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Neutrophil-Lymphocyte Ratio as a Prognostic Marker in Adrenocortical Carcinoma
Mirsala Solak, Ivana Kraljević, Karin Zibar Tomšić, Marko Kaštelan, Luka Kakarigi, Darko Kaštelan & Croatian ACC Study Group
To cite this article: Mirsala Solak, Ivana Kraljević, Karin Zibar Tomšić, Marko Kaštelan, Luka Kakarigi, Darko Kaštelan & Croatian ACC Study Group (2021) Neutrophil-Lymphocyte Ratio as a Prognostic Marker in Adrenocortical Carcinoma, Endocrine Research, 46:2, 74-79, DOI: 10.1080/07435800.2020.1870234
To link to this article: https://doi.org/10.1080/07435800.2020.1870234
Published online: 08 Jan 2021.
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Neutrophil-Lymphocyte Ratio as a Prognostic Marker in Adrenocortical Carcinoma
Mirsala Solakª, Ivana Kraljevića,b, Karin Zibar Tomšića, Marko Kaštelanb, Luka Kakarigib, Darko Kaštelana,b, and Croatian ACC Study Group
aDepartment of Endocrinology, University Hospital Center Zagreb, Zagreb, Croatia; bSchool of Medicine, University of Zagreb, Zagreb, Croatia
ABSTRACT
Purpose: The purpose of the present study was to analyze the impact of the neutrophil-lympho- cyte ratio (NLR) on the long-term outcomes of patients with adrenocortical carcinoma (ACC). Methods: This retrospective, single-institution study included 48 patients with the diagnosis of ACC. The primary outcomes of the study were differences in overall survival (OS) and disease- specific survival (DSS) with respect to the NLR level.
Results: Patients with ENSAT stage IV had higher levels of NLR compared to those with ENSAT stage I-III (5.7 (1.6-12.5) vs 3.3 (1.3-11); p = . 01). A higher NLR was also observed among patients with cortisol-secreting tumors (4.6 (1.7-12.5) vs 2.8 (1.3-10.3); p = . 003) and those with Ki-67 index >10% (4.3 (1.3-12.5) vs 2.6 (1.6-11.0); p = . 005). With respect to survival, the univariate analysis revealed worse ACC-related survival (p = . 02) and OS (p = . 004) in patients with NLR >3.9 than in those with NLR ≤3.9. In addition, patients with NLR >3.9 had a higher Weiss score (p = . 046), a higher Ki-67 index (p = . 006) and a higher disease stage (p = . 01) compared to patients with NLR ≤3.9. No differences between the groups were observed regarding excess glucocorticoid secretion.
Conclusion: The study demonstrated that a higher NLR level in ACC patients was associated with unfavorable outcomes in terms of DSS and OS. These results indicate that NLR might be used as an additional marker in ACC risk stratification and identification of patients with the most adverse prognosis.
ARTICLE HISTORY
Received July 12, 2020 Revised September 26, 2020 Accepted December 26, 2020
KEYWORDS
Neutrophil-lymphocyte ratio; adrenocortical carcinoma; prognosis; prognostic marker
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an adverse prognosis.1-4 Complete tumor resection offers the best chance for a prolonged disease-free survival but even in these patients prognosis is quite variable since many of them experience disease recurrence.
A few factors, such as Ki-67,6 tumor size7 and the stage of the disease8 have been associated with the out- come of ACC patients. However, the prognostic role of these factors was quite inconsistent across studies.9 A novel prognostic marker with a better foresight con- sidering ACC outcome would therefore be of great importance.
A number of recent reports indicated the role of systemic inflammatory response to tumors in the patho- genesis and progression of various types of cancers. 10-16 These studies demonstrated that systemic inflammation markers in the peripheral blood such as the neutrophil- lymphocyte ratio (NLR) may be considered as a reliable,
yet simple and inexpensive test, for the prognosis of tumor outcome.
However, the prognostic value of patient inflam- matory status on ACC recurrence and progression has only been sparsely investigated. Mochizuki et al. showed in a small group of patients with ACC that NLR is helpful in differentiating ACC patients from those with benign adrenal tumors.1º Furthermore, in group of 84 ACC patients, Bagante et al. demonstrated that NLR could be used as an indepen- dent predictor of long-term survival after ACC resection.16 However, since it was a retrospective study that included patients from 13 different centers the observed results could be affected by inter-center variability in terms of surgical technique, treatment options and postoperative surveillance.16 Hence, in order to obtain a better insight into this matter, this study analyzed the impact of NLR, as a measure of systemic inflammation, on the long-term outcomes of patients with ACC.
