Diagnostic and Prognostic Value of Neutrophil-Lymphocyte Ratio in Adrenocortical Carcinoma
Chengquan Ma,1 Bin Yang,2 Quanzong Mao3
Abstract
The aim was to explore the value of neutrophil-lymphocyte ratio (NLR) as a biomarker for predicting the progno- sis or diagnosis in adrenocortical carcinoma (ACC). We identified 262 patients with adrenal gland disease who underwent operation at our institution. NLR carry a differential property was evaluated with ROC curve to distin- guish the ACC and non-ACC groups. The cut-off value of NLR was estimated as 2.65 according to the Youden index. With this value, sensitivity was found as 67.5%, specificity was 83.8% and AUC was 0.749 (p < 0.001). In ACC, the higher NLR group was not shown significantly poorer overall survival than the lower NLR group (p > 0.05).
Background: The aim was to explore the value of neutrophil-lymphocyte ratio (NLR) as a biomarker for predicting the prognosis or diagnosis in adrenocortical carcinoma (ACC). Methods: We identified 262 patients with adrenal gland disease who underwent operation at our institution between 2013 and 2018. According to postoperative pathology, patients were divided into 2 groups: ACC and non-ACC groups. The neutrophil and lymphocyte count of patients were recorded. Within the intergroup comparison, data obtained from ACC and non-ACC groups were evaluated using ANOVA test. The cut-off values of NLR for the prognosis in ACC were determined according to 3 methods. Results: The NLR values of ACC and non-ACC groups were 5.36 ± 5.30 and (1.73 ± 0.26) ~ (2.56 ± 1.35), respectively (P < . 001). NLR carry a differential property was evaluated with ROC curve to distinguish the above 2 groups. The cut-off value of NLR was estimated as 2.65 according to the Youden index. With this value, sensitivity was found as 67.5%, specificity was 83.8% and AUC was 0.749 (P < . 001, confidence interval = 0.638-0.860). In ACC, the higher NLR group was not shown significantly poorer overall survival than the lower NLR group (NLR ≥2.65 vs. NLR < 2.65, NLR ≥5 vs. NLR <5, NLR ≥5.36 vs. NLR <5.36) (P > .05). Conclusion: According to the data in this study, it can be said that adrenocortical tumors are likely to be malignant by 67.5% if the NLR value is greater than 2.65. When we use the NLR to predict the prognosis of ACC, there is not statistically significant.
Clinical Genitourinary Cancer, Vol. 22, No. 2, 109-114 @ 2023 Elsevier Inc. All rights reserved.
Keyword: Neutrophil-lymphocyte ratio, Adrenocortical carcinoma, Diagnosis, Prognosis, Receiver operating characteristic
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with variable morbidity and mortality. It is mostly sporadic, and the age of onset is bimodal, which is below 5 years old and above 50 years old, accounting for 1.3% of malignant tumors in children and 0.02% to 0.2% of malignant tumors in adults.1 For patients
1 Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
2 Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
3 Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
Submitted: Sep 23, 2022; Revised: Sep 24, 2023; Accepted: Sep 25, 2023; Epub: 1 October 2023
Address for correspondence: Chengquan Ma, MD, Department of Urology, Tianjin Medical University General Hospital, No 154. Anshan Road, Tianjin 300052, China E-mail contact: machqu163@163.com
with incidental adrenal masses, thorough preoperative diagnosis is essential to distinguish ACC from adrenocortical adenoma.2 ACC with distant metastasis and/or invasive growth are easy to recog- nize. However, the distinction of noninvasive low-grade ACC from adrenal cortical adenoma (ACA) poses a diagnostic challenge that has resulted in the use of terms such as “atypical adenoma” or “adrenal cortical neoplasm of uncertain malignant potential.” The primary assessment of the risk of malignancy is done primarily by radiological features of CT or MRI.3 MRI may provide additional diagnostic information if CT plain plus enhanced examination does not reveal typical ACC findings .4 Although these ancillary tests do not always provide a definitive diagnosis, CT scan or MRI features are currently routinely used to guide adrenal protocol. In addition, 18F-FDG PET/CT may be complementary in the initial diagnosis and recurrence detection of ACC.5 18F-FDG PET/CT is consid-
NLR predicting the prognosis or diagnosis for ACC
ered to be less specific and sensitive for smaller lesions,6 and the use of 18F-FDG PET/CT measurement as a prognostic marker remains ambiguous. ACC has a poor prognosis, high degree of malignancy, strong invasiveness and rapid progression.7 However, there are significant individual differences in the progression, recur- rence and prognosis of ACC, and some advanced patients can still achieve a long survival time. The occurrence and development of ACC may be related to IGF2 overexpression, TP53 gene mutation8 and abnormal activation of Wnt/B catenin pathway .? Due to the complexity of ACC and the small number of cases available for study, there are many shortcomings in the diagnosis and prognosis of ACC.
