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Ki-67 “hot spot” digital analysis is useful in the distinction of hepatic adenomas and well-differentiated hepatocellular carcinomas

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Abstract

This study aims to investigate the utility of digital protocols for Ki-67 immunohistochemistry quantitative analysis (“hot spot” method) in the setting of well-differentiated hepatocellular neoplasms. Resection cases of typical hepatic adenomas (HAs) (n = 40), atypical HAs (n = 9), and well-differentiated hepatocellular carcinomas (WD HCCs) (n = 56) were selected. HAs were further classified by immunohistochemistry using antibodies against liver fatty acid binding protein, glutamine synthetase, B-catenin, hepatic serum amyloid A, and C-reactive protein. Ki-67 proliferative index by immunohistochemistry was evaluated in all cases by digital analysis using a modified neuroendocrine tumor “hot spot” protocol. The proliferative rate of HAs (typical, median 1.2% (range 0–7.4%) and atypical, median 1.0% (range 0.3–3%)) was significantly lower than that of WD HCCs (median 4.5%, range 0–49.8%) (P < 0.0001). Only a few (7.5%) of the adenomas (all inflammatory/telangiectatic type) had proliferative rates higher than 4%, compared to most (51%) of HCCs. Ki-67 is a potentially useful adjunct marker in the evaluation of WD hepatocellular neoplasms, as “hot spot” proliferative rates are consistently very low in HAs but vary significantly in WD HCCs.

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References

  1. Shafizadeh N, Kakar S (2011) Diagnosis of well-differentiated hepatocellular lesions: role of immunohistochemistry and other ancillary techniques. Adv Anat Pathol 18:438–445

    Article  CAS  Google Scholar 

  2. Singhi AD, Jain D, Kakar S, Wu TT, Yeh MM, Torbenson M (2012) Reticulin loss in benign fatty liver: an important diagnostic pitfall when considering a diagnosis of hepatocellular carcinoma. Am J Surg Pathol 36:710–715

    Article  Google Scholar 

  3. Wilkens L, Bredt M, Flemming P, Schwarze Y, Becker T, Mengel M, von Wasielewski R, Klempnauer J, Kreipe H (2001) Diagnostic impact of fluorescence in situ hybridization in the differentiation of hepatocellular adenoma and well-differentiated hepatocellular carcinoma. J Mol Diagn 3:68–73

    Article  CAS  Google Scholar 

  4. Wilkens L, Bredt M, Flemming P, Becker T, Klempnauer J, Heinrich Kreipe H (2001) Differentiation of liver cell adenomas from well-differentiated hepatocellular carcinomas by comparative genomic hybridization. J Pathol 193:476–482

    Article  CAS  Google Scholar 

  5. Kakar S, Chen X, Ho C, Burgart LJ, Adeyi O, Jain D, Sahai V, Ferrell LD (2009) Chromosomal abnormalities determined by comparative genomic hybridization are helpful in the diagnosis of atypical hepatocellular neoplasms. Histopathology 55:197–205

    Article  Google Scholar 

  6. Chen Z-ME, Crone KG, Watson MA, Pfeifer JD, Wang HL (2005) Identification of a unique gene expression signature that differentiates hepatocellular adenoma from well-differentiated hepatocellular carcinoma. Am J Surg Pathol 29:1600–1608

    Article  Google Scholar 

  7. Coston WMP, Loera S, Lau SK, Ishizawa S, Jiang Z, Wu CL, Yen Y, Weiss LM, Chu PG (2008) Distinction of hepatocellular carcinoma from benign hepatic mimickers using glypican-3 and CD34 immunohistochemistry. Am J Surg Pathol 32:433–444

    Article  Google Scholar 

  8. Shafizadeh N, Ferrell LD, Kakar S (2008) Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum. Mod Pathol 21:1011–1018

    Article  CAS  Google Scholar 

  9. Wang X et al (2006) Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas. Hum Pathol 37:1435–1441

    Article  CAS  Google Scholar 

  10. Yamauchi N, Watanabe A, Hishinuma M, Ohashi KI, Midorikawa Y, Morishita Y, Niki T, Shibahara J, Mori M, Makuuchi M, Hippo Y, Kodama T, Iwanari H, Aburatani H, Fukayama M (2005) The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma. Mod Pathol 18:1591–1598