Methods
This is a retrospective, single-institution study which included 59 patients referred to the Croatian Referral Center for adrenal gland disorders with the diagnosis of ACC. Data on demographics, preoperative blood counts, hormonal work-up, surgery and pathology reports, medical treatment and follow-up were collected from electronic medical records. In 11 patients, data on the preoperative blood count were not available for analysis (ACC surgery performed in another hospital (n = 8) or before 2010 (n = 3) when the electronic medical record software started to be used in our cen- ter). Therefore, the final study population comprised of 48 patients. The study was approved by the University Hospital Center Zagreb ethics committee.
The diagnosis of ACC was based on the Weiss scoring system.17 However, in three patients with the ACC ENSAT stage IV in whom surgery was not performed, diagnosis of ACC was made by hormonal workup and radiological imaging alongside with tumor biopsy. The European Network for the Study of Adrenal Tumors (ENSAT) classification system was used to stratify patients in four stages, according to tumor size, nodal involvement and distant metastases.17 Furthermore, Ki- 67 immunohistochemistry was performed in all patients as part of standard pathologist report and the threshold level of >10% was used to indicate patients with a high risk of tumor recurrence following R0 resection.17 Patients’ postoperative surveillance has been described in our previous publication.5
The primary outcome of the study was a difference in overall survival (OS) and disease-specific survival (DSS) 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, whereas DSS was determined as the time elapsed from the date of the ACC diagnosis to the date of death, if related to ACC, or the last follow-up visit.
NLR was calculated from the absolute neutrophil and absolute lymphocyte count before the surgery.
Statistical Analysis
Statistical analysis was performed using the SPSS version 17.0 for Windows. Variables were described as median and range whereas nominal variables were presented as frequencies. The differences between the variables were tested using the Mann-Whitney test or x2 test, as appro- priate. Correlation between two variables was assessed using the Spearman correlation test. Survival analysis was performed using the Kaplan-Meier method and differences were assessed with the log-rank test. For
multivariate analysis, the Cox regression model was applied. Receiver operating characteristic (ROC) curve analysis was used to determine an optimal cutoff value for NLR to predict DSS. Significance level was set at p < . 05.
Results
A total of 48 patients (34 females, 14 males) with ACC were enrolled in this study. The median age at diag- nosis was 51 years (17-82), and the median tumor size was 93.5 mm (26-250). Of 34 (70.8%) patients with functional tumors, the majority were presented with exclusive glucocorticoid hypersecretion or in combina- tion with androgen and steroid precursors excess (N = 25; 73.5%), followed by androgens/estrogens (n = 7; 20.6%) and mineralocorticoids (n = 2; 5.9%) overproduction. At presentation, 38 patients (79.2%) had ACC ENSAT stages I-III whereas 10 patients had ACC ENSAT stage IV (20.8%). Out of 38 patients with ACC ENSAT stages I-III, 36 (94.7%) underwent com- plete surgical resection of the tumor, and R2 resection was performed in two patients (5.3%). In seven patients with ACC ENSAT stage IV (70.0%) surgery was per- formed with the palliative intent to control the symp- toms of hormonal excess. In the remaining three patients with ACC ENSAT stage IV (30.0%) surgery was declined. The median follow-up time was 42.5 months (1-165). Overall, 15 (31.3%) patients died during follow up (1/4 (25.0%) ENSAT stage I, 2/ 24 (8.3%) ENSAT stage II, 3/10 (30.0%) ENSAT stage III and 9/10 (90.0%) ENSAT stage IV). In 11 of them, death was related to ACC (one patient ENSAT stage II, two patients ENSAT stage III and eight patients ENSAT stage IV) whereas two patients died due to sepsis, one due to pneumonia and one due to stroke. In five patients, recurrence of disease was detected after 11, 22, 28, 43 and 85 months of follow-up.
Patients with ENSAT stage IV had higher NLR levels compared to those with ENSAT stage I-III (5.7 (1.6 — 12.5) vs 3.3 (1.3-11); p = . 01). Similarly, higher NLR was observed among patients with cortisol-secreting tumors (4.6 (1.7-12.5) vs 2.8 (1.3-10.3); p =. 003) and those with Ki-67 index >10% (4.3 (1.3-12.5) vs 2.6 (1.6-11.0); p = . 005). Finally, a trend toward positive correlation between NLR and size of the tumor was also observed (r = 0.27; p = . 06).
With respect to DSS, the receiver operating charac- teristic curve (ROC) analysis indicated the NLR value of 3.9 as the optimal cutoff to predict DSS, with the sensi- tivity and specificity of 90.9% and 64.9%, respectively (Figure 1). The area under the ROC curve (AUC) for NLR was 0.743 (95% CI: 0.597-0.858).