Inflammation is a major driving force in the development and progression of various cancers. Immune cells are most commonly associated with disease progression include neutrophils and lympho- cytes. The neutrophil-lymphocyte ratio (NLR) is a primary proxy for immune status for several reasons. Unlike immune scores, these metrics are simple, inexpensive, widely used and have the poten- tial to provide insight into a patient’s immune status.10 First, in the context of tumor immunity, lymphocytes are well known for their antitumor effects. A low lymphocyte count may indicate deficient cell-mediated immunity. Neutrophils, on the other hand, are the most abundant immune cell type in circulation and are also frequently found to be recruited to tumors.11 Similar to lympho- cytes and macrophages, they play an active, reciprocal role in cancer: tumors can induce an increase in neutrophils in the bone marrow and recruit them to the site.12 In some types of tumors, such as gastric cancer, elevated neutrophil counts confer a better progno- sis.13 This means that neutrophils can suppress tumors in some cases. In fact, the ability of neutrophils to directly kill tumor cells in vitro and in vivo has been reported for a long time.14 In addition, neutrophils from tumor-bearing animals have been reported to have enhanced cytotoxic activity15; Neutrophils isolated from the blood of some healthy individuals show direct cytotoxicity to several tumor cell lines.16 Therefore, the exact role of neutrophils in tumors is a matter of debate.17 In conclusion, this makes NLR an indicator that contains both pro-tumor and anti-tumor immunity and thus may provide diagnostic and prognostic value in ACC.
A large number of studies have raised the possibility of NLR to be valuable materials in detecting cancers, informing prognoses, and monitoring treatment responses. However, value of NLR in assess- ing the prognosis of ACC is currently controversial.18-21 And the detecting value of NLR levels for ACC has not yet been reported. In this study, we researched if the NLR had an importance in discrim- inating between ACC and non-ACC patients.
Methods
We retrospectively evaluated the data of 262 patients with adrenal gland disease who underwent resection and were monitored at Tianjin Medical University General Hospital and Peking Union Medical College Hospital from January 1, 2013 to January 1, 2018. The tumors were graded according to the Union for International Cancer Control TNM 2004 staging system. All pertinent labora- tory and pathology results (tumor size and number, postopera- tive immunotherapy, and chemotherapy), and medical data were obtained from the hospital databases. Data obtained from the
patients’ routine preoperative test results included the neutrophil and lymphocyte counts, NLR, age. The NLR was determined by dividing the absolute neutrophil count by the absolute lymphocyte count. Ki-67, type of surgery, marginal condition, mitotane-based specific chemotherapy and radiotherapy were also collected. We excluded patients with coexisting hematologic diseases and those in the inflammatory phase. Patients were divided into 2 groups: ACC and non-ACC groups (adrenal cyst, adrenal adenoma, adrenal corti- cal nodular hyperplasia and pheochromocytoma) according to their pathology after the surgery. The primary outcome of the study was a difference in overall survival (OS) according to NLR level. OS was defined as the time elapsed from the date of the ACC diagnosis to the date of death or the last follow-up visit.
Statistical analyses were performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp, Armonk, NY). For data comparison, within the intergroup comparison, data obtained from ACC and non-ACC groups were evaluated using ANOVA test. We applied the receiver operating characteristic (ROC) curve to test the effectiveness of NLR in distinguishing ACC and non-ACC groups. A cutoff value was calculated for the NLR with a ROC curve and Youden’s J statistic according to the tumor was benign or malig- nant. Kaplan-Meier product limit estimator was used to estimate the overall survival. A log-rank test was performed for comparison. The cut-off values of NLR for the prognosis in ACC were deter- mined according 3 methods include cutoff of ROC curve, mean and previously reported in the literature. P < . 05 was considered as statistically significant.
Results
According to study results shown as Figure 1, ACC group consisted of 40 patients (NLR, 5.36 ± 5.30) while non-ACC group consisted of 222 patients including 21 cases of adrenal cyst (NLR, 1.73 ± 0.26), 171 cases of adrenal adenoma (NLR, 2.01 ± 1.01), 15 cases of adrenal cortical nodular hyperplasia (NLR, 2.25 ± 1.48), 15 cases of pheochromocytoma (NLR, 2.47 ± 1.54).
All the 40 cases with ACC underwent surgery, with the diameter from 3.5 cm to 19 cm and an average diameter of 9.1 cm. The follow-up time ranged from 5 to 101 months with an average of 34.4 months. Their tumor stages were 29.2% in stage III or IV. All the general information of 222 cases with group-non-ACC was presented in Table 1.
