Concept of Depth of Invasion Can Improve Staging Performance in Patients with Resected Distal Cholangiocarcinoma: Validation of the American Joint Committee on Cancer Staging System
Article information
Abstract
Purpose
The American Joint Committee on Cancer (AJCC) staging system for distal cholangiocarcinoma (dCC) has evolved significantly. However, the prognostic correlation of the newly proposed staging system remains unclear. Therefore, we aimed to compare the staging performance between AJCC 7th and 8th editions for dCC.
Materials and Methods
We reviewed pathological slides of consecutive patients who underwent resection for dCC between 2000 and 2022. According to the AJCC 8th edition, depth of invasion was defined as the distance from the basement membrane of adjacent normal or dysplastic epithelium to the deepest tumor invasion. We analyzed changes in the T category from the AJCC 7th to 8th edition and assessed overall survival and recurrence based on these staging systems.
Results
Among 428 patients, application of the 8th edition resulted in down-staging of 272 (63.6%) patients and up-staging of only 13 (3.0%). Lymph node metastases were identified in 150 (35.1%) patients, with 29 (6.8%) having ≥ 4 metastatic nodes. The C-indices for overall survival and recurrence are 0.557 and 0.569 for the T category of the AJCC 7th edition, and 0.606 and 0.631 for that of the AJCC 8th edition (95% confidence interval for delta, 0.005 to 0.092 for survival, 0.023 to 0.100 for recurrence). Additionally, the T category of the 8th edition correlated more strongly with lymph node metastases than that of the 7th edition.
Conclusion
In dCC, the T category of the AJCC 8th edition demonstrates improved prognostic correlation and better alignment with lymph node metastases compared to that of the 7th edition.
Introduction
Although cholangiocarcinoma is rare, accounting for 3% of gastrointestinal cancers, its incidence is rising worldwide [1]. There is significant global variation in cholangiocarcinoma incidence, with the highest rates observed in Asia [2]. Extrahepatic biliary malignancies comprise both hilar cholangiocarcinoma and distal cholangiocarcinoma (dCC), with an estimated annual incidence of 4,639 patients in South Korea [3]. Although hilar cholangiocarcinoma and dCC originate from the extrahepatic bile duct, they differ significantly in clinical characteristics, including surgical approach and prognosis [4]. Since chemotherapy is generally ineffective, curative surgery remains the primary treatment for both diseases. However, hilar cholangiocarcinoma frequently extends into the liver, necessitating distinct surgical approaches compared to dCC. Additionally, recent research has revealed differences in genomic alterations between hilar cholangiocarcinoma and dCC [5].
Since 1977, the American Joint Committee on Cancer (AJCC) has developed staging systems for various malignancies, which have been widely used to assess cancer extent. The current 8th version was released in 2016 [6]. Compared to other cancer types, the staging system for dCC has undergone substantial modifications over time. First, until the 6th edition, hilar cholangiocarcinoma and dCC shared the same staging system. However, beginning with the 7th edition, separate staging systems were developed to account for their distinct clinical characteristics. Second, the T category of the AJCC 7th edition was determined by whether the tumor was confined to the bile duct wall, whereas the 8th edition introduced the concept of depth of invasion, replacing the previous layer-based system. Hong et al. (2007) [7] first proposed this concept, as many pathologists encountered difficulties in distinguishing the T category of the AJCC 7th edition due to the irregularly arranged concentric tissue layers of the extrahepatic bile duct and the thin wall of the normal bile duct. Although the primary goal of a staging system is to predict patient prognosis, only a limited number of studies have addressed this issue [8-11]. Third, in the 7th edition, the N category was classified into N0 and N1 based on the presence of lymph node involvement. In contrast, the 8th edition introduced a new N2 category for patients with four or more involved lymph nodes. Some studies suggest that incorporating the number or ratio of involved lymph nodes could enhance staging system performance [12-16]. However, due to the small sample sizes in previous studies, the prognostic value of these nodal parameters remains debatable. Therefore, we aimed to evaluate and compare the performance of the AJCC 7th and 8th edition staging systems in a large cohort of patients with resected dCC.
