Tin-Ming Go , , ,Dou-Sheng Bi , ,Jin-Jun Qin ,Chi Zhng ,Sheng-Jie Jin ,Guo-Qing Jing ,

a Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou 225001, China

b Department of Hepatobiliary Surgery, The Second Clinical College, Dalian Medical University, Dalian 116023, China

Keywords:Hepatocellular carcinoma Growth rate TNM stage SEER

ABSTRACT Background: Hepatocellular carcinoma (HCC) progresses fast and has a poor prognosis,but the growth rate in different TNM stages is not clear.The present study was to estimate the growth rate of HCC with different TNM stages at diagnosis.Methods: Baseline demographics and tumor characteristics were analyzed for 10145 patients in Surveillance,Epidemiology,and End Results (SEER) Program-registered HCC.Multiple linear regression models were used for age adjustment with patient race,sex,marital status,and HCC grade.Results: The age at diagnosis was younger in Caucasians and males.The adjusted average age of patients with stage I HCC was 65.26 years.The adjusted age of patients with stage II,IIIA,IIIB,and IIIC was -0.17,-0.25,-0.29,and -0.55 adjusted-year younger compared with patients with stage I HCC (all P ＜ 0.001).The adjusted average age of patients with T1 was 65.26 years.The age adjustment was -0.17,-0.26,and-0.55 respectively (all P ＜ 0.001) for T2,T3 or T4 tumors without distant metastases.Conclusions: These findings demonstrated that the more advanced the HCC stage at diagnosis,the younger the age at diagnosis and the faster the HCC growth from tumor occurrence.

Introduction

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-specific mortality worldwide.During the past decade,HCC was one of the few common cancers showing an upward trend in frequency in both sexes in several countries [1] .More than 250000 new cases of HCC occur annually,and approximately 500000-600000 patients with the disease die each year [2,3].

The development of HCC is a multistep process that normally needs many years.Patients with HCC at diagnosis usually present at an advanced stage and have a poor prognosis because of rapid disease progression.It is unethical and impractical to investigate and follow up HCC patients offering no treatments in order to observe HCC progression.Hence,little is known about the growth rate of HCC.In this study,we analyzed HCC patients and their tumor data from the Surveillance,Epidemiology and End Results(SEER) database to evaluate factors associated with age at diagnosis.In order to estimate the characteristics of HCC growth rate according to tumor size and stage,we then used this information to compare the average age of patients at diagnosis with small and low-stage HCC versus larger and higher stage cancers.

Patients and methods

Patient selection

We analyzed the data of HCC patients from the SEER database,which regularly collects data on patient demographics,the tumor morphology and stage at diagnosis,treatments,and the follow up for survival [4] .A total of 10145 patients aged between 30 and 96 years were diagnosed with stage I to IV HCC between January 2010 and December 2015 with all required data for this study(demographics,tumor grade,tumor stage,and tumor size).Tumor stages were assigned according to the criteria of the tumornode-metastasis (TNM) classification described in the cancer staging manual (7th edition) of American Joint Committee on Cancer (AJCC) [5] .We included HCC patients who had available data concerning the following characteristics:race (codes:white,black,other),sex (codes:male and female),age at diagnosis (codes:30-96 years),histologic type (codes:8170,8171,8172,8173,8174,and 8175),grade (codes:well/moderately/poorly differentiated and undifferentiated),diagnostic confirmation,AJCC TNM stage (codes:I,II,IIIA,IIIB,IIIC,IVA,and IVB),derived AJCC T stage (codes:T1,T2,T3a,T3b,and T4),derived AJCC N stage (codes:N0 and N1),tumor size (codes:1-996),marital status at diagnosis (codes:married,divorced,separated,single,unmarried or domestic partner,and widowed).

Liver cancer in young patients usually presents at an advanced stage with a poor pathological grading,which tends to have a poorer prognosis compared to that in elderly patients [6,7].The primary endpoint of this study was liver cancer-specific survival,which was calculated from the date of diagnosis to the date of cancer-specific death.

Statistical analysis

The primary goal of the analysis was to use adjusted patient ages to estimate the progression speed of HCC through and within its clinical stages.Because the primary tumor burden is more accurately quantified than the extent of metastatic disease,the analysis focused on investigating the progression speed among patients who had localized or locally advanced disease.Patient demographics and tumor characteristics associated with age at diagnosis were analyzed using the Kruskal-Wallis test,Chi-square test,or Student’st-test.Differences in age of patient groups categorized by disease stage and tumor size were analyzed with multivariable linear regression models that adjusted for patient race,sex,marital status,and grade (analogous methodology was reported by Yu et al.[8]).Because no a priori hypothesis was defined,Pvalues were not adjusted for multiple comparisons and were presented for descriptive purposes only.All statistical analyses were performed using SPSS software for Windows,version 22.0 (IBM,Armonk,NJ,USA).AP＜0.05 was considered statistically significant.

