Association of the Preoperative Controlling Nutritional Status (CONUT) Score with Clinicopathological Characteristics in Patients with Papillary Thyroid Carcinoma
Article information
Abstract
Background
The Controlling Nutritional Status (CONUT) score is an immunonutritional test tool based on serum albumin, total cholesterol, and lymphocyte counts. It has been studied as a simple prognostic predictor for various carcinomas. This study aimed to investigate the association between preoperative CONUT scores and the clinicopathological characteristics in papillary thyroid carcinoma (PTC) patients.
Methods
This study included 2,403 PTC patients who underwent total thyroidectomy between 2012 and 2016 at a single tertiary medical center. The CONUT scores were calculated based on preoperative blood tests. The clinicopathological characteristics were retrospectively reviewed. The patients were categorized by the CONUT score (relatively low, 0–2; relatively high, 3–5).
Results
Among the 2,997 PTC patients who underwent total thyroidectomy at Pusan National University Hospital between 2012 and 2016, those without preoperative blood test were excluded (n=149). Finally 2,403 patients were analyzed after excluding 439 patients taking lipid-lowering drugs and six patients without available T stage data after surgery. Based on the CONUT score, the relatively high score group had a lower body mass index (23.7±3.3 kg/m2 vs. 21.9±2.9 kg/m2, P<0.001), more advanced T stage (T stage 3/4, 5.9% vs. 11.4%, P=0.045), and higher extrathyroidal extension (2.1% vs. 7.6%, P=0.005).
Conclusion
Patients included in this large, single-center study all had a preoperative CONUT score of 0–5, but this study demonstrated that higher preoperative CONUT scores were significantly associated with advanced T stage and extrathyroidal extension. The CONUT score, which can be easily used in clinical practice, is thought to be helpful in predicting the aggressiveness of PTC.
INTRODUCTION
Thyroid cancer is the most prevalent type of endocrine cancer. Over the past three decades, the incidence of thyroid cancer has risen globally [1,2]. Currently, the primary treatment for papillary thyroid carcinoma (PTC) is thyroidectomy, and multidisciplinary treatment involving surgery, radioiodine therapy, thyroid-stimulating hormone (TSH) suppression in high risk patients, and targeted therapy are the most common methods for treating thyroid cancer [3]. Deciding the optimal treatment is crucial for improving the patient’s prognosis. Therefore, it is essential to find potential biomarkers for selecting optimal treatment strategies and predicting the prognosis of patients with PTC.
Cancer prognosis may be related to the host’s status, such as nutrition or inflammation. Moreover, inadequate nutritional conditions may be linked to metabolic elevation and compromised immunity in patients with cancer. Preoperative nutritional status, including albumin levels, is associated to prognosis in various malignant tumors [4]. Immune status is associated with tumor development and recurrence. Blood lymphocyte, neutrophil, monocyte, and platelet counts indicate systemic and local inflammation associated with cancer progression and prognosis [5,6].
Recent studies have shown that the preoperative nutritional status is a significant predictor of cancer prognosis [7,8]. The geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI) are indicators of nutritional scoring systems that have been validated as independent prognostic factors for various types of cancer [9,10].
Similarly, the Controlling Nutritional Status (CONUT) score is a newly developed biomarker score that is calculated using three parameters (serum albumin concentration, total peripheral lymphocyte count [TLC], and total cholesterol [TC] concentration) and reflects both the nutritional and immunological environment of the investigated patient [11]. The CONUT score has been used to predict positive outcomes in several carcinomas, including gastric, prostate and breast cancer [12-14]. However, there was no study for association between the CONUT score and aggressiveness and prognosis of PTC.
This study aimed to investigate the association between preoperative CONUT score and clinicopathological characteristics in patients with PTC and the clinical utility of the CONUT score as a simple and valuable prognostic biomarker in PTC.
METHODS
Participants
We gathered clinical and demographic information from 2,997 patients who underwent total thyroidectomy for PTC at Pusan National University Hospital between January 1, 2012, and December 31, 2016, by performing a retrospective chart review. We excluded 149 patients with unknown preoperative white blood cell, albumin, and TC levels. Patients taking lipid-lowering drugs, including statins, and patients whose T stage was not available after surgery were also excluded (n=445). Finally, 2,403 subjects were included in the analysis (Fig. 1).
