Ann Surg Treat Res.  2023 Sep;105(3):148-156. 10.4174/astr.2023.105.3.148.

The prognostic and predictive value of plasma D-dimer in children with neuroblastoma: a 7-year retrospective analysis at a single institution

• Wang ZN
• Zhang Y
• Sun J
• Zhao ZZ
• Wang S
• Yang C

• KMID: 2545906
• DOI: http://doi.org/10.4174/astr.2023.105.3.148

Abstract

Purpose
Elevated plasma D-dimer level is a poor prognostic factor for many solid tumors. However, limited research has been conducted on D-dimer in children with neuroblastoma (NB), and its clinical significance remains unclear. The present study investigated the clinical and prognostic significance of D-dimer in pediatric NB patients.
Methods
A retrospective analysis of all newly admitted NB patients was conducted from January 2014 to December 2020. Baseline clinicopathological features, preoperative laboratory parameters, and follow-up information were collected. Univariate and multivariate analyses were performed to determine the relationship between D-dimer level, clinical features, and the prognostic value.
Results
Among 266 patients, the median value of D-dimer was 2.98 ng/mL, of which 132 patients showed elevated D-dimer levels before surgery (>2.98 ng/mL). Univariate analysis revealed that elevated D-dimer was significantly associated with age, hemoglobin, neutrophil-to-lymphocyte ratio, neuron-specific enolase, 24-hour vanillylmandelic acid, overall survival, and so on (P < 0.05). Patients with elevated D-dimer levels had shorter median overall survival time when compared with normal D-dimer levels (P = 0.01). The prognosis was better in patients with normal D-dimer levels when combined with lower age, ganglioneuroblastoma tumor type, lower stage on International Neuroblastoma Staging System, low-risk group, and without bone metastasis or bone marrow metastasis. The continuous increase of D-dimer level after treatment indicated tumor recurrence or progression.
Conclusion
A high D-dimer level is associated with low overall survival, and an elevated D-dimer level after treatment indicates tumor recurrence and progression. D-dimer can be used as one of the evaluation factors for NB treatment or prognosis.

Keyword

Child; D-dimer; Neuroblastoma; Prognosis

Figure

• 

  Fig. 1 Kaplan-Meier survival curves of plasma D-dimer and neuroblastoma (NB) subgroup. (A) Survival curve of plasma D-dimer with age. a, D-dimer ≤2.98 ng/mL + age <18 months; b, D-dimer >2.98 ng/mL + age <18 months; c, D-dimer ≤2.98 ng/mL + age ≥18 months; and d, D-dimer >2.98 ng/mL + age ≥18 months. (B) Survival curve of plasma D-dimer by tumor class. a, D-dimer 2.98 ng/mL + ganglioneuroblastoma (GNB); b, D-dimer >2.98 ng/mL + GNB; c, D-dimer ≤2.98 ng/mL + NB; and d, D-dimer >2.98 ng/mL + NB. (C) Survival curve of plasma D-dimer with tumor stage (International Neuroblastoma Staging System). a, D-dimer ≤2.98 ng/mL + stage I + II + IVs; b, D-dimer >2.98 ng/mL+ stage I + II + IVs; c, D-dimer ≤2.98 ng/mL + stage III + IV; and d, D-dimer >2.98 ng/mL + stage III + IV. (D) Survival curve of plasma D-dimer with tumor risk group. a, D-dimer ≤2.98 ng/mL + low risk; b, D-dimer >2.98 ng/mL + low risk; c, D-dimer ≤2.98 ng/mL + high risk; and d, D-dimer >2.98 ng/mL + high risk. (E) Survival curve of plasma D-dimer with bone metastasis. a, D-dimer ≤2.98 ng/mL + no bone metastasis; b, D-dimer >2.98 ng/mL + no bone metastasis; c, D-dimer ≤2.98 ng/mL + bone metastasis; and d, D-dimer >2.98 ng/mL + bone metastasis. (F) Survival curve of plasma D-dimer with bone marrow metastasis. a, D-dimer ≤2.98 ng/mL + no bone marrow metastasis; b, D-dimer >2.98 ng/mL + no bone marrow metastasis; c, D-dimer ≤2.98 ng/mL + bone marrow metastasis; and d, D-dimer >2.98 ng/mL + bone marrow metastasis.

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  Fig. 2 The relationship between plasma D-dimer and overall survival (OS) before and after treatment. N, normal; H, high. *P < 0.05, ***P < 0.001.

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  Fig. 3 Plasma D-dimer level and prognosis after treatment. *P < 0.05, **P < 0.01, ***P < 0.001.

Reference

1. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am. 2010; 24:65–86. PMID: 20113896.

2. Johnsen JI, Dyberg C, Wickström M. Neuroblastoma: a neural crest derived embryonal malignancy. Front Mol Neurosci. 2019; 12:9. PMID: 30760980.

3. Cheung NK, Dyer MA. Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer. 2013; 13:397–411. PMID: 23702928.

4. Park JR, Bagatell R, Cohn SL, Pearson AD, Villablanca JG, Berthold F, et al. Revisions to the international neuroblastoma response criteria: A Consensus Statement from the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol. 2017; 35:2580–2587. PMID: 28471719.

5. Schulte M, Köster J, Rahmann S, Schramm A. Cancer evolution, mutations, and clonal selection in relapse neuroblastoma. Cell Tissue Res. 2018; 372:263–268. PMID: 29478075.

6. von Stedingk K, Gisselsson D, Bexell D. Multidimensional intratumour heterogeneity in neuroblastoma. Oncotarget. 2019; 10:3–5. PMID: 30713595.

