Relationship between hepatocellular carcinoma circulating tumor cells and tumor volume

Lipika Goyal,Shyamala Maheswaran,Rahmi Öklü ,Mahnaz Zeinali,Melissa Choz,Shannon L. Stott,David T. Ting ,Rahul A. Sheth ,Mehmet Toner,Andrew X. Zhu,Vikram Deshpande,Irun Bhan,Hassan Albadawi,A. Fatih Sarioglu,Daniel A. Haber

doi:10.1186/s41236-018-0009-z

Abstract

BackgroundMicrofluidic platforms have demonstrated the ability to isolate rare circulating tumor cells from a wide variety of cancers. Our group has recently shown the ability to isolate circulating tumor cells (CTCs) from hepatocellular carcinoma (HCC) patients using a hematopoietic cell depletion microfluidic platform. However, the relationship of CTC generation and HCC progression is still not well understood. Tumor size is often used as a clinical prognostic factor, but there has been an inconsistent relationship of tumor size and metastatic recurrence. Characterizing the relationship of primary tumor size and CTCs would provide a better understanding of HCC tumor size and metastatic potential.ResultsCTCs in a cohort of HCC patients with quantitative tumor volume analysis was performed to determine if there was a relationship of tumor size to CTC generation. A total of 24 tumor volumetric analyses were used in this study, and a cutoff of 25 cc was used to create a low and high tumor volume group (median 5.56 vs 108 cc; p < 0.0001). Using an antigen agnostic microfluidic CTC isolation platform and immunofluorescent staining for cytokeratin and glypican-3, CTCs were detected in 18 of 22 (82%) HCC patients. CTCs/mL of blood did not correlate with either tumor volume or serum AFP. Interestingly, CTCs were found to be significantly higher in small compared to large volume tumors (median 18.5 vs 5 CTCs/mL; p = 0.0454).ConclusionAltogether, HCC CTCs provide additional data about the tumor independent of standard imaging and blood biomarkers, and there may be biological differences in small volume tumors that facilitate CTC entry into the blood stream. This has implications for HCC CTCs as a biomarker for predicting recurrence and as an early detection platform.

Highlights

Microfluidic platforms have demonstrated the ability to isolate rare circulating tumor cells from a wide variety of cancers
We tested our assay in 10 healthy donors (HD) to establish a baseline for the assay demonstrating all samples with < 1 Circulating Tumor Cell (CTC)/mL
We chose a baseline cutoff of ≥ 2 CTCs/mL for positive detection and applied the assay on 22 patients with hepatocellular carcinoma (HCC) diagnosed by histological confirmation by biopsy (n = 17) or established radiological criteria (n = 5) (Additional file 2: Table S1)

Summary

Introduction

Microfluidic platforms have demonstrated the ability to isolate rare circulating tumor cells from a wide variety of cancers. The detection of serum AFP has historically been used for HCC surveillance and disease monitoring, but has been shown to be negative in up to 40% of HCC patients making it a suboptimal biomarker (Song et al, 2016) This has led to the use of ultrasound (US) as a primary diagnostic tool for most screening programs with or without AFP testing. The sensitivity of US for HCC is as low as 21% for small tumors, and the accuracy of the test is user dependent (Yu et al, 2011a) Given these limitations, the development of novel blood based biomarkers to complement AFP and US is greatly needed for the early diagnosis and monitoring of HCC

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Discussion

Conclusion