Modelling the probability of erroneous negative lymph node staging in patients with colon cancer

Colon cancer is the most frequent malignancy in both sexes in Western countries, with an incidence of approximately 471,000 cases per year and a mortality of 228,000 cases per year in Europe [1]. Lymph node (LN) involvement is the prognostic factor most directly related to the survival and disease-free interval of cancer patients. Thus, patients with stages I and II cancers have a 5-year overall survival (OS) rate higher than 75% compared to 30%–60% in patients with stages III and IV cancers [2–4]. Tumor-node-metastasis (TNM) classification is the gold standard method for staging colon cancer, however, this system recommends collecting at least 12 LNs for correct staging. Despite the multidisciplinary approach to LN analysis in colon cancer, for various reasons related to patients, surgeons, and pathologists, the number of LNs analysed is very variable between patients [5], and significantly fewer than 12 are usually analysed [6, 7]. Without a doubt, patients with a pN0 LN staging have the highest risk (in terms of their therapeutic management) of suffering the most harmful consequences of being given an incorrect classification and prognosis. Calculation of the final error probability (FEP), i.e. the probability that the patients will present undiagnosed LN involvement, would be very useful for predicting the real prognosis and possible indications for adjuvant treatment among these patients.

The Bayes’ theorem statistical method can be used to calculate the probability of presenting affected LNs even when a patient presents negative anatomopathological study results. It considers the anatomopathological study of the surgical specimen as a diagnostic test with a binary result in this case: positive LNs (presence of disease) or negative LNs (absence of disease) [8]. The probability of a patient having the disease, even when given a negative test result (i.e., the probability that a patient with a negative histological study result has an unidentified lymph-node metastasis) is represented by the complementary value of the final negative predictive value. The objective of this work was to establish the predictive capacity and prognostic discriminative ability of the FEP among patients with colon cancer and with a potentially incorrectly-staged LN-negative disease.

During the period from January 2004 to December 2007, 944 patients were diagnosed with colon cancer in Castellon province (Spain), 140 of which were not operated on because they had contraindications for anaesthesia or because they had unresectable neoplasms. Eighty-three patients were operated on with palliative intention and did not have an accurate lymphadenectomy record and so were not included in this work. We also excluded 116 cases with colon neoplasms that did receive an intervention but who also presented synchronous distant metastases. Insufficient data were obtained regarding the number of LNs analysed and affected in 49 cases and for 8 of the patients, there were no follow-up data recorded. Thus, here we eventually analysed 548 patients (Fig. 1).

According to the adjusted FEP and the optimal cut-off points, the low-risk (FEP < 2%) category corresponded to patients who had > 20 analysed LNs; the intermediate-risk (FEP 2%–15%) corresponded to cases with 6–20 analysed LNs; and high-risk (FEP > 15%) corresponded to patients with ≤ 5 analysed LNs.

Table 3 shows the FEP results according to the number of analysed LNs and is accompanied by a contour plot (Fig. 2) which represents its calculation graphically.

Number of analysed lymph nodes	Final error probability (%)	Risk assessment
1	26.0	High risk
2	23.0
3	20.0
4	18.0
5	16.0
6	14.0	Intermediate risk
7	12.0
8	10.0
9	9.0
10	8.0
11	7.0
12	6.0
13	5.0
14	4.0
15	4.0
16	3.0
17	3.0
18	2.0
19	2.0
20	2.0
21	1.0	Low risk
22	1.0
23	1.0
24	1.0
25	1.0
26	1.0
27	1.0
28	0.5
29	0.4
30	0.3
35	0.2
40	0.1
45	0
50	0

The OS charts (Fig. 3a) show that patients with LN involvement had the lowest OS rate than the three risk groups. This difference was statistically significant for the low- and intermediate-risk groups (P = 0.002 and P = 0.004, respectively), but not with respect to the high-risk group (P = 0.505). In other words, N0 patients with a high-risk FEP (> 15%) had an OS rate like that of pN+ patients.

We subsequently carried out a similar analysis in which we divided patients with LN involvement into pN1 and pN2 groups. As shown in Fig. 3b, the OS rates differed between the low- and high-risk groups (P = 0.014). The pN1 group had statistically significant difference to the low-risk and pN2 group (P = 0.008 and P = 0.034, respectively). On the other hand, pN2 group had a significantly worse prognosis than low- and intermediate-risk groups (all P < 0.001), but there were no statistically significant differences between high-risk group (P = 0.066). Interestingly, the survival curves of the high-risk and pN1 patient were very similar (P = 0.980). In terms of DFS (Fig. 4a), the curves for the intermediate- and high-risk groups were similar until approximately 60 months’ follow-up (P = 0.906). After 80 months’ follow-up, the curve of high-risk group coincided with that of the pN+ group (P = 0.172). The curves for the intermediate- and high-risk group and pN1 groups were all similarly (Fig. 4b; intermediate-risk vs. high-risk, P = 0.441; intermediate-risk vs. pN1, P = 0.289; high-risk vs. pN1, P = 0.978).

