Predictive performance of m TNM staging system
The differences in prognostic prediction between the eighth edition of
the TNM staging system and the mTNM classification system were compared
directly. The -2 log likelihood of the mTNM stage was 4688.361, which
was less than the value of the TNM staging system (4694.876), which
indicates a better performance in predicting survival (Table
V ). The ROC curves showed that the
AUC of the mTNM stage was significantly greater than that of the TNM
stage (AUC: 0.646 vs 0.587%,
P=0.0007) (Figure 6 ).
Discussion
Both tumor burden and malignant degree can reflect biological
characteristics of tumor, and they are also associated with the survival
of patients with malignancy. The AJCC TNM classification which reflects
tumor burden was the most widely used staging system for malignancy,
however, it was a macroscopic classification mainly based on anatomy and
did not incorporate the factors reflecting microscopic tumor burden
which could not be detected by imageology[14],
neither the factors reflecting malignant degree of tumor. As a result,
there were always biases of accuracy when the TNM stage was used to
predict prognosis[8,9]. In the present study, we
supposed to incorporate preoperative serum CA19-9, which could
compensate the deficiency of TNM stage in evaluating microscopical tumor
burden, and histology grate, which could make up for the defect of TNM
stage in reflecting malignant degree, into the TNM staging system to
reduce the biases.
In this study, patients with preopertive serum CA19-9 level
>112 U/ml demonstrated a significantly lower OS rate than
those with CA19-9 ≤112U/ml (5-year OS: 15.9% vs. 22.6%,
P<0.001). Patients with high grade also had a significant
decreased OS than those with low grade (5-year OS: 15.7% vs. 23.5%,
P<0.001). In the multivariate analysis, both preoperative
serum CA19-9 and histology grade were identified as independent
prognostic factors for OS. Our proposed biological risk of PDAC was
established according to the preoperative serum CA19-9 and histology
grade. All patients were categorized into three groups according to the
biological risk of PDAC: low-risk, middle-risk and high-risk group.
Significant differences in OS were observed among the three groups.
After incorporating the biological risk into the eighth edition of TNM
staging system, mTNM staging was established. It was confirmed that the
mTNM staging system was more accurate in predicting postoperative
prognosis of PDAC patients than the eighth edition of the AJCC TNM
staging system.
CA19-9 was the most widely used serum tumor marker. Kang et al reported
that both pretreatment and posttreatment CA19-9 levels or their changes
after treatment had good prognostic value in determining the survival of
pancreatic cancer patients[17]. At present, there
was no recognized cut-off value of CA19-9 to predict the prognosis of
PDAC [18,19,20,21], as the level of CA19-9
fluctuated very widely, in our study, the CA19-9 level ranged from 0.6
to 178850 U/ml, besides, the proportion of negative Lewis-antigen
patients varied across countries, ethnicities and studies (6% in white
population, 22% in black population, 5-10% in yellow
population)[22,23,24,25]. Even so, multiple
researches have confirmed the advantage of CA19-9 over other serum tumor
markers in predicting prognosis of PDAC[26,27,28],
which was consistent with our results.
Histology grade was defined as the degree of differentiation of the
tumor. Differentiation refers to the morphologic and functional
resemblance between a tumor cell and a normal cell of the same tissue.
Malignant neoplasms usually evolve from low grade to high grade. In the
process of malignancy, the higher the tumor grade, the more aggressive,
and the greater the tumor burden[29,30]. Many
studies have demonstrated that histology grade was significantly
associated with survival of patients with PDAC and could be used to
modify the TNM staging system[31,32], so was the
case in our study.
To the best of our knowledge, this study is the first to categorize
patients with PDAC according to the biological risk based on
preoperative CA19-9 and histology grade, and assess the impact of tumor
biology on the survival. Our results reveled that patients with low risk
had a significant higher OS than those with middle risk, and patients
with middle risk also demonstrated a better prognosis than those with
high risk. The biological risk was confirmed to be an independent
prognostic factor in the multivariate analysis. In our opinion, the
combination of preoperative serum CA19-9 and histology grade contains
unique prognostic information which represents the microscopic tumor
burden and malignant degree, which is not included in the TNM staging
system.
There are several limitations to the study. First, it was a
retrospective study conducted at a single center. Second, patients were
included from 2011 to 2020, therefore, current neoadjuvant therapy were
not used routinely. In addition, we could not exclude patients with
negative Lewis antigen, which may have an uncertain impact on accuracy.
As the constraints listed above may cause bias in the results, data from
other centers is required for further validation of our findings.