Flow chart of patient selection. WBC, white blood cell; CONUT, Controlling Nutritional Status.
Methods
All participants underwent a medical history review, physical examination, and hematological and biochemical tests. Body mass index (BMI) was calculated by dividing weight in kilograms by the square of height in meters.
During total thyroidectomy, dissections of the central compartment of the neck were performed routinely; selective neck dissections were conducted if node metastasis was suspected based on ultrasonography or computed tomography findings or when cytological findings were positive in suspicious cervical neck lymph nodes. Tumor size was evaluated by the largest diameter of the lesion according to postoperative pathologic results. Patients were staged using the tumor, node, metastasis (TNM) classification system of the American Joint Committee on Cancer (7th edition). T stage was divided into categories 1/2 or 3/4, and N stage was classified based on lymph node metastasis (LNM) (N0 vs. N1) and lateral LNM (N1a vs. N1b). The Seeplex BRAF ACE detection kit (Seegene, Seoul, Korea) was used to identify the BRAF V600E mutation in tumor samples obtained from patients following thyroidectomy.
Laboratory data were gathered from screening blood samples collected within a timeframe of up to 2 weeks before total thyroidectomy, and TSH levels were measured prior to the surgery. Complete blood counts (CBCs) and automated differential counts were conducted 1 day before surgery. Biochemical measurements were performed after at least 8 hours of overnight fasting.
The CONUT score, an immunonutritional status marker, was derived using TC, TLC, and serum albumin concentration. Standard methods were used to measure the concentrations of these parameters, with Sysmex XN-10 and XN-20 (Sysmex Corp., Kobe, Japan) for CBC and Cobas 8000 c702 (Roche Diagnostics System, Basel, Switzerland) for albumin and cholesterol.
The CONUT score was calculated by summing the values of TC, TLC, and albumin, with the following point allocation: serum albumin level ≥3.5=0 point; 3.0–3.49=2 points; 2.5–2.99=4 points; and <2.5=6 points. A serum cholesterol level of 180 or more=0 point; 140–179=1 point; 100–139=2 points; and less than 100=3 points. A TLC of 1,600 or more=0 point; 1,200–1,599=1 point; 800–1,199=2 points; and less than 800=3 points (Supplemental Table S1). Finally, we analyzed the association between the CONUT score and clinicopathologic characteristics of PTC. The Institutional Review Board of Pusan National University Hospital (South Korea) approved the study protocol (IRB No.2403-011-137). Written informed consent from the patients was waived due to the retrospective nature of this study.
Statistical analysis
All the statistical analyses were conducted using SPSS version 23 (IBM Corp., Armonk, NY, USA), R statistical language version 4.3.1 (R Core Team, 2023; R Foundation for Statistical Computing, Vienna, Austria). The Student t test was utilized to assess the correlation between the CONUT score and other clinicopathological characteristics of PTC. Pearson’s chi-square tests were employed to compare the different groups. To see the correlation between the two groups and the postoperative outcome, a binary logistic regression model using odds ratio (OR) was used. Statistical significance was defined as P<0.05.
RESULTS
A total of 2,403 patients diagnosed with PTC were included in the analysis. Descriptive statistics of all 2,403 baseline characteristics are presented in Supplemental Table S2. Table 1 shows the association between the preoperative CONUT score and the clinicopathological characteristics of PTC. The CONUT score showed a notable increase in patients with LNM. However, the CONUT score was not associated with tumor size, T stage, multifocality, extrathyroidal extension (ETE), or vascular invasion (VI).
The Association between Preoperative CONUT Score and the Clinicopathologic Characteristics of Papillary Thyroid Cancer (n=2,403)
In our study, all PTC patients had a CONUT score of normal to moderate (0–5). Using the common CONUT score scale, these correspond to normal (0–1), mild (2–4), and moderate (5–8), respectively, but in this study, we divided CONUT scores into relatively high and low group. Therefore, the patients were stratified into two groups according to their initial preoperative CONUT scores: relatively low score group, with scores 0–2, and relatively high score group, with scores 3–5. Table 2 shows a comparison of the prevalence of prognostic factors between the CONUT groups. There was no difference in age between the two groups. The relatively high CONUT score group had lower BMI values compared to those in the relatively low group (23.7±3.3 kg/m2 vs. 21.9±2.9 kg/m2, P<0.001). The preoperative TSH level and presence of underlying Hashimoto thyroditis was not statistically associated with higher or lower CONUT scores. The higher CONUT score group was significantly associated with advanced T stage (T stages 3 and 4: 5.9% vs. 11.4%, P=0.045) and ETE (2.1% vs. 7.6%, P=0.005) compared to the lower CONUT score group.
