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Integrated Nomograms for Preoperative Prediction of Microvascular Invasion and Lymph Node Metastasis Risk in Hepatocellular Carcinoma Patients

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The aim of the present work is to develop and validate accurate preoperative nomograms to predict microvascular invasion (MVI) and lymph node metastasis (LNM) in hepatocellular carcinoma.

Patients and Methods

A total of 268 patients with resected hepatocellular carcinoma (HCC) were divided into a training set (n = 180), in an earlier period, and a validation set (n = 88), thereafter. Risk factors for MVI and LNM were assessed based on logistic regression. Blood signatures were established using the least absolute shrinkage and selection operator algorithm. Nomograms were constructed by combining risk factors and blood signatures. Performance was evaluated using the training set and validated using the validation set. The clinical values of the nomograms were measured by decision curve analysis.

Results

The risk factors for MVI were hepatitis B virus (HBV) DNA loading, portal hypertension, Barcelona liver clinic (BCLC) stage, and three computerized tomography (CT) imaging features, namely tumor number, size, and encapsulation, while only BCLC stage, Child–Pugh classification, and tumor encapsulation were associated with LNM. The nomogram incorporating both risk factors and blood signatures achieved better performance in predicting MVI in the training and validation sets (C-indexes of 0.828 and 0.804) than the LNM nomogram (C-indexes of 0.765 and 0.717). Calibration curves also demonstrated a good fit. The decision curves indicate significant clinical usefulness.

Conclusions

The novel validated nomograms for HCC patients presented herein are noninvasive preoperative tools that can effectively predict the individualized risk of MVI and LNM, and this predictive power can aid doctors in explaining the illness for patient counseling.

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References

  1. McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015;19(2):223–38.

    PubMed  PubMed Central  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    PubMed  Google Scholar 

  3. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.

    Google Scholar 

  4. Earl TM, Chapman WC. Hepatocellular carcinoma: resection versus transplantation. Semin Liver Dis. 2013;33(3):282–92.

    PubMed  Google Scholar 

  5. Lu LC, Cheng AL, Poon RT. Recent advances in the prevention of hepatocellular carcinoma recurrence. Semin Liver Dis. 2014;34(4):427–34.

    PubMed  Google Scholar 

  6. Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 2012;13(1):e11–22.

    PubMed  Google Scholar 

  7. Lim KC, Chow PK, Allen JC, et al. Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria. Ann Surg. 2011;254(1):108–13.

    PubMed  Google Scholar 

  8. Banerjee S, Wang DS, Kim HJ, et al. A computed tomography radiogenomic biomarker predicts microvascular invasion and clinical outcomes in hepatocellular carcinoma. Hepatology. 2015;62(3):792–800.

    PubMed  PubMed Central  Google Scholar 

  9. Hirokawa F, Hayashi M, Miyamoto Y, et al. Outcomes and predictors of microvascular invasion of solitary hepatocellular carcinoma. Hepatol Res. 2014;44(8):846–53.

    CAS  PubMed  Google Scholar 

  10. Kobayashi S, Takahashi S, Kato Y, et al. Surgical treatment of lymph node metastases from hepatocellular carcinoma. J Hepatobiliary Pancreat Sci. 2011;18(4):559–66.

    PubMed  Google Scholar 

  11. Hasegawa K, Makuuchi M, Kokudo N, et al. Impact of histologically confirmed lymph node metastases on patient survival after surgical resection for hepatocellular carcinoma: report of a Japanese nationwide survey. Ann Surg. 2014;259(1):166–70.

    PubMed  Google Scholar 

  12. Bianco FJ, Jr. Nomograms and medicine. Eur Urol. Nov 2006;50(5):884–6.

    PubMed  Google Scholar 

  13. Lei Z, Li J, Wu D, et al. Nomogram for preoperative estimation of microvascular invasion risk in hepatitis B virus-related hepatocellular carcinoma within the milan criteria. JAMA Surg. 2016;151(4):356–63.

    PubMed  Google Scholar 

  14. Roayaie S, Blume IN, Thung SN, et al. A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma. Gastroenterology. 2009;137(3):850–5.

