Advancements in the Diagnosis of Hepatocellular Carcinoma
, Heather M. Ross 1, Adnan Khan 2,*, Marisa Wu 1, Risa Goldberg 2, Lokesh Shah 1, Sarah Mukhtar 1, Jacob Beiriger 1, Alexis Gerber 2 and Dina Halegoua-DeMarzio 3Round 1
Reviewer 1 Report
This is a simple review manuscript on diagnostic modalities of HCC.I would suggest reconsidering for publication after minor revision. However, there are some aspect missing in the review and some important literature work are not included such as the following should be included for machine learning side of diagnosis https://www.frontiersin.org/articles/10.3389/fbioe.2020.00254/full; https://www.frontiersin.org/articles/10.3389/fmed.2022.853261/full ;
https://www.sciencedirect.com/science/article/pii/S187705092030661X
Author Response
Response: Added new descriptions of AI/CNN applications using the articles provided by the reviewer to more accurately reflect existing work on algorithmic models, which were added as new references. The previous radiomics statement was moved to new paragraph to accommodate the new AI descriptions and improve the flow of the updated section. As seen above, we also included new aspects of the literature and clarified parts of each section
Reviewer 2 Report
Comments:
This review aimed to summarize the current advances of approaches for diagnosing of HCC. I had the following comments:
P1-2: Introduction
1. Please provide the relevant literature to support the numbers mentioned in the manuscript. The same as for the whole manuscript.
2. What’s the meaning of “incidence and mortality at 9.3 and 8.5”? Unit? Please describe it with an accurate way.
3. This is an update of BCLC system recently, please cite it.
P2-3: HCC pathophysiology
1. The risk factors mentioned here is repeated with above.
2. In this part of “HCC pathophysiology”, the authors talked about screening options and early diagnosis – a little confusing.
P3-6 (“Diagnostic modalities” part):
1. This review focused on “HCC”, interestingly in this part, it frequently talked about “liver disease” or NASH, inflammation, seeming off-target to the theme. Please focus more on HCC.
2. Please provide support for the statement “MRI is the gold standard for diagnosing liver disease”.
3. Please proved the latest evidence of gadoxetic acid enhanced MRI for diagnosing HCC.
4. What is the sensitivity and specificity of liver biopsy for diagnosing HCC? Please also provide the complication rate after liver biopsy. This method should also be put before imaging modalities as it serves as a gold standard of HCC diagnosis.
5. Please provide the efficacy of Li-RADS for diagnosing HCC, the comparison with conventional method. Please also cite Table 1 in the text.
P6-8: Biomarker/NGS
1. Microvascular invasion is also associated with AFP.
P8-9: AI
1. What is the difference/advantage between radiomics and conventional radiological description for HCC diagnosis?
2. Please check references 65 are relevant here.
3. What is the general efficacy for radiomics models in diagnosis of HCC?
4. What is “vascular microinvasion”? Did you mean “microvascular invasion”?
P11-12: Liquid biopsy
1. Please specify “promising clinical application of…”. Besides, reference 95 cannot fully cover the four cancers.
P12: future direction
1. Please refine the description of the study direction of this field.
Author Response
Thank you to you and your reviewers for taking the time to read and comment on our manuscript. We appreciate your comments and hope that we have sufficiently addressed them in this revision. Below are our point-by-point responses to each of the comments. On the manuscript itself, our edits should be clearly visible via the “track changes” function.
Response to Reviewer 1
This review aimed to summarize the current advances of approaches for diagnosing of HCC. I had the following comments:
P1-2: Introduction
- Please provide the relevant literature to support the numbers mentioned in the manuscript. The same as for the whole manuscript.
Response:Included the name and citation of the database, the Global Cancer Observatory 2020 Database, to provide a specific reference supporting the numbers mentioned in the manuscript. “Second leading cause of cancer deaths” changed to “third” based on updated sources from Globocan 2020 data.
- What’s the meaning of “incidence and mortality at 9.3 and 8.5”? Unit? Please describe it with an accurate way.
Response:Added “age-standardized” to clarify the calculation of incidence and mortalityand specified that units are per 100,000 person-years to better contextualize the numbers.Incidence and mortality values were updated based on Globocan 2020 data.
- This is an update of BCLC system recently, please cite it.
Response:Updated “Stage 0-C” to “A” and edited inclusion criteria for transplant based on 2022 BCLC staging guidelines. Added the reference for an article relevant to the updated BCLC guidelines, which now takes the place of the previous references #14-17.
P2-3: HCC pathophysiology
- The risk factors mentioned here is repeated with above.
Response:Deleted this sentence as it was mentioned previously. In doing so, the previous reference #24 was removed.
- In this part of “HCC pathophysiology”, the authors talked about screening options and early diagnosis – a little confusing.
Response:Created a new sub-section so screening is separate from pathophysiology.
