side (P=.059; Figure 2). Corresponding LR risks were 36% and 16% (P=.054) and DM risks were 40% and 35% (P=.586), respectively. All patients with multiple enlarged unilateral LLNs had at least 1 LLN with malignant features compared with 78% of patients who had only 1 enlarged LLN per side (P=.011). In 3 patients with multiple enlarged LLNs, the malignant features were not present in the largest LLN; 1 of these patients developed an LLR.

Figure 2.
Figure 2.

Number of enlarged LLNs related to LR and LLR risk. Graphs show 4-year (A) LR rates for patients with 1 (16.5%) or ≥2 (35.9%) enlarged LLNs (≥7.0 mm; P=.054), and (B) LLR rates for patients with 1 (10.8%) or ≥2 (28.4%) enlarged LLNs (≥7.0 mm; P=.059).

Abbreviations: LLN, lateral lymph node; LR, local recurrence; LLR, lateral local recurrence.

Citation: Journal of the National Comprehensive Cancer Network 22, 1; 10.6004/jnccn.2023.7081

Malignant Features on Primary MRI per Size Category

Of 71 patients with small LLNs, 3 developed an LLR, of which 1 had an LLN demonstrating malignant features (irregular margin and internal heterogeneity). Of the 91 patients intermediate LLNs, 5 developed an LLR (4-year LLR rate, 5%). In this group, 10 patients had 1 malignant feature, which resulted in 1 LLR. The LLR rate in the presence of ≥1 malignant features was 8% compared with 2% in the absence of malignant features (P=.561).

In those with a single enlarged LLN (≥7.0 mm; n=97), none of the patients without malignant features or with only 1 malignant feature developed an LLR (Figure 3). The presence of multiple (≥2) malignant features increased 4-year LLR risk to 17% (P=.060) compared with the absence or presence of 1 malignant feature. Corresponding LR rates for 0, 1, and multiple malignant features were 5%, 0%, and 24% (P=.050), whereas DM rates were 23%, 21%, and 43%, respectively (P=.190; Figure 3 and Supplementary Table S1). In multivariate analyses, the presence of multiple (≥2) malignant features was not associated with increased DM rate (Supplementary Table S1).

Figure 3.
Figure 3.

Number of malignant features related to LR and LLR rate. Analysis of 4-year (A) LR rates for patients with 0 (11.4%), 1 (9.6%), or ≥2 (23.4%) malignant features present in their largest LLN (P=.058), and (B) LLR rates for patients with 0 (3.6%), 1 (3.3%), or ≥2 (15.6%) malignant features present in their largest LLN (P=.008). Subanalysis of 4-year (C) LR rates for patients with a single enlarged LLN (≥7.0 mm) and 0 (5.0%), 1 (0%), or ≥2 (24.2%) malignant features (P=.0497), and (D) LLR rates for patients with a single enlarged LLN (≥7.0 mm) and 0 (0%), 1 (0%), or ≥2 (17.1%) malignant features (P=.060).

Abbreviations: LLN, lateral lymph node; LLR, lateral local recurrence; LR, local recurrence.

Citation: Journal of the National Comprehensive Cancer Network 22, 1; 10.6004/jnccn.2023.7081

Malignant Features of the Largest LLN on Restaging MRI

In 138 patients with malignant features on primary MRI, a restaging MRI was performed. In 41% (n=57) of the patients, malignant features disappeared; specifically, in 54% (7/13) of those with small LLNs, 50% (18/36) of those with intermediate LLNs, and 36% (32/89) of those with enlarged LLNs. If an LLN had 4 malignant features on primary MRI (n=18), 22% disappeared, compared with 39%, 40%, and 58% when 3 (n=44), 2 (n=45), or 1 (n=31) malignant feature(s) were present, respectively (P=.091). If a primarily enlarged LLN shrank to ≤4.0 mm short-axis size, malignant features disappeared more often (26/29 vs 24/78; P<.001), but shrinkage was not associated with a decrease in LLR rate (2/29 vs 2/78; P=.260).

In patients with intermediate LLNs (n=36), disappearance of malignant features resulted in a 4-year LLR rate of 7%, compared with 13% when they persisted (P=.409). In those with a single enlarged LLN with ≥2 malignant features, remaining malignant features (≥1) increased the 4-year LLR rate to 20%, compared with 13% when they disappeared (P=.532). In 2 patients, malignant features were found on restaging MRI but not on primary MRI; of those patients, 1 developed an LLR.

Based on short-axis size categories, the presence of multiple enlarged nodes, and the presence of malignant features and their disappearance on restaging MRI, LLNs can be classified into risk categories by 4-year LLR rates, as shown in Figure 4.

Figure 4.
Figure 4.

Recursive partitioning analyses of LLR risk based on radiologic features.

Abbreviations: LLN, lateral lymph node; LLR, lateral local recurrence; NA, not applicable.

aThe number of patients in which a restaging MRI was performed.

bDue to low number of patients, this group is classified as intermediate risk.