Comparisons of Prognostic Factors between Two CONUT Groups
To further examine the correlation between postoperative outcome values in the comparatively low and high CONUT groups, we performed adjusted matching and propensity score matching (PSM), the results of which are shown in Table 3. For 2,403 patients, even after adjusted matching for gender, age, BMI, preoperative TSH, and underlying Hashimoto thyroiditis, we found that higher CONUT scores were still statistically significantly associated with advanced T stage and ETE after surgery (Table 3).
Correlation between Postoperative Outcome Values in the Low and High CONUT Groups
PSM was performed on the 79 individuals with a relatively high CONUT scores of 3–5, covariating for gender, age, BMI, preoperative TSH. After PSM, we found a higher OR for ETE in the relatively high CONUT score group compared to other postoperative outcomes, but it was not statistically significant (OR, 6.411; P=0.089) (Table 4).
Correlation between Postoperative Outcome Values in the Low and High CONUT Groups
We further sub-analyzed whether any of the three parameters of CONUT (albumin, lymphocyte count, and TC) were particularly problematic in PTC patients by using a binary logistic regression model with OR for each parameters. In our data, albumin levels were mostly in the normal range and did not contribute significantly to postoperative outcomes (2,401 people in the normal albumin range). For the other two parameters, we identified ORs for advanced T stage and ETE that correlated with higher CONUT among postoperative outcomes.
Lymphocyte count was marginally significant association with ETE, with ORs of 42%, 49.1%, and 46.4%, respectively, at a significance level of P<0.1 not at P<0.05, while TC did not show statistical significance. When checked in the same way to find the parameters that contributed to the advanced T stage, neither parameter showed statistical significance, so we were unable to determine which factor contributed more (Supplemental Table S3).
DISCUSSION
In our study, we found that a relatively high preoperative CONUT score was significantly associated with an advanced T stage and ETE. Recently, much research has been conducted on the various factors that predict preoperative prognosis in various cancers. In particular, numerous studies have focused on nutritional markers, including the GNRI, PNI, and CONUT scores, examining their correlation with cancer prognosis [9-11].
The CONUT nutritional tool first emerged as an effective method for to detect malnutrition in hospitals early and to manage undernutrition on an ongoing basis [11]. Previously, the use of CONUT was limited to assess nutritional status alone. However more evidence has emphasized its capacity to predict cancer survival [15,16].
As the CONUT score is based on serum albumin level, TC level, and total lymphocyte count, the CONUT score may serve as an indicator of both malnutrition and systemic inflammation status. Furthermore, tumor progression and treatment tolerance are closely linked to nutritional and inflammatory status; therefore, the CONUT score could theoretically be a comprehensive predictive indicator [7].
The specific biological mechanisms by which the CONUT score functions as a prognostic indicator for PTC are not yet fully understood. Some investigation has been conducted into the potential mechanism that links the parameters included in the CONUT score with cancer prognosis [17,18].
Serum albumin levels are widely recognized as reflecting both nutritional status and systemic inflammatory responses and has been associated with the prognosis of cancer [19]. Moreover, the TC level has been associated with cancer survival [20]. Previous reports have indicated that low circulating cholesterol concentrations in diffuse large B-cell lymphoma and peripheral T-cell lymphoma are linked to improved cancer morbidity and mortality, suggesting that this serves as a promising prognostic marker [21,22]. Additional studies proposed that reduced cholesterol levels might impact immune cell membranes, potentially limiting their immune function, and consequently, contributing to a poorer prognosis for cancer patients [23].
The total lymphocyte count plays a pivotal role in mediating cell-mediated immunity. Lymphocytes, which can be categorized as T lymphocytes (T cells), B lymphocytes (B cells), and natural killer cells, are vital in regulating the proliferation, invasion, and metastasis of cancer cells [24,25].