    PubMed  PubMed Central  Google Scholar 

  15. Collins GS, Reitsma JB, Altman DG, Moons KG. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. BMJ. Jan 7 2015;350:g7594.

  16. Ranstam J, Cook JA. LASSO regression. Br J Surg. 2018;105(10):1348.

    Google Scholar 

  17. Qiu J, Peng B, Tang Y, et al. CpG methylation signature predicts recurrence in early-stage hepatocellular carcinoma: results from a multicenter study. J Clin Oncol. 2017;35(7):734–42.

    CAS  PubMed  Google Scholar 

  18. Xu C, Fang J, Shen H, Wang YP, Deng HW. EPS-LASSO: test for high-dimensional regression under extreme phenotype sampling of continuous traits. Bioinformatics. 2018;34(12):1996–2003.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Gao J, Kwan PW, Shi D. Sparse kernel learning with LASSO and Bayesian inference algorithm. Neural Netw. 2010;23(2):257–64.

    PubMed  Google Scholar 

  20. Mayr A, Schmid M. Boosting the concordance index for survival data-a unified framework to derive and evaluate biomarker combinations. PLoS ONE. 2014;9(1):e84483.

    PubMed  PubMed Central  Google Scholar 

  21. Kramer AA, Zimmerman JE. Assessing the calibration of mortality benchmarks in critical care: the Hosmer–Lemeshow test revisited. Crit Care Med. 2007;35(9):2052–56.

    PubMed  Google Scholar 

  22. Vickers AJ, Cronin AM, Elkin EB, Gonen M. Extensions to decision curve analysis, a novel method for evaluating diagnostic tests, prediction models and molecular markers. BMC Med Inform Decis Mak. 2008;8:53.

    PubMed  PubMed Central  Google Scholar 

  23. Vickers AJ, Elkin EB. Decision curve analysis: a novel method for evaluating prediction models. Med Decis Mak. 2006;26(6):565–74.

    Google Scholar 

  24. Huang YQ, Liang CH, He L, et al. Development and validation of a radiomics nomogram for preoperative prediction of lymph node metastasis in colorectal cancer. J Clin Oncol. 2016;34(18):2157–64.

    PubMed  Google Scholar 

  25. Kerr KF, Brown MD, Zhu K, Janes H. Assessing the clinical impact of risk prediction models with decision curves: guidance for correct interpretation and appropriate use. J Clin Oncol. 2016;34(21):2534–40.

    PubMed  PubMed Central  Google Scholar 

  26. Rodriguez-Peralvarez M, Luong TV, Andreana L, Meyer T, Dhillon AP, Burroughs AK. A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic variability. Ann Surg Oncol. 2013;20(1):325–39.

    PubMed  Google Scholar 

  27. Lee S, Kim SH, Lee JE, Sinn DH, Park CK. Preoperative gadoxetic acid-enhanced MRI for predicting microvascular invasion in patients with single hepatocellular carcinoma. J Hepatol. 2017;67(3):526–34.

    CAS  PubMed  Google Scholar 

  28. Pote N, Cauchy F, Albuquerque M, et al. Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion. J Hepatol. 2015;62(4):848–54.

    CAS  PubMed  Google Scholar 

  29. Yu Y, Song J, Zhang R, et al. Preoperative neutrophil-to-lymphocyte ratio and tumor-related factors to predict microvascular invasion in patients with hepatocellular carcinoma. Oncotarget. Oct 3 2017;8(45):79722–30.

    PubMed  PubMed Central  Google Scholar 

  30. Katyal S, Oliver JH, 3rd, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastases of hepatocellular carcinoma. Radiology. 2000;216(3):698–703.

    CAS  PubMed  Google Scholar 

  31. Yamashita H, Nakagawa K, Shiraishi K, et al. Radiotherapy for lymph node metastases in patients with hepatocellular carcinoma: retrospective study. J Gastroenterol Hepatol. 2007;22(4):523–7.