NLR
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80
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60
40
20
0
0
20 40 60 80 100
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Patients with NLR >3.9 had a higher Weiss score (p = . 046), higher Ki-67 index (p = . 006) and a higher disease stage (p = . 01) compared to the patients with NLR ≤3.9. No differences between the two groups were observed in their age, tumor size, excess glucocorticoid secretion and tumor recurrence rate (Table 1). With regard to survival, the univariate analysis revealed worse DSS (p = . 02) and OS (p = . 004) in patients with NLR >3.9 than in those with NLR ≤3.9 (Figures 2 and 3). However, in a multivariate Cox regression model, after controlling for Ki-67 index, Weiss score and excess glucocorticoid secretion the effect of NLR on DSS and OS was no longer significant.
| Variable | NLR >3.9 | NLR ≤3.9 | P value |
|---|---|---|---|
| (n=23) | (n=25) | ||
| Age (year) | 56 (22-83) | 48 (17-72) | 0.2 |
| Female gender (n, %) | 18 (78) | 16 (64) | 0.28 |
| BMI | 28 (18-42) | 26 (20-42) | 0.48 |
| Tumor size (mm) | 96 | 88 | 0.15 |
| (28-250) | (26-156) | ||
| ENSAT tumor stage (n, %) | 0.01 | ||
| Stage I | 1 (4) | 3 (12) | |
| Stage II | 11 (48) | 13 (52) | |
| Stage III | 2 (9) | 8 (32) | |
| Stage IV | 9 (39) | 1 (4) | |
| Excess glucocorticoid secretion (n, %) | 15 (65) | 10 (40) | 0.08 |
| Ki-67 (%) | 19 (3-50) | 10 (1-65) | 0.006 |
| Weiss score | 6 (4-9) | 6 (3-9) | 0.046 |
| Follow-up (months) | 25 (1-165) | 47 (6-158) | 0.21 |
| Recurrence (n, %) | 3 (13) | 2 (8) | 0.66 |
| Death (n, %) | 12 (52) | 3 (12) | 0.004 |
| ACC related death(n, %) | 10 (43) | 1 (4) | 0.002 |
Discussion
In recent years, it has been recognized that outcomes in cancer patients are not determined by tumor character- istics alone, such as tumor size, stage and Ki-67 index, but that patient-related factors like weight loss and poor performance status play an important role as well. There is increasing and consistent evidence that tumor micro- environment and, in particular, the host systemic inflammatory response has a significant role in cancer development and progression. Cancer-associated inflammation may therefore be one of the major deter- minants of poor patient survival.18 Many recent studies found that an elevated NLR might be an indicator of more aggressive tumor behavior in a number of malignancies.15,19 However, few studies investigated the impact of NLR on the long-term outcome of ACC patients, so data on that topic are quite limited.10,16
The present study analyzed NLR in 48 patients with ACC and demonstrated higher levels in patients with more advanced disease (ENSAT stage IV) compared to those with less advanced disease, which is in accordance with previous reports on other solid malignancies.15 Moreover, the NLR levels in our cohort were higher in patients with Ki-67 index >10% and the same trend was observed in those with larger tumors. Similar to our results, Bagante et al. demonstrated that ACC patients with higher NLR levels had larger tumors, more advanced disease stage and were more likely to require an extended surgical resection.16 In addition, they demonstrated independent association of NLR with DSS.16 However, in their cohort, the proportion of patients with functional tumors, especially those with glucocorticoid hypersecretion, was substantially lower than reported in other studies which might represent a certain selection bias.16 Furthermore, a study by Mochizuki et al. also demonstrated that NLR is helpful in differentiating ACC from other adrenal tumors; how- ever, due to a rather small number of ACC patients included, the results of that study are of limited value.10
There is considerable heterogeneity across studies related to the NLR thresholds used to determine patients who were at increased risk of adverse disease outcome. In our study, the ROC curve analysis indicated the NLR value of 3.9 as the optimal cutoff to predict DSS in ACC patients with the sensitivity of 90.9% and specificity of 64.9%. In the univariate analysis, patients with NLR >3.9 had worse DSS and OS compared to those with NLR ≤3.9. Moreover, patients with NLR >3.9 demonstrated less favorable pathological characteristics of the tumor such as a higher Weiss score and Ki-67 index, as well as a higher ENSAT stage. Similar findings were also reported for other solid tumors: breast cancer,20
1.0
P=0.02
NLR > 3.9
NLR ≤ 3.9
-+-NLR > 3.9- censored
0.8
+ NLR ≤ 3.9- censored
Disease specific survival
0.6
0.4
0.2
0.0
0
50
100
150
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P=0.004
NLR > 3.9
INLR ≤ 3.9
NLR > 3.9- censored
+ NLR ≤ 3.9- censored