Citation: Journal of the National Comprehensive Cancer Network 22, 1; 10.6004/jnccn.2023.7081

Discussion

This national, cross-sectional cohort study included 284 patients with cT3–4 rectal cancer ≤8 cm from the ARJ treated with neoadjuvant therapy, and evaluated the prognostic impact of radiologic features of LLNs, primarily on 4-year LLR rate and secondarily on LR and DM rates. Although these findings should be interpreted with caution due to sample size and restricted statistical power, our data suggest that patients might be stratified into low-risk (0%–5%), intermediate-risk (5%–9%), and high-risk (≥10%) at LLR based on a combination of short-axis size, number of LLNs, and malignant features on primary and restaging MRI (Figure 4). The presence of multiple enlarged LLNs or one enlarged LLN with multiple malignant features is associated with a high 4-year LLR rate (28% and 17%, respectively), as are intermediate LLNs with persisting malignant features on restaging MRI (13%). In this high-risk group, on average 7 LLNDs are needed to prevent 1 LLR, assuming the LLR rate after LLND is <6%.7

The low-risk group includes patients with small LLNs or intermediate-sized LLNs without malignant features. The intermediate-risk group includes patients with intermediate-sized LLNs with malignant features that have disappeared on restaging MRI. No LLRs occurred in patients with 1 enlarged LLN without malignant features or with only 1 malignant feature, but because of the low patient numbers, these patients should, in our opinion, be classified as intermediate-risk.

Our results differ from previous studies, which found no influence of malignant features on LR and LLR rates or only increased DM rates for LLNs with irregular margins or internal heterogeneity.16,17 However, previous studies did not use loss of fatty hilum and internal heterogeneity as malignant features, whereas round shape is used as a prognostic factor in mesorectal lymph nodes, and loss of fatty hilum is commonly used in axillary lymph nodes in breast cancer.1214 Moreover, we incorporated dedicated training of radiologists, with a focus on systematically reporting all malignant features of LLNs. This study found LLR rates between 16% and 22% associated with the presence of any type of malignant feature. Only the presence of round shape was associated with lower LLR rates (16%) compared with its absence (18%), but this feature was more often present as a single feature in small LLNs, and this effect diminished in subanalyses of enlarged lymph nodes. The heterogeneous distribution of malignant features and their contribution to LLR rates stresses that it is important for all 4 malignant features to be adequately mentioned in radiology reports.

Lateral nodal disease behavior is still not thoroughly understood, and data can become confusing because there are few key publications on which to base treatment decisions. The Consortium Study7,15 found that compartment and restaging sizes in LLNs were important. However, our previous publication argued against this, based on probably more reliable Snapshot data due to training of radiologists.11 In addition to our previous publication in which LLND is recommended based on primary short-axis size, evaluation of malignant features and number of LLNs brings new insights and should therefore be mentioned in all radiology reports. Because standardized training can increase reporting of malignant features from 23% to 53%, we recommend that standardized assessment and reporting of LLNs be incorporated into the training program for all abdominal radiologists, especially for those with specific interest in rectal cancer.18 Because malignant features were present in only 157 patients (out of 1,227 with a ≥cT3 tumor located ≤8 cm from the ARJ), the extra workload for radiologists was negligible compared with the additional clinical value.

This study is limited by the number of events, with only 23 of the 284 included patients developing an LLR, which contributed to results concerning multiple LLNs and the influence of malignant features not reaching statistical significance. Enlarged LLNs in an unselected rectal cancer population are uncommon in a nonmetastasized setting (∼4%), and due to improved treatment, LLRs have a low incidence.11 Cohorts in which laternal nodal disease was analyzed are scarce, and a similar external cohort to validate data presented in Figure 4 is not easily available. The low event numbers limited the ability to assess the outcomes in a multivariable way and to correct for other poor prognostic factors (eg, higher cT stage, abdominoperineal resection, and involved resection margins). Still, thus far this is the largest cohort in which these specific research questions have been studied.

Another limitation is that no patients treated with a watch-and-wait approach or total neoadjuvant therapy (TNT) were included. Although a watch-and-wait trajectory is increasingly applied to patients with a complete clinical response, further research is needed, especially because neither downsizing nor disappearance of LLNs showed a decrease in recurrence rates in our cohort (still up to 15%). Although this cannot be derived from our current study, we believe that in the case of a clinical complete response of the primary tumor and shrinkage or disappearance of the LLN(s), an LLND is not needed and close surveillance is justified. Our experience is that there are patients in whom the LLN continues to grow, although there is no tumor regrowth, and an LLND is needed with the rectum left in situ, but this is very uncommon. Although more complete responders and thus fewer LLNDs might be expected after TNT, future studies must show what to do when there is an incomplete response of the tumor with downstaging of the LLNs by TNT.