7. Bosse KR, Maris JM. Advances in the translational genomics of neuroblastoma: from improving risk stratification and revealing novel biology to identifying actionable genomic alterations. Cancer. 2016; 122:20–33. PMID: 26539795.

8. Davidoff AM. Neonatal neuroblastoma. Clin Perinatol. 2021; 48:101–115. PMID: 33583499.

9. Eisenhofer G, Peitzsch M, Bechmann N, Huebner A. Biochemical diagnosis of catecholamine-producing tumors of childhood: neuroblastoma, pheochromocytoma and paraganglioma. Front Endocrinol (Lausanne). 2022; 13:901760. PMID: 35957826.

10. Zhu FY, Yan J, Cao YN, Jin Y, Li J, Zhao Q. Early decline of neuron-specific enolase during neuroblastoma chemotherapy is a predictive factor of clinical outcome. Pediatr Hematol Oncol. 2021; 38:543–554. PMID: 34106032.

11. Moroz V, Machin D, Hero B, Ladenstein R, Berthold F, Kao P, et al. The prognostic strength of serum LDH and serum ferritin in children with neuroblastoma: a report from the International Neuroblastoma Risk Group (INRG) project. Pediatr Blood Cancer. 2020; 67:e28359. PMID: 32472746.

12. Deme D, Telekes A. Prognostic importance of cross-linked fibrin degradation products (D-dimer) in oncology. Magy Onkol. 2017; 61:319–326. PMID: 29257150.

13. Kim EY, Song KY. Prognostic value of D-dimer levels in patients with gastric cancer undergoing gastrectomy. Surg Oncol. 2021; 37:101570. PMID: 33839443.

14. Ma M, Cao R, Wang W, Wang B, Yang Y, Huang Y, et al. The D-dimer level predicts the prognosis in patients with lung cancer: a systematic review and meta-analysis. J Cardiothorac Surg. 2021; 16:243. PMID: 34454552.

15. Fang P, Du L, Cai D. Evaluation of plasma D-dimer for the diagnosis in Chinese patients with hepatocellular carcinoma: a meta-analysis. Medicine (Baltimore). 2020; 99:e19461. PMID: 32195943.

16. Lu Y, Zhang L, Zhang Q, Zhang Y, Chen D, Lou J, et al. The association of D-dimer with clinicopathological features of breast cancer and its usefulness in differential diagnosis: a systematic review and meta-analysis. PLoS One. 2019; 14:e0221374. PMID: 31487295.

17. Lin Y, Liu Z, Qiu Y, Zhang J, Wu H, Liang R, et al. Clinical significance of plasma D-dimer and fibrinogen in digestive cancer: a systematic review and meta-analysis. Eur J Surg Oncol. 2018; 44:1494–1503. PMID: 30100361.

18. Nakashima J, Tachibana M, Ueno M, Baba S, Tazaki H. Tumor necrosis factor and coagulopathy in patients with prostate cancer. Cancer Res. 1995; 55:4881–4885. PMID: 7585524.

19. Luo YL, Chi PD, Zheng X, Zhang L, Wang XP, Chen H. Preoperative D-dimers as an independent prognostic marker in cervical carcinoma. Tumour Biol. 2015; 36:8903–8911. PMID: 26071675.

20. Aravindan N, Herman T, Aravindan S. Emerging therapeutic targets for neuroblastoma. Expert Opin Ther Targets. 2020; 24:899–914. PMID: 33021426.

21. Castel V, Cañete A, Navarro S, García-Miguel P, Melero C, Acha T, et al. Outcome of high-risk neuroblastoma using a dose intensity approach: improvement in initial but not in long-term results. Med Pediatr Oncol. 2001; 37:537–542. PMID: 11745893.

22. London WB, Castel V, Monclair T, Ambros PF, Pearson AD, Cohn SL, et al. Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol. 2011; 29:3286–3292. PMID: 21768459.

23. Nasser NJ, Fox J, Agbarya A. Potential mechanisms of cancer-related hypercoagulability. Cancers (Basel). 2020; 12:566. PMID: 32121387.

24. Nadir Y. Decreasing tumor growth and angiogenesis by inhibition of coagulation. Semin Thromb Hemost. 2019; 45:622–628. PMID: 31398734.

25. Palumbo JS, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood. 2005; 105:178–185. PMID: 15367435.

26. Ward MP, Kane LE, Norris LA, Mohamed BM, Kelly T, Bates M, et al. Platelets, immune cells and the coagulation cascade: friend or foe of the circulating tumour cell? Mol Cancer. 2021; 20:59. PMID: 33789677.

27. Lee AY. Cancer and thromboembolic disease: pathogenic mechanisms. Cancer Treat Rev. 2002; 28:137–140. PMID: 12234564.

28. Chen Y, Chai Y, Huang H, Zhang M, Zhang S. Circulating D-dimer level is a predictor of overall survival and correlates with clinicopathologic characteristics of patients with neuroblastoma. Int J Clin Exp Pathol. 2018; 11:5436–5440. PMID: 31949627.

29. Pellini B, Chaudhuri AA. Circulating tumor DNA minimal residual disease detection of non-small-cell lung cancer treated with curative intent. J Clin Oncol. 2022; 40:567–575. PMID: 34985936.

30. Boonstra PA, Wind TT, van Kruchten M, Schuuring E, Hospers GA, van der Wekken AJ, et al. Clinical utility of circulating tumor DNA as a response and follow-up marker in cancer therapy. Cancer Metastasis Rev. 2020; 39:999–1013. PMID: 32367253.