Materials and Methods
1. Patient cohort
This study included patients who were histologically diagnosed with dCC following upfront curative pancreaticoduodenectomy between 2000 and 2022. Patients were excluded if they had insufficient clinical or pathological data (n=175), a histological subtype other than adenocarcinoma (n=6), a history of previous bile duct resection (n=4), a history of other cancers within the past 5 years (n=4), or were classified as T4 (n=1). The T4 category was excluded due to the difficulty in determining statistical significance. Since resection is not feasible for most patients with T4 tumors, these cases were excluded from the pathological stage-based analysis. Ultimately, 428 eligible patients were included (S1 Fig.).
2. Surgery and pathological evaluation
All surgeries included regional lymph node dissection, targeting nodes around the common hepatic artery, hepatoduodenal ligament, and posteriosuperior pancreatic head [17]. Surgical specimens were serially sectioned at 5-7 mm intervals. Pathologic slides were digitized as electronic files using a slide scanner and imaging program (APERIO ImageScope software, v12.3.2.8013, Leica Biosystems Imaging Inc.). After sufficient discussion to obtain a consensus on the staging evaluation, two specialized gastrointestinal pathologists reviewed the computerized image files according to the AJCC 7th and 8th edition staging systems. In cases that were challenging to assess, additional discussion was required to determine the AJCC stage. Additionally, all possible cases (n=618) were reviewed using archived slides, but cases that were inadequate to assess the depth of invasion or had insufficient clinical information were excluded (n=175). For the AJCC 8th edition, depth of invasion was measured as the distance from the basement membrane of the adjacent normal or dysplastic epithelium to the point of deepest tumor invasion [7].
3. Postoperative evaluation
Computed tomography was performed on postoperative day 4 to assess operative morbidity. A clinically relevant complication was defined as that with Clavien-Dindo grade 3 or higher, and a clinically relevant postoperative pancreatic fistula was defined as that with International Study Group of Pancreatic Surgery grade B or C [18,19]. Patients were followed up with computed tomography of the abdomen and pelvis and tumor marker assessments every 3 months for 2 years after surgery and every 6 months thereafter until 5 years postoperatively. Recurrence was diagnosed based on radiological evidence of disease. Overall recurrence was defined as any form of recurrence occurring first during follow-up, and overall survival was measured as the interval from the date of surgery to death or the last hospital visit.
At our institution, adjuvant treatment was recommended for all patients except those with pathological stage T1N0. However, the decision to proceed with adjuvant treatment was finalized after a multidisciplinary meeting and discussion with the patient regarding the potential adverse effects and their performance status.
4. Statistical analysis
Continuous variables are expressed as median values with interquartile ranges or as counts with percentages based on standard cut-off values (carcinoembryonic antigen, 5 ng/mL; carbohydrate antigen 19-9, 37 U/mL). Categorical variables are expressed as counts with percentages. Kaplan-Meier analyses and log-rank tests were used to assess differences in overall recurrence and survival among groups stratified by pathological stage. Variables associated with overall recurrence or survival were included in Cox proportional hazards regression models. Independent variables with p < 0.25 in the univariate analysis were included in the multivariate models. Results are reported as hazard ratios (HR) with 95% confidence intervals (CI). Harrell’s concordance index (C-index) was applied to the Cox proportional hazards regression models to compare the discriminatory power of the staging systems; a higher C-index value indicated greater precision in outcome prediction [20]. Throughout the study, statistical significance was set at p < 0.05. All statistical analyses were conducted using R software, ver. 4.4.0 (R Foundation for Statistical Computing).
Results
1. Patient, tumor, and treatment characteristics
Clinical characteristics are summarized in Table 1. The cohort consisted of 292 men (68.2%) and 136 women (31.8%) with a median age of 67 years. Following surgery, 280 patients (65.4%) were classified as T3 according to the AJCC 7th edition, whereas only 62 patients (14.5%) were classified as T3 under the AJCC 8th edition. Lymph node metastases were identified in 150 patients (35.1%), and only 29 patients (6.8%) had four or more metastatic lymph nodes. Fewer than half of the patients received adjuvant chemotherapy (n=204, 47.7%) or radiotherapy (n=192, 44.9%).