    Article  CAS  Google Scholar 

  11. Nguyen TB, Roncalli M, Di Tommaso L, Kakar S (2016) Combined use of heat-shock protein 70 and glutamine synthetase is useful in the distinction of typical hepatocellular adenoma from atypical hepatocellular neoplasms and well-differentiated hepatocellular carcinoma. Mod Pathol 29:283–292

    Article  CAS  Google Scholar 

  12. Luo Y, Ren F, Liu Y, Shi Z, Tan Z, Xiong H, Dang Y, Chen G (2015) Clinicopathological and prognostic significance of high Ki-67 labeling index in hepatocellular carcinoma patients: a meta-analysis. Int J Clin Exp Med 8:10235–10247

    PubMed  PubMed Central  Google Scholar 

  13. van Dekken H, Verhoef C, Wink J, van Marion R, Vissers KJ, J. Hop WC, de Man RA, IJzermans JN, J. van Eijck CH, Zondervan PE (2005) Cell biological evaluation of liver cell carcinoma, dysplasia and adenoma by tissue micro-array analysis. Acta Histochem 107(3):161–171

    Article  Google Scholar 

  14. Grigioni WF, D'Errico A, Bacci F, Gaudio M, Mazziotti A, Gozzetti G, Mancini AM (1989) Primary liver neoplasms: evaluation of proliferative index using MoAb Ki67. J Pathol 158(1):23–29

    Article  CAS  Google Scholar 

  15. Yang Z, Tang LH, Klimstra DS (2011) Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification. Am J Surg Pathol 35:853–860

    Article  Google Scholar 

  16. Coons SW, Johnson PC (1993) Regional heterogeneity in the proliferative activity of human gliomas as measured by the Ki-67 labeling index. J Neuropathol Exp Neurol 52:609–618

    Article  CAS  Google Scholar 

  17. Dowsett M, Nielsen TO, A'Hern R, Bartlett J, Coombes RC, Cuzick J, Ellis M, Henry NL, Hugh JC, Lively T, McShane L, Paik S, Penault-Llorca F, Prudkin L, Regan M, Salter J, Sotiriou C, Smith IE, Viale G, Zujewski JA, Hayes DF, International Ki-67 in Breast Cancer Working Group (2011) Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst 103:1656–1664

    Article  CAS  Google Scholar 

  18. Siegers HP, Zuber P, Hamou MF, van Melle GD, de Tribolet N (1989) The implications of the heterogeneous distribution of Ki-67 labelled cells in meningiomas. Br J Neurosurg 3:101–107

    Article  CAS  Google Scholar 

  19. Shepherd NA, Richman PI, England J (1988) Ki-67 derived proliferative activity in colorectal adenocarcinoma with prognostic correlations. J Pathol 155:213–219

    Article  CAS  Google Scholar 

  20. Adsay V (2012) Ki67 labeling index in neuroendocrine tumors of the gastrointestinal and pancreatobiliary tract. Am J Surg Pathol 36:1743–1746

    Article  Google Scholar 

  21. Shi C, Gonzalez RS, Zhao Z, Koyama T, Cornish TC, Hande KR, Walker R, Sandler M, Berlin J, Liu EH (2015) Liver metastases of small intestine neuroendocrine tumors: Ki-67 heterogeneity and World Health Organization grade discordance with primary tumors. Am J Clin Pathol 143:398–404

    Article  Google Scholar 

  22. Polley M-YC et al (2013) An international Ki67 reproducibility study. J Natl Cancer Inst 105:1897–1906

    Article  Google Scholar 

  23. Polley M-YC et al (2015) An international study to increase concordance in Ki67 scoring. Mod Pathol 28:778–786

    Article  Google Scholar 

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Correspondence to Roger K. Moreira.

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Jones, A., Kroneman, T.N., Blahnik, A.J. et al. Ki-67 “hot spot” digital analysis is useful in the distinction of hepatic adenomas and well-differentiated hepatocellular carcinomas. Virchows Arch 478, 201–207 (2021). https://doi.org/10.1007/s00428-020-02868-8

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  • DOI: https://doi.org/10.1007/s00428-020-02868-8

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