ROC
Whether the NLR carries a differential property for tumors in ACC and non-ACC groups was evaluated with ROC curve. The cut-off value of NLR was estimated as 2.65 according to the Youden index. With this value, sensitivity was found as 67.5%, specificity was 83.8% and AUC was 0.749 (P < . 001, confidence inter- val = 0.638-0.860) (Figure 2).
Overall Survival
To determine whether NLR can be used as a prognostic marker for ACC, we selected 3 NLR cutoff values 2.65, 5 and 5.36. We found that the higher NLR group was not shown significantly poorer overall survival than the lower NLR group (NLR ≥2.65 vs.
6.0000
5.364
5.0000
4.0000
NLR (Mean)
3.0000
2,563
2.0000
2.251
2.007
1.730
1.0000
Adrenal cyst
Adrenal adenoma
Adrenal cortical nodular hyperplasia
Pheochromocytoma
ACC
| Adrenal Cyst (21cases) | Adrenal Adenoma (171cases) | Adrenal Cortical Nodular Hyper- Plasia (15 Cases) | Pheochromocytoma (15 cases) | Adrenocortical Adenoma (40 cases) | |
|---|---|---|---|---|---|
| Age (y) | 45.76 ± 12.23 | 55.78 ± 11.34 | 51.67 ± 15.29 | 49.27 ± 12.15 | 49.74 ± 12.24 |
| Maximum diameter (mm) | 44.20 ± 31.67 | 21.14 ± 7.53 | 11.29 ± 5.02 | 56.21 ± 37.91 | 91.6 ± 62.4 |
| NLR | 1.73 ± 0.26 | 2.01 ± 1.01 | 2.25 ± 1.48 | 2.47 ± 1.54 | 5.36 ± 5.30 |
Abbreviations: NLR = neutrophil-lymphocyte ratio.
NLR < 2.65, NLR ≥5 vs. NLR <5, NLR ≥5.36 vs. NLR <5.36) (P > .05) (Figure 3A-C).
Discussion
The relationship between inflammation and cancer has been a topic of great interest.22 Virchow first hypothesized that cancer occurs at sites of chronic inflammation and immune cells release factors that stimulate tumor cell proliferation, whereas Coley successfully treated sarcomas with a mixture of bacteria that resulted in acute activated cytotoxic immune cell-mediated tumor regres- sion.23,24 The different properties of the immune system are due in part to the functional plasticity of bone marrow cells and lymphoid cells, which may exert both protumor or antitumor effects.25 It was suggested that the combination of the 2, namely NLR, might be valuable in the diagnosis and prognosis of tumors.
Since most adrenal masses are benign adenomas, it is important to identify new markers to determine whether a suspected adrenal mass is benign or malignant before surgery. The development of new tools for the early diagnosis and prognosis of ACC is a challenge. It is therefore desirable in clinical practice to be able to assess disease activity with simple, inexpensive, and objective tools. The present study was to assess whether the NLR would be useful in identi- fied ACC from many types of adrenal tumors. The clinical data of patients with adrenocortical carcinoma and benign adrenal tumor in our hospital were analyzed. The NLR of ACC group (5.36 ± 5.30) was significantly higher than that of non-ACC group. ACC showed the highest NLR among all adrenal tumors. ROC curves were created to identify optimal cut-offs and identified ACC from many types of adrenal tumors. The cut-off value of NLR was 2.65,
NLR predicting the prognosis or diagnosis for ACC
1.0
0.8
0.6
Sensitivity
0.4-
0.2-
0.0
0.0
0.2
0.4
0.6
0.8
1.0
1 - specificity
sensitivity was 67.5%, specificity was 83.8%. These results suggest that NLR may be valuable in differentiating ACC from relatively benign adrenal tumors. In the study of Mirsala Solak et al., Ki-67 index was & GT; Ten percent of patients had higher NLR levels, and the same trend was observed in patients with larger tumors.20 In the study of Pinar Sisman et al., neutrophils, lymphocytes, and NLR were markedly different between adrenal adenoma and ACC patients. However, when NLR was compared between patients with positive and negative recurrence and/or metastasis, no significant differences were found.21
The overall ACC patient population is very heterogeneous, and even among patients at the same tumor stage, long-term outcomes may differ as the effects of different clinical, pathological, and molecular factors remain largely unknown.26 Several prognostic factors that may influence ACC have been reported, including tumor size, Ki-67 positive rate, completeness of resection margin, and clinical stage.27 However, the prognostic role of these factors
has not been consistent across studies.28 In recent years, it has been recognized that the prognosis of ACC patients is not determined by tumor characteristics alone, such as tumor size, stage, Ki-67 index, etc. NLR has been widely reported as a prognostic factor of cancer, and the size of NLR predicts the survival time of some cancer patients to a certain extent. However, the association between NLR and adrenocortical carcinoma is rarely reported. Also, the NLR was uncertain to be an independent prognostic factor in predicting survival. This paper analyzed the clinical follow-up data of patients with adrenocortical carcinoma in our hospital, and found that NLR was not correlated with OS. Similar to the findings of Bagante et al., it was also confirmed that ACC patients with higher NLR levels had larger tumors and later disease stages. ROC curve analysis showed that the sensitivity and specificity of NLR value 3.9 as the best cut- off for predicting DSS in ACC were 90.9% and 64.9%, respec- tively. In multivariate Cox regression models, elevated NLR levels in ACC patients were not associated with outcomes in DSS and