Clinicians might encounter lateral nodal disease more often in a metastasized setting, given that LLNs are associated with advanced disease stage, strengthening the idea that LLNs might be considered as systemic tumor spread. However, this study analyzed LLNs in a nonmetastatic setting, and although 16 of 23 patients with an LLR developed metastases at the time of or after the LLR, LLNs lost prognostic value to distant spread in multivariate analyses, confirming previous publications arguing that lateral nodal disease is localized.11,15 In addition to lowering the LLR risk by LLND, this procedure might hypothetically also prevent DM.21 Most important is that preventing an LR, with its associated significant morbidity, should be the main goal in LLND. The oncologic benefit of the LLND should be weighed against possible harm in a shared decision-making process, taking patient preferences into account. The results of the currently open Lateral Nodal Recurrence in Rectal Cancer (LaNoReC) study, which aims to assess the LLR rate, morbidity, and quality of life in the population with enlarged LLNs when treated with LLND, may help to further develop a risk stratification to carefully select patients for LLND.

Conclusions

This study demonstrates the importance of number of enlarged LLNs and malignant features on primary and restaging MRI in addition to size for predicting oncologic outcomes for patients with stage cT3–4 rectal cancer ≤8 cm from the ARJ. These results provide novel insights into the prognostic importance of LLN characteristics other than size, which facilitates a more tailored treatment and/or follow-up approach for this population.

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    Schaap DP, Boogerd LSF, Konishi T, et al. Rectal cancer lateral lymph nodes: multicentre study of the impact of obturator and internal iliac nodes on oncological outcomes. Br J Surg 2021;108:205213.

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Submitted April 26, 2023; final revision received August 22, 2023; accepted for publication September 1, 2023.

A list of the Dutch Snapshot Research Group collaborators is provided in Appendix 1 in the supplementary materials (available online with this article).

Author contributions: Conceptualization: van Geffen, Sluckin, Hazen, Horsthuis, Beets-Tan, Marijnen, Tanis, Kusters. Statistical analysis: van Geffen, van Dieren. Supervision: Tanis, Kusters. Manuscript preparation: van Geffen, Beets-Tan, van Dieren, Marijnen, Tanis, Kusters.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by KWF Kankerbestrijding (12768; M. Kusters).

Supplementary material: Supplementary material associated with this article is available online at https://doi.org/10.6004/jnccn.2023.7081. The supplementary material has been supplied by the author(s) and appears in its originally submitted form. It has not been edited or vetted by JNCCN. All contents and opinions are solely those of the author. Any comments or questions related to the supplementary materials should be directed to the corresponding author.

Correspondence: Miranda Kusters, MD, PhD, Department of Surgery, Amsterdam UMC, Vrije Universiteit Amsterdam, P.O. Box 7057, 1007 MB, Amsterdam, the Netherlands. Email: m.kusters@amsterdamumc.nl

Supplementary Materials

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  • Figure 1.

    Oncologic outcomes for patients with malignant features in their largest LLN; in patients with malignant features, the presence of each feature (heterogeneity, irregular margins, loss of fatty hilum, and round shape) is compared with absence of this feature in the largest LLN. Charts show 4-year (A) LR and (B) LLR rates for the whole cohort, and 4-year (C) LR and (D) LLR rates for patients with enlarged (≥7.0 mm) LLNs.

    Abbreviations: LLN, lateral lymph node; LLR, lateral local recurrence; LR, local recurrence.

  • Figure 2.

    Number of enlarged LLNs related to LR and LLR risk. Graphs show 4-year (A) LR rates for patients with 1 (16.5%) or ≥2 (35.9%) enlarged LLNs (≥7.0 mm; P=.054), and (B) LLR rates for patients with 1 (10.8%) or ≥2 (28.4%) enlarged LLNs (≥7.0 mm; P=.059).

    Abbreviations: LLN, lateral lymph node; LR, local recurrence; LLR, lateral local recurrence.

  • Figure 3.

    Number of malignant features related to LR and LLR rate. Analysis of 4-year (A) LR rates for patients with 0 (11.4%), 1 (9.6%), or ≥2 (23.4%) malignant features present in their largest LLN (P=.058), and (B) LLR rates for patients with 0 (3.6%), 1 (3.3%), or ≥2 (15.6%) malignant features present in their largest LLN (P=.008). Subanalysis of 4-year (C) LR rates for patients with a single enlarged LLN (≥7.0 mm) and 0 (5.0%), 1 (0%), or ≥2 (24.2%) malignant features (P=.0497), and (D) LLR rates for patients with a single enlarged LLN (≥7.0 mm) and 0 (0%), 1 (0%), or ≥2 (17.1%) malignant features (P=.060).

    Abbreviations: LLN, lateral lymph node; LLR, lateral local recurrence; LR, local recurrence.

  • Figure 4.

    Recursive partitioning analyses of LLR risk based on radiologic features.

    Abbreviations: LLN, lateral lymph node; LLR, lateral local recurrence; NA, not applicable.

    aThe number of patients in which a restaging MRI was performed.

    bDue to low number of patients, this group is classified as intermediate risk.

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