1.0
0.8
Overall survival
0.6
0.4
0.2
0.0
0
50
100
150
Months
colorectal cancer21 and hepato-pancreatico-biliary malignancies.2
The mechanisms underlying the association of high NLR and unfavorable outcomes of cancer patients are poorly understood. This might be related to relative neutrophilia and lymphocytopenia that occur as a part of the systemic inflammatory response triggered by can- cer. Hanahan et al. argued that every tumor contains
immune cells ranging from subtle infiltrations to gross inflammations.18 Until recently it was thought that this reflected an attempt of the immune system to eradicate tumor. However, it has been demonstrated that the tumor-associated inflammatory response has a paradoxical effect of enhancing tumorigenesis and progression, by supplying bioactive molecules to the tumor microenvironment, including growth and pro-
angiogenic factors, survival factors that limit cell death, as well as extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion and metastatic spread of the tumor.1 18
To some extent, the results of our study might be influenced by a functional status of the tumor and resulting excess glucocorticoid secretion. It is well known that prolonged exposure to increased glucocor- ticoid levels induces alterations of the white blood cell and lymphoid cell count and function, possibly similar to those in tumor-associated inflammatory response. In our cohort, higher NLR was observed among patients with cortisol-secreting tumors compared to those with non-secreting tumors (p = . 003). However, when patients were divided on the basis of the NLR level, no difference in excess glucocorticoid secretion was found between patients with NLR >3.9 and those with NLR ≤3.9. Given the fact that glucocorticoid hypersecretion was shown to be an independent factor associated with poor prognosis in ACC ENSAT stage IV disease1, the NLR level might be a helpful tool to further stratify the survival prognosis in a group of patients with the most adverse outcome.
There are several limitations of this study including its retrospective nature and a relatively small sample size due to the rarity of ACC. Furthermore, the fact that the effect of NLR on DSS and OS was no longer significant after controlling for the Ki-67 index, Weiss score and excess glucocorticoid secretion might indicate a possible bias toward overestimation of the prognostic role of NLR. All the patients reported in this study were man- aged in a single high-volume center for adrenal tumors, using a uniform protocol regarding diagnostics, treat- ment and patients’ follow-up, which represents the major strength of the study.
In conclusion, our study demonstrated that a higher NLR level in ACC patients was associated with a more advanced stage of the disease and a higher Ki-67 index. Accordingly, patients with NLR >3.9 had worse DSS and OS compared to those with NLR ≤3.9. These results indicate that NLR is a simple, inexpensive and readily available test which, together with other prognostic fac- tors, might be used as a marker in ACC risk stratification and identification of patients with the most unfavorable prognosis.
Acknowledgments
Croatian ACC Study Group: Annemarie Balaško, Department of Endocrinology, University Hospital Center Zagreb, Zagreb, Croatia; Tina Dušek, Department of Endocrinology, University Hospital Center Zagreb, Zagreb, Croatia; Ante Mandić, Department of Endocrinology, Clinical Hospital
Mostar, Mostar, Bosnia and Herzegovina; Anela Novak, Department of Endocrinology, University Hospital Center Split, Split, Croatia; Sanja Selak, Department of Endocrinology, Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina; Tina Slunjski, Department of Endocrinology, General Hospital Varaždin, Varaždin, Croatia; Tanja Škorić Polovina, Department of Endocrinology, University Hospital Center Zagreb, Zagreb, Croatia; Ivana Šunić, Department of Endocrinology, General Hospital Karlovac, Karlovac, Croatia; Marija Tripolski, Department of Endocrinology, University Hospital Center Osijek, Osijek, Croatia.
We thank Tamara Sladoljev Agejev for the valuable com- ments in the preparation of the manuscript.
Disclosure Statement
The authors declare that they have no conflict of interest.
References
1. Abiven G, Coste J, Groussin L, et al. Clinical and Biological Features in the Prognosis of Adrenocortical Cancer: poor Outcome of Cortisol-Secreting Tumors in a Series of 202 Consecutive Patients. J Clin Endocrinol Metab. 2006;91(7):2650-2655.
2. Berruti A, Baudin E, Gelderblom H, et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagno- sis, treatment and follow-up. Ann Oncol. 2012;23 (7):131-138.doi:10.1093/annonc/mds231.
3. Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal cancer: recom- mendations of an international consensus conference. Endocr Relat Cancer. 2005;12(3):667-680.doi:10.1677/ erc.1.01029.
4. Fassnacht M, Krois M, Allolio B. Update in adrenocor- tical carcinoma. J Clin Endocrinol Metab. 2013;98 (12):4551-4564. doi:10.1210/jc.2013-3020.
5. Kastelan D, Knezevic N, Tomsic KZ, et al. Open versus laparoscopic adrenalectomy for localised adrenocortical carcinoma. Clin Endocrinol (Oxf). 2020. doi:10.1111/ cen.14251.
6. Beuschlein F, Weigel J, Saeger W, et al. Major prognos- tic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab. 2015;100(3):841-849.doi:10.1210/jc.2014-3182.
7. Canter DJ, Mallin K, Uzzo RG. Egleston BL, Simhan J, Walton J, et al. Association of tumor size with meta- static potential and survival in patients with adrenocor- tical carcinoma: an analysis of the National Cancer Database. Can J Urol. 2013;20:6915-6921.
8. Lebastchi AH, Kunstman JW, Carling T. Adrenocortical carcinoma: current therapeutic state-of-the-art. J Oncol. 2012;2012:234726.
9. Fassnacht M, Johanssen S, Quinkler M, et al. Limited prognostic value of 2004 International Union Against Cancer staging classification for adrenocortical carci- noma: proposal for a revised TNM classification. Cancer. 2009;115(2):243-250.doi:10.1002/cncr.24030.
10. Mochizuki T, Kawahara T, Takamoto D, et al. The neutrophil-to-lymphocyte ratio (NLR) predicts adreno- cortical carcinoma and is correlated with the prognosis.
BMC Urol. 2017;17(1):49.doi:10.1186/s12894-017-0240- 4.
11. Lee SF, Luque-Fernandez MA. Prognostic value of lymphocyte-to-monocyte ratio and neutrophil-to- lymphocyte ratio in follicular lymphoma: a retrospective cohort study. BMJ Open. 2017;3(11): e017904. doi:10.1136/bmjopen-2017-017904.
12. Faria SS, Jr PC F, Barbosa Silva MJ. et al. The neutrophil-to-lymphocyte ratio: a narrative review. Ecancermedicalscience. 2016;10:702. doi:10.3332/ ecancer.2016.702.
13. Templeton AJ, Ace O, McNamara MG, et al. Prognostic role of platelet to lymphocyte ratio in solid tumors: a systematic review and meta-analysis. Cancer. Epidemiol Biomarkers Prev. 2014;23(7):1204-1212. doi:10.1158/1055-9965.EPI-14-0146
14. Choi WJ, Cleghorn MC, Jiang H, Jackson TD, Okrainec A, Quereshy FA. Preoperative neutrophil-to- lymphocyte ratio is a better prognostic serum biomar- ker than platelet-to-lymphocyte ratio in patients undergoing resection for nonmetastatic colorectal cancer. Ann Surg Oncol. 2015;22(3):S603-13. doi:10.1245/s10434-015-4571-7.
15. Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, McMillan DC, Clarke SJ. The systemic inflammation-based neutrophil lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol. 2013;88(1):218-230. doi:10.1016/j. critrevonc.2013.03.010.
16. Bagante F, Tran TB, Postlewait LM, et al. Neutrophil-lymphocyte and platelet-lymphocyte ratio as predictors of disease specific survival after
resection of adrenocortical carcinoma. J Surg Oncol. 2015;112(2):164-172.doi:10.1002/jso.23982.
17. Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179(4):G1-G46. doi:10.1530/EJE-18-0608.
18. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. doi:10.1016/j.cell.2011.02.013.
19. Templeton AJ, McNamara MG, Šeruga B, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014;106(6):dju124.doi:10.1093/ jnci/dju124.
20. Liu X, Qu JK, Zhang J. et al. Prognostic role of pretreatment neutrophil to lymphocyte ratio in breast cancer patients: a meta-analysis. Medicine (Baltimore). 2017;96:e8101. doi:10.1097/MD.0000000000008101.
21. Pedrazzani C, Mantovani G, Fernandes E, et al. Assessment of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and platelet count as predictors of long-term outcome after R0 resection for colorectal cancer. Sci Rep. 2017;7(1):1494. doi:10.1038/s41598-017-01652-0.
22. Spolverato G, Maqsood H, Kim Y, et al. Neutrophil- lymphocyte and platelet-lymphocyte ratio in patients after resection for hepato-pancreatico- biliary malignancies. J Surg Oncol. 2015;111 (7):868-874.doi:10.1002/jso.23900.