1.0-
NLR≥2.649
NLR≥5.363
NR<2.649
1.0-
NLR<5.363
$ Censored Date
+ Censored Date
+ Censored Date
Censored Date
0.8
0.8-
Overall Survival
0.6-
Overall Survival
0.6
0.4-
0.4-
0.2-
02
0.0
0.0
0
20
40
ல்
80
100
120
0
20
40
60
80
100
120
Months
Months
a
b
1.0
NLR25
NLR<5
+ Censored Date
Censored Date
0.8
Overall Survival
0.6
0.4
0.2
0.0
0
20
40
60
80
100
120
Months
c
OS. Mechteld C de Jong’s study involving 57 ACC cases found that Median NLR was 4.63 as the cutoff value, and high NLR was closely associated with shorter OS, a high NLR did not influence recurrence-free survival (RFS).19 Pinar Sisman et al. suggested that red blood cell count can be used as one of the indicators for the differential diagnosis of adrenal adenoma and adrenal carcinoma, and NLR has no prognostic value for ACC.21 Apostolos Gaitani- dis et al. found that the optimal cut-off of NLR was identified 3.7 in recurrent ACC patients, and found that there was no correla- tion between NLR and DSS in recurrent ACC patients.29 In 2015, Bagante et al. reported a study comparing NLR and ACC outcomes and found that NLR> 5.0 was associated with poorer disease- specific and progression-free survival in ACC.30 Taku Mochizuki et al. found that higher NLR in adrenal tumors was associated with
a higher incidence of malignancy, the higher NLR group (NLR≥5) showed a significantly poorer overall survival than the lower NLR group (NLR < 5) (P =. 032) .The cut-off NLR of 5.0 was relatively high in comparison to other studies, which indicated the aggressive nature of ACC in comparison to other types of cancer. 18
Some limits of the present study must be mentioned. Firstly, due to the retrospective nature of this study, attributable factors suffer from a recall bias and are not analyzable. Secondly, long-term exposure to elevated glucocorticoid levels is known to lead to alter- ations in white blood cell and lymphocyte numbers and function, possibly similar to tumor-associated inflammatory responses. To some extent, our findings may be influenced by the functional status of the tumor and the resulting glucocorticoid overproduc- tion. Thirdly, the survival of our study was OS as the end point;
NLR predicting the prognosis or diagnosis for ACC
disease free survival (DFS) and progression-free survival (PFS) were not statistically analyzed, so there was a possibility that NLR might be meaningful for them. Fourthly, preoperative values of systemic inflammatory markers are highly influenced by many factors, so small increases or decreases in these values may affect prognostic assessment. Therefore, this marker should be used with caution and clinicians should be aware of these weaknesses. We believe that more comprehensive and extensive patient studies may more clearly reveal the significance of NLR in the diagnosis and prognosis of ACC.
Clinical Practice Points
· What is already known about this subject:
The development of new tools for the early diagnosis and progno- sis of ACC is a challenge. The diagnostic value of NLR levels for ACC has not yet been reported and the value of NLR in assessing the prognosis of ACC is currently controversial.
· What are new findings:
Adrenocortical tumors are likely to be malignant by 67.5% if the NLR value is greater than 2.65. The NLR was used to predict- ing the prognosis of ACC, there is not statistically significant.
Author Contributions
Chengquan Ma designed the study; Chengquan Ma and Quanzong Mao were involved with the conception of the analyses; Chengquan Ma and Bin Yang were involved with performing the analyses; and all authors were involved with interpretation of the data. Chengquan Ma wrote the paper. All authors provided their approval for the final version to be published. All authors agreed to be accountable for the accuracy and integrity of the work.
Informed Consent
Informed consent was obtained from all individual participants included in the study.
Ethical Statement
The study was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amend- ments; local ethical approval was obtained from the Ethics Commit- tee of the Peking Union Medical College Hospital and Tianjin Medical University General Hospital.
Disclosure
All authors declare they have no competing of interests.
Data availability
The data could not be shared available on open access; Informed consent was obtained from all individual participants included in the study which the open access may affect the concerns of patient privacy. If needed during the review process, we could provide datasets to the editor or editorial staff upon request.
Acknowledgments
This work is supported in the absence of any commercial or finan- cial relationships that could be construed as a potential conflict of interest.
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