    PubMed  Google Scholar 

  32. Zhuang PY, Zhang JB, Zhu XD, et al. Two pathologic types of hepatocellular carcinoma with lymph node metastasis with distinct prognosis on the basis of CK19 expression in tumor. Cancer. 2008;112(12):2740–8.

    PubMed  Google Scholar 

  33. Zhang L, Xiang ZL, Zeng ZC, Fan J, Tang ZY, Zhao XM. A microRNA-based prediction model for lymph node metastasis in hepatocellular carcinoma. Oncotarget. 2016;7(3):3587–98.

    PubMed  Google Scholar 

  34. Xiang ZL, Zeng ZC, Fan J, Tang ZY, Zeng HY, Gao DM. Gene expression profiling of fixed tissues identified hypoxia-inducible factor-1alpha, VEGF, and matrix metalloproteinase-2 as biomarkers of lymph node metastasis in hepatocellular carcinoma. Clin Cancer Res. 2011;17(16):5463–72.

    CAS  PubMed  Google Scholar 

  35. Cucchetti A, Piscaglia F, Grigioni AD, et al. Preoperative prediction of hepatocellular carcinoma tumour grade and micro-vascular invasion by means of artificial neural network: a pilot study. J Hepatol. 2010;52(6):880–8.

    PubMed  Google Scholar 

  36. Balachandran VP, Gonen M, Smith JJ, DeMatteo RP. Nomograms in oncology: more than meets the eye. Lancet Oncol. 2015;16(4):e173–180.

    PubMed  PubMed Central  Google Scholar 

  37. Wu TH, Hatano E, Yamanaka K, et al. A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of hepatocellular carcinoma. Surg Today. 2016;46(11):1275–81.

    CAS  PubMed  Google Scholar 

  38. Amini N, Ejaz A, Spolverato G, Maithel SK, Kim Y, Pawlik TM. Management of lymph nodes during resection of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: a systematic review. J Gastrointest Surg. 2014;18(12):2136–48.

    PubMed  Google Scholar 

  39. Cucchetti A, Qiao GL, Cescon M, et al. Anatomic versus nonanatomic resection in cirrhotic patients with early hepatocellular carcinoma. Surgery. 2014;155(3):512–21.

    PubMed  Google Scholar 

  40. Vitale A, Cucchetti A, Qiao GL, et al. Is resectable hepatocellular carcinoma a contraindication to liver transplantation? A novel decision model based on “number of patients needed to transplant” as measure of transplant benefit. J Hepatol. 2014;60(6):1165–71.

    CAS  PubMed  Google Scholar 

  41. Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38(2):200–207.

    PubMed  Google Scholar 

  42. Tomimaru Y, Wada H, Eguchi H, et al. Clinical significance of surgical resection of metastatic lymph nodes from hepatocellular carcinoma. Surg Today. 2015;45(9):1112–20.

    PubMed  Google Scholar 

  43. Zeng YR, Yang QH, Liu QY, et al. Dual energy computed tomography for detection of metastatic lymph nodes in patients with hepatocellular carcinoma. World J Gastroenterol. 2019;25(16):1986–96.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

This work was supported by the National Natural Science Foundation of China (Nos. 81572407, 81602112, 81672405), Young Teachers Training Program of Sun Yat-sen University (19ykpy112), Key Project of the Natural Science Foundation of Guangdong Province, China (No. 4210016041), Science and Technology Program of Guangdong Province, China (Nos. 2015A030313096, 2016A030313184), Natural Science Foundation of Guangzhou, China (No. 4250016043), a grant ([2013]163) from the Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology, a grant (KLB09001) from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, and a grant from the Guangdong Science and Technology Department (2017B030314026).

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Correspondence to Kai Mao MD, PhD or Zhiyu Xiao MD, PhD.

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Yan, Y., Zhou, Q., Zhang, M. et al. Integrated Nomograms for Preoperative Prediction of Microvascular Invasion and Lymph Node Metastasis Risk in Hepatocellular Carcinoma Patients. Ann Surg Oncol 27, 1361–1371 (2020). https://doi.org/10.1245/s10434-019-08071-7

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