Baseline characteristics of entire cohort
2. Changes of T category according to the staging system
Table 1 demonstrates significant differences in the distribution of T categories between the AJCC 7th and 8th editions. Fig. 1 illustrates the changes of T category classification between the two staging systems. Overall, when the 8th edition was applied, 272 patients (63.6%) were down-staged, while only 13 patients (3.0%) were up-staged. Among the 113 patients classified as T2 under the AJCC 7th edition, 50 (44.2%) were re-classified as T1. Among the 280 patients classified as T3 under the 7th edition, 47 (16.8%) and 175 (62.5%) were re-classified as T1 and T2, respectively.
Changes in distribution of the T category from the American Joint Committee on Cancer (AJCC) 7th edition to the 8th edition.
Fig. 2 shows representative examples of T category transition. These two cases were both classified as T3 according to the AJCC 7th edition because they invaded pancreas; however, these turned out to be T1 and T2 based on the AJCC 8th edition because the depths of invasion were 3.03 and 7.02 mm, respectively.
Representative histologic images of cases categorized as T1 (A) and T2 (B) according to the American Joint Committee on Cancer (AJCC) 8th edition but as T3 according to the AJCC 7th edition.
3. Prognostic power of T category
Based on the AJCC 7th edition, no significant differences were observed in 5-year overall survival rates between patients with T1 and T2 categories (71.7% vs. 57.7%, p=0.071), nor between those with T2 and T3 categories (57.7% vs. 48.7%, p=0.116) (Fig. 3A). However, based on the AJCC 8th edition, patients with T1 category had a significantly higher 5-year overall survival rate than those with T2 category (71.5% vs. 48.2%, p < 0.001), and a similar trend was observed between patients with T2 and T3 categories (48.2% vs. 37.2%, p=0.044) (Fig. 3B). A similar pattern was observed for overall recurrence. Based on the AJCC 7th edition, there was no significant difference in 5-year overall recurrence rates between patients with T1 and T2 categories (34.9% vs. 47.4%, p=0.219) (Fig. 3C). However, in the AJCC 8th edition, the T category provided significantly stratified 5-year overall recurrence rates (T1 vs. T2 vs. T3, 30.5% vs. 62.7% vs. 80.4%) (Fig. 3D).
Overall survival according to the T category of American Joint Committee on Cancer (AJCC) 7th (A) and 8th (B) editions and overall recurrence according to the T category of AJCC 7th (C) and 8th (D) editions.
To further evaluate prognostic differences based on T category changes, survival analyses were conducted according to the T category classifications of the 8th edition in patients originally classified as T1, T2, and T3 under the 7th edition (S2 Fig.). Among patients classified as T2 or T3 in the 7th edition, those reclassified as T1 in the 8th edition had better survival outcomes than those reclassified as T2. Conversely, survival analyses were performed according to the T category classifications of the 7th edition in patients originally classified as T1, T2, and T3 under the 8th edition (S3 Fig.). No significant differences in overall survival were observed in any comparison between groups.
4. N category according to T category
Patients without lymph node metastases had a significantly higher 5-year overall survival rate than those with lymph node metastases (61.8% vs. 36.1%, p < 0.001) (S4A Fig.). Additionally, there were significant differences in 5-year overall recurrence rates between these two groups (48.1% vs. 72.7%, p < 0.001) (S4B Fig.). Regarding the N2 category introduced in the AJCC 8th edition, patients with N2 category had a significantly higher 5-year overall recurrence rate than those with N1 category (100.0% vs. 68.4%, p=0.026) (S4C Fig.). However, no significant differences in overall survival were observed between patients with N1 and N2 categories (S4D Fig.).
Given that lymph node metastases are established as poor prognostic factors, we examined the ability of the T category to predict lymph node metastasis status (Fig. 4). Among patients with lymph node metastases, lymph node ratio (number of involved lymph nodes/number of harvested lymph nodes) did not significantly correlate with the T category of the 7th edition (p=0.250). However, it increased gradually with higher T categories of the 8th edition (p=0.003) (Fig. 4A and B). Significant differences were observed in the proportion of N2 category between patients with T2 and T3 categories based on the 8th edition (6.6% vs. 16.1%, p=0.009). However, no significant differences were found according to the 7th edition (4.5% vs. 7.9%, p=0.228) (Fig. 4C).
Lymph node ratio in patients with lymph node metastases according to the T category of the American Joint Committee on Cancer (AJCC) 7th (A) and 8th (B) editions and N category (C) according to the T category of the AJCC 7th and 8th editions.