All the components of the CONUT score are associated to the individual’s nutritional status and immunological capacity. Each parameter plays a significant role in tumor initiation, occurrence, and progression [14]. These results imply that the CONUT score may serve as a prognostic factor for various types of cancers.
This study sought to determine whether a preoperative CONUT score would be useful in predicting the prognosis of thyroid cancer in a clinical setting, as shown in previous studies investigating many other cancers.
In general, the CONUT scores are divided into four levels based on the sum of the three parameter scores (Supplemental Table S1). However, in the case of our data, the highest CONUT score was 5 (two participants), and there were no more than that; therefore, we analyzed the data by dividing the CONUT score into two groups, one with a relatively low CONUT score of 0–2 and the other with a relatively high score of 3–5.
Our results showed that individuals with higher CONUT scores had ETE and a more advanced T stage. In contrast, there was no association between tumor size and LNM.
Table 1 shows the statistical significance of LNM in patients with a relatively high CONUT score (P<0.05). For characteristics other than LNM, a relatively high CONUT score was associated with a larger tumor size, higher T stage, multifocality, ETE, and VI, but without statistical significance. Presumably, our cohort comprised a large number of patients who were incidentally identified early on; thus, the majority were in the CONUT 0–2 group (n=2,324), resulting in a narrow range of CONUT scores. This may explain the results of this study.
The clinical features of thyroid cancer are less likely to be systemic; therefore, nutritional deterioration is less likely to be caused by thyroid cancer itself. In addition, thyroid cancer is often detected by chance during health checkups or other disease-related tests when individuals are in good health and nutritional status [26]. Thyroid cancer is indicated by a lower CONUT score at diagnosis compared to other cancers because it is often detected before the disease has progressed and is therefore less likely to present with severe weight loss and malnutrition. Therefore, in our data, there were patients with good nutritional and immune status, i.e., low CONUT scores.
Unlike other studies, patients diagnosed with thyroid cancer in our center are more likely to have low CONUT scores, but we wanted to explore the clinical differences in CONUT scores between the relatively low (0–2) and relatively high (3–5) groups, and to confirm its usefulness. Therefore, we found that a higher preoperative CONUT score was significantly associated with advanced T stage and ETE.
In addition, we attempted to determine the association of baseline characteristics with postoperative prognosis in the 79 patients with relatively high CONUT scores, but we were unable to analyze the 79 patients due to more than 50% patients were follow-up loss.
This study has some limitations. First, our study was a retrospective analysis and included only Korean patients from a single center, which may have led to selection bias, and our study does not represent the general population. Second, we focused on the preoperative health status and did not include postoperative follow-up data. And we have not addressed other factors that may affect the CONUT score, such as hypertension, diabetes mellitus, dyslipidemia, smoking, alcohol consumption, etc. Future research might consider designing for these additional factors. Third, as this was a cross-sectional retrospective study, the underlying mechanisms remain unclear. Therefore, further prospective multicenter studies are required to elucidate these underlying mechanisms. In addition, although this study found an association of ETE, high T stage and CONUT with poor prognosis, it did not examine the relationship between preoperative CONUT scores and postoperative recurrence or mortality, and other studies are needed to investigate the prognostic relevance.
Despite these limitations, this study contributes to our understanding of the link between the preoperative CONUT score and clinicopathological characteristics in patients diagnosed with PTC. To our knowledge, our study is the first to demonstrate a connection between the preoperative CONUT score and clinicopathological factors in patients with PTC who underwent total thyroidectomy.
In conclusion, this large, single-center study demonstrated that a higher preoperative CONUT score was significantly linked with advanced T stage and ETE which are known poor prognostic factors. The CONUT score, which can be easily used in clinical practice, is thought to be helpful in predicting the aggressiveness of PTC.
Supplementary Material
Supplemental Table S1.
Controlling Nutritional Status Index Score: Assessment of Malnutrition State [11]
Supplemental Table S2.
Characteristics at Baseline and Postoperative (n=2,403)
Supplemental Table S3.
Correlation between Postoperative Outcome Values in the Low and High CONUT Groups
Notes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS
Conception or design: D.K., B.H.K. Acquisition, analysis, or interpretation of data: D.K., M.I., S.R. Drafting the work or revising: D.K., M.K., Y.K.J. Final approval of the manuscript: S. S.K., B.H.K.