LN involvement is one of the most important prognostic factors in colon cancer. Given its enormous importance, especially in terms of prognostic and therapeutic decisions, gaining a detailed picture of the true LN status of patients with colon cancer should be a priority for clinicians involved in the diagnostic–therapeutic process of these patients. In this sense, the use of FEP may be useful, especially for patient groups which more frequently see staging errors. Our group has extensive experience in using FEP to assess LN involvement in the contexts of colon [11], gastric [12], and breast cancers [13]. This method aims to calculate the probability that a pN+ patient in whom with insufficient analysed LNs will be erroneously classified as pN0. This has obvious clinical and prognostic consequences, especially in the light that stage III patients (i.e., those with LN involvement) can significantly benefit from chemotherapy [2, 14–16]. Correctly staging patients with colon cancer is very important given that around 60% of them do not currently present LN involvement at diagnosis [6, 7], a figure similar to the 63.3% staged as pN0 in this study.

FEP is particularly important for the patients in whom with insufficient analysed LNs because their TNM classification would not necessarily be accurate. This was the case in the series used in this study, in which the threshold 12 LNs were not analysed in 56% of the cases. Similar results have been reported in several previous studies, especially in population analyses like ours, in which this lymph-node threshold goal was not reached [2, 6, 17, 18]. There are likely several reasons why it is common for so few LNs to be analysed, likely because of factors related to the patient and surgeons, and to the type of anatomopathological study undertaken. Our results clearly show that FEP is strongly negatively related to lower OS rates (Fig. 3a). Moreover, patients with LN metastases have a poorer prognosis than those classified into the three risk groups. Most importantly, there were no statistically significant differences between the pN+ and high-risk patients. In other words, patients categorised into the high-risk FEP group had similar OS rates to those with LN involvement.

To try to increase the accuracy of our analysis, we further categorised pN1 and pN2 patients with LN infiltration and, as expected, pN2 patients had the poorest prognosis of the three groups whereas the low-risk group had the best OS rate (Fig. 3b). It is also important to highlight that the high-risk and pN1 patients had very similar OS curves. Therefore, the pN1 patients had a similar OS rate to the pN0 patients with a high staging error risk. In terms of DFS, patients with an intermediate and high risk had a DFS rate like that of pN1 patients (Fig. 4b). Thus, our data confirm that a minimum of 12 LNs must be analysed to reduce TNM classification staging errors. It should also be noted that low-risk patients had more right-colon neoplasms, were younger, and had larger tumours, i.e., their tumour characteristics favoured easier LN analysis [5, 19]. Similarly, when younger patients were included in this group and more of LNs were analysed, their OS rate was better.

The use of this mathematical model, which is based on the Bayes’ theorem, has been previously described in the literature in the identification of groups with similar prognoses from among patients with different cancers but with similar characteristics to those of our patient cohort. This model was first described by Kiricuta et al. [8] in 1992 and was applied in breast cancer to calculate the probability of tumour persistence after an incomplete axillary dissection, staging the patients according to the T category of the TNM classification. Later, Okamoto et al. [20] studied the probability of LN involvement in patients with negative sentinel-LN breast cancer using a Bayesian model. Iyer et al. [21] further demonstrated the usefulness of this method in 1652 patients with breast cancer in a study which aimed to evaluate the probability of LN involvement by staging it into T1 and T2. Following on from this work, Joseph et al. [22] studied 1585 patients with colorectal cancer and used this method to demonstrate the probability of LN involvement according to the number of analysed LNs using the same staging as Kiricuta et al. [8]. In a study of 480 patients with colon cancer, Martínez et al. [11] also showed that the risk of an erroneous negative ganglionic classification in colon cancer can be individualised by calculating its probability according to Bayes’ theorem.

According to the European Society for Medical Oncology guidelines, in our speciality a specific adjuvant treatment regimen is recommended for stage II patients with poor prognosis factors, including the analysis of fewer than 12 LNs. However, this regimen is not routinely applied, and the patient must sign their express informed consent to undergo this treatment [23].

It is useful to know the final probability of error in this field because it allows pN0 patients to be divided into several risk categories. This work shows that high-risk patients (patients without LN involvement but with five or fewer analysed LNs), have a similar prognosis to pN1 patients. The main limitations of this work lie in its retrospective non-randomised population study design which resulted in a loss of evidence. Another limitation was our use of the T category from the sixth rather than the seventh edition of the TNM classification; this was because this version was in effect during the period in which the study data was collected. However, to help reduce this bias, we allocated the patients either into a group with earlier-stage tumours (T1 and T2) or into one with locally more advanced tumours (stages T3 and T4). This minimised the effect of any modifications to the T factor classification made between these two TNM editions.

The application of Bayes’ theorem in the calculation of FEP is useful to delimit risk subgroups from among patients without LN involvement. Therefore, the FEP system complements the TNM LN staging classification well by improving the discrimination of the colon cancer prognosis in pN0 patients with a high-risk of having been misclassified as free of LN involvement because too few of their LNs had been analysed.