5. Comparison of prognosis predictability of staging systems
S5 Table summarizes the independent factors associated with overall survival and recurrence. Male sex, elevated carcinoembryonic antigen, lymph node metastases, and the absence of adjuvant chemotherapy were identified as poor prognostic factors for both overall survival and recurrence. A higher T category (T1 vs. T2, T2 vs. T3) based on the AJCC 8th edition was identified as a poor prognostic factor for overall recurrence. However, a higher T category (T2 vs. T1) based on the 7th edition was not a significant prognostic factor for overall recurrence (HR, 0.71; 95% CI, 0.38 to 1.32; p=0.278).
The C-indices for overall survival and recurrence are 0.557 and 0.569, respectively, for the T category of the AJCC 7th edition, and 0.606 and 0.631 for that of the 8th edition (Tables 2 and 3). Additionally, the area under the curve for predicting lymph node metastases and N2 category was 0.575 and 0.558, respectively, for the T category of the AJCC 7th edition, compared to 0.632 and 0.661 for that of the 8th edition. These findings suggest that the 8th edition provides superior prognostic stratification compared to the 7th edition. The C-indices for overall survival and recurrence were 0.602 and 0.599, respectively, for the N category of the AJCC 7th edition, and 0.605 and 0.605 for that of the 8th edition. Although the C-indices of the 8th edition were slightly higher than those of the 7th edition, the differences were not statistically significant, as the 95% CI included 0.
Comparison of the prognostic predictability between the AJCC 7th and 8th edition
Comparison of lymph node metastasis predictability between the AJCC 7th and 8th edition
Discussion
In the T category of the AJCC 8th edition, the concept of depth of invasion was newly introduced. Although an increasing number of studies report the strong prognostic value of the new T category, measuring the depth of invasion remains challenging, and validation using large-scale databases is still limited. This study represents one of the largest cohort studies evaluating the performance of the AJCC staging system for dCC. When the 8th edition was applied, more than 60% of patients were down-staged, while only approximately 3% were up-staged. Our findings indicate that the T category of the AJCC 8th edition demonstrates superior staging performance compared to that of the 7th edition. Additionally, higher N category and lymph node ratio, which are well known as poor prognostic factors, well correlated with the T category of the AJCC 8th edition.
The T category, an independent prognostic factor, typically refers to the size and extent of the primary tumor in most cancers. In most gastrointestinal malignancies, including esophageal, gastric, and colorectal cancers, the T category is determined by the depth of invasion into specific tissue layers [21-23]. However, unlike other gastrointestinal cancers, which have uniformly arranged concentric tissue layers, the histology of the extrahepatic bile duct wall varies along its length. While the upper extrahepatic bile duct wall contains sparse or absent muscle fibers, the lower portion consists of large bundles of smooth muscle fibers [24]. Additionally, muscle fibers are interspersed with varying amounts of fibrous or loose connective tissue and are not always arranged in a continuous layer. Therefore, pathologists face challenges in evaluating the T category of the AJCC 7th edition due to indistinct tissue boundaries, further complicated by desmoplastic response-induced distortion. Furthermore, under the AJCC 7th edition, invasion through the extrahepatic bile duct wall is considered equivalent to invasion into an adjacent organ, given that the extrahepatic bile duct courses through the pancreas. In our study, the distribution of patients across T categories in the AJCC 7th edition was highly skewed, with fewer than 10% classified as T1 and over 60% as T3. This pattern has also been reported in other studies [25,26]. As illustrated in Fig. 2, the prognoses for patients classified as T1 in both the 7th and 8th editions were similar. However, patients classified as T2 or T3 of the 8th edition have worse prognoses compared to those classified as T2 or T3 of the 7th edition. These findings suggest that the histological complexity of the extrahepatic bile duct may have contributed to an overestimation of T2 and T3 categories of the 7th edition.