P3-6 (“Diagnostic modalities” part):
- This review focused on “HCC”, interestingly in this part, it frequently talked about “liver disease” or NASH, inflammation, seeming off-target to the theme. Please focus more on HCC.
Response:Fixed this issue in semantics and either changed liver disease to HCC if that was what was intended or deleted extraneous information about liver disease other than HCC.
- Please provide support for the statement “MRI is the gold standard for diagnosing liver disease”.
Response:Clarified this statement and changed it to its intended meaning; MRI is the gold standard for imaging of HCC due to its diagnostic accuracy and significantly higher sensitivity, as well as significantly lower negative likelihood ratio as compared to CT.
- Please proved the latest evidence of gadoxetic acid enhanced MRI for diagnosing HCC.
Response:A 2017 systematic review and meta-analysis conducted with support from the AASLD (Roberts et al.) found that there is an increase in sensitivity for gadoxetate-enhanced MRI and for extracellular contrast-enhanced MRI over CT. Gadoxetate-MRI is more sensitive for <2 cm HCCs than CT or extracellular contrast MRI. Extracellular contrast agent MRI is marginally more specific for <2 cm HCCs than gadoxetate-MRI and may be preferred in clinical practice for liver transplantation evaluation without tissue biopsy.
- What is the sensitivity and specificity of liver biopsy for diagnosing HCC? Please also provide the complication rate after liver biopsy. This method should also be put before imaging modalities as it serves as a gold standard of HCC diagnosis.
Response:The specificity and positive predictive value of tumor biopsy is 100%, but the sensitivity may vary between 66 to 93% depending on the size of the needle and nodule, thus making ruling out diagnosis less reliable with biopsy. A comprehensive review of 30 cohort studies reporting on complications from percutaneous liver biopsy procedures from 2010-2020 found anincidence of major (2.4%) and minor (9.5%) complications, and technical failure (0.91%). As suggested, we appropriately moved the liver biopsy section up so that it would be addressed before discussing imaging in depth.
- Please provide the efficacy of Li-RADS for diagnosing HCC, the comparison with conventional method. Please also cite Table 1 in the text.
Response: Included diagnostic accuracy of LI-RADS in comparison to the conventional method. LI-RADS has a sensitivity of 92% and a specificity of 55.5% as compared to qualitative imaging which has a sensitivity of 92.3% and a specificity of 41.4%. When used in conjunction, LI-RADS with qualitative imaging has a sensitivity of 97% and a specificity of 30%. Table 1 was cited in the text.
P6-8: Biomarker/NGS
- Microvascular invasion is also associated with AFP.
Response:Discussed that AFP is associated with microvascular invasion of HCC and included two references to support this statement. Also discussed that microvascular invasion is associated with higher recurrence risk of HCC after resection as well as overall poorer disease prognosis.
P8-9: AI
- What is the difference/advantage between radiomics and conventional radiological description for HCC diagnosis?
Response:Modified statement of goals of radiomics to reflect advantages of radiomics compared with traditional radiological review. Defined radiomics as a specific approach to analyzing radiologic images using AI and described the algorithmic correlation of radiographic features with biological processes.
- Please check references 65 are relevant here.
Response:The previous reference 65 was included due to a typological error during writing; it has been removed from the reference list and is not relevant to this article.
- What is the general efficacy for radiomics models in diagnosis of HCC?
Response:Included objective description of radiomics model efficacy pertaining to predicting pathological grade. Radiomics models have demonstrated superior predictive value of HCC pathological grade compared with clinical factors-based models (AUC: 0.74 vs 0.60). Moreover, a combined approach using both radiomics and clinical features outperformed each individual model (AUC 0.80).
- What is “vascular microinvasion”? Did you mean “microvascular invasion”?
Response:“Vascular microinvasion” was written incorrectly in the initial draft and inappropriately carried over to subsequent versions. “Microvascular invasion” was the intended term.
P11-12: Liquid biopsy
- Please specify “promising clinical application of…”. Besides, reference 95 cannot fully cover the four cancers.
Response:Specified “promising clinical application” to be the use of liquid biopsy for disease and therapy monitoring, which are described later in that same paragraph. Added 3 new separate references to encompass the existing use of liquid biopsy for colorectal, prostate, lung, and breast cancer.
P12: future direction
- Please refine the description of the study direction of this field.
Response:Changed the title of subsection to be “conclusion”, which is better representative of the content. The newer diagnostic methods discussed are still in their early stages and along with identifying appropriate genes, targets, or methods researchers need to better define generalizability, cost, and logistics of their use for implementation in patient care. Multi-center, prospective studies are needed to determine benefits and limitations of each method when compared to one another and to standard practice. Further research is needed to explore how they can be used in conjunction with one another to be most effective for early detection of HCC.
Round 2
Reviewer 2 Report
The concerns have been well addressed.
Good work.