Although the T category of the AJCC 8th edition appears to be more objective and serves as a prognostic factor in dCC, accurately measuring the depth of invasion remains challenging. To obtain precise measurements, the basal lamina defining the tumor boundary and the deepest point of cancer infiltration must be clearly visible on the same histological slide. However, several factors often hinder clear visualization of the basal lamina. First, preoperative cholangitis and catheter placements for biliary drainage can induce fibrosis both within and outside the bile duct wall [27,28]. Second, in terms of specimen handling, depth of invasion measurement may be feasible only in specimens where the bile duct is sectioned longitudinally, allowing the most advanced tumor area to be sampled along with the tumor boundary on the same histological slide [29]. Third, Aoyama et al. (2018) [11] reported that depth of invasion is difficult to measure in advanced tumors with a non-papillary configuration. They reported that depth of invasion could be measured in 91.0% of patients with papillary tumors but only in 32.3% of those with non-papillary tumors [11]. Additionally, they reported that invasive tumor thickness may be a more versatile and reliable parameter for assessing tumor depth compared to depth of invasion [9]. Similarly, Park et al. (2020) [26] applied three distinct methods to quantify tumor depth and confirmed that all three were effective in differentiating prognoses. These findings suggest that while the T category of the AJCC 8th edition provides valuable prognostic information, further refinement is needed. Future studies incorporating perspectives from surgeons, pathologists, and medical oncologists will be essential to improving staging accuracy.
Number-based node classification is straightforward to apply and aligns with tumor staging in other gastrointestinal cancers. However, while lymph node ratio is a well-established prognostic indicator for several malignancies, its prognostic value in dCC remains debatable. Kiriyama et al. (2015) [16] proposed that a cut-off of four metastatic lymph nodes was significantly associated with poor outcomes. However, this finding has not been consistently reproduced in other studies. Kang et al. (2019) [30] reported that the N category of the AJCC 8th edition had superior prognostic accuracy compared to that of the 7th edition, whereas Jun et al. (2019) [25] found no significant difference in overall survival between patients classified as N1 and N2 (p=0.579). These discrepancies may result from regional variations in medical practices and healthcare settings. First, lymph node dissection techniques vary among surgeons; some perform station-by-station dissection, while others opt for en-bloc dissection. In the latter case, the number of involved lymph nodes could be underestimated. Second, Kang et al. (2019) [30] reported significant differences in the proportion of patients classified as N2 across Korean (2.3%), Japanese (14.7%), and American (25.0%) centers (p < 0.001). Numerous factors, including differences in dCC prevalence and access to medical care, may contribute to these variations. Therefore, the newly proposed three-tier N category requires further validation using international datasets.
The current findings should be interpreted considering several limitations. First, this was a retrospective cohort study, which may have introduced potential selection bias. Second, considering the difficulty in measuring depth of invasion and the issues of reproducibility, the ideal approach for staging evaluation would be for several pathologists to independently examine every slide. However, in practice, this would be too burdensome, and we have made up for some of these drawbacks based on our previous experience conducting research on a similar topic. Third, the indication for adjuvant treatment at our institution is relatively ambiguous, as this study includes patients treated over an extended period, during which international consensus on the role of adjuvant treatment in dCC has remained debatable.
This study demonstrated that the T category of the AJCC 8th edition correlates more strongly with patient prognosis in dCC than that of the 7th edition. Additionally, the higher T category of the 8th edition correlates well with a higher N category and lymph node ratio. Further studies are needed to establish objective measurement methods for the depth of invasion and to validate the prognostic accuracy of the newly introduced three-tier N category.
Electronic Supplementary Material
Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).
Notes
Ethical Statement
This single-center retrospective cohort study was approved by the Institutional Review Board of Seoul National University Hospital (H-2412-062-1594). This study was conducted in accordance with the 1975 Declaration of Helsinki and its later versions. The requirement for informed consent was waived.
Author Contributions
Conceived and designed the analysis: Yun WG, Jang JY.
Collected the data: Yun WG, Chae YS, Han Y, Cho YJ, Jung HS, Kwon W, Park JS, Kim H, Lee KB, Jang JY.
Contributed data or analysis tools: Yun WG, Chae YS, Han Y, Cho YJ, Jung HS, Kwon W, Park JS, Kim H, Lee KB, Jang JY.
Performed the analysis: Yun WG.
Wrote the paper: Yun WG.
Paper review: Yun WG, Chae YS, Han Y, Cho YJ, Jung HS, Kwon W, Park JS, Kim H, Lee KB, Jang JY.
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
Funding
This work was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Number: HI23C1591).