Results

Patient demographics and tumor characteristics associated with age at diagnosis in the SEER database were listed in Tables 1 and 2 .There were 7693 (75.8%) males and 2452 (24.2%) females.Males were significantly younger at diagnosis than females (64.6 ± 10.4 vs.66.9 ± 11.3 years;P＜0.001).White patients with HCC comprised the smallest percentage of races,and were significantly younger at diagnosis than other races (allP＜0.001).Widowed patients with HCC were significantly older at diagnosis than patients with other marital statuses (allP＜0.001).Tumors larger than 5 cm in diameter were the most frequent,and patients with these tumors were significantly older at diagnosis (allP＜0.001).Stage T1 was the most frequent T stage,and patients with T1 were significantly older at diagnosis compared with other T stages (allP＜0.001).Stage N0 was more frequent than stage N1 and patients with N0 were significantly older at diagnosis than those with stage N1 (P＜0.001).

Relationships between patient age at diagnosis and different T stages within I, II, or III stage cancers

We compared the adjusted average age of patients with localized or locally advanced cancers without distant metastases after adjusting for patient race,sex,marital status,and grade.Among patients diagnosed with stage I,II,or III cancers,those with T1 stage (adjusted mean age,65.26 years) were on average 0.23 (95%CI:0.16-0.30) adjusted years older (P＜0.001) than patients with higher T (T2-4) stages (adjusted mean age,65.03 years).Moreover,the adjusted average age of patients with T2,T3,or T4 tumors was significantly younger than those with T1 tumors (by -0.17 adjusted years for T2 vs.T1,-0.26 adjusted years for T3 vs.T1,and -0.55 adjusted years for T4 vs.T1,allP＜0.001;Table 3).Notably,the adjusted average age of patients with T1,T2,T3,and T4 tumors was gradually younger as the stage progressed.

Relationships between patient age at diagnosis and different TNM stages within I, II, or III stage cancers

We compared the adjusted average age of patients in TNM I to III stages after adjusting for patient race,sex,marital status,and grade.Patients with stage I tumors (adjusted mean age,65.26 years) were on average 0.23 (95% CI:0.16-0.30) adjusted years older (P＜0.001) than patients with higher TNM II-III stages (adjusted mean age,65.03 years).Furthermore,the adjusted average age of patients with stage II,IIIA,IIIB,or IIIC tumors was significantly younger than that of patients with stage I tumors (by -0.17 adjusted years for II vs.I,-0.25 adjusted years for IIIA vs.I,-0.29 adjusted years for IIIB vs.I,and -0.55 adjusted years for IIIC vs.I,allP＜0.001;Table 4).Notably,the average adjusted age of patients with stage I,II,IIIA,IIIB,and IIIC tumors was gradually younger as the stage progressed.

Relationships between patient age at diagnosis and different TNM stage I and II stratified by tumor size

We next examined differences in the adjusted age of patients with localized or locally advanced disease according to their primary tumor size within and between different TNM stages.Compared with TNM stage I tumors smaller than 3 cm,there were no significant adjusted age differences for TNM stage I tumors ranging from 3-5 cm or larger than 5 cm,or TNM stage II tumors smaller than 3 cm;however,the adjusted average ages of patients with TNM stage II tumors ranging from 3-5 cm (n=996) and larger than 5 cm were significantly younger (by -0.22 and -0.30 adjusted years,respectively,allP＜0.05;Table 5).

Compared with TNM stage I tumors ranging from 3-5 cm,there were no significant adjusted age differences for TNM stage I tumors larger than 5 cm,or TNM stage II tumors smaller than 3 cm,but the adjusted average ages of patients with TNM stage II tumors ranging from 3-5 cm and larger than 5 cm were significantly younger (by -0.18 and -0.25 adjusted years,respectively,allP＜0.05;Table 5).

Compared with TNM stage I tumors larger than 5 cm,there were no significant adjusted age differences for TNM stage II tumors smaller than 3 cm,but the adjusted average ages of patients with TNM stage II tumors ranging from 3-5 cm and larger than 5 cm were significantly younger (by -0.23 and -0.30 adjusted years,respectively,allP＜0.05;Table 5).

Compared with TNM stage II tumors less than 3 cm,there were no significant adjusted age differences for TNM stage II tumors ranging from 3-5 cm,but the adjusted average age of patients with TNM stage II tumors larger than 5 cm was significantly younger (by-0.22 adjusted years,P＜0.05;Table 5).

Compared with TNM stage II tumors ranging from 3-5 cm,there were no significant adjusted age differences for TNM stage II tumors larger than 5 cm (Table 5).

Table 3 Estimates from multiple linear regression models for age at diagnosis,adjusting for patient race,sex,marital status,and grade among patients with stage I,II,or III disease stratified by T subgroup.

Table 4 Estimates from multiple linear regression models for age at diagnosis,adjusting for patient race,sex,marital status,and grade among patients stratified by TNM stage.

Relationships between patient age at diagnosis and different TNM stage I, II or III stages stratified by tumor size

Finally,we examined differences in the adjusted age of patients with localized or locally advanced disease between TNM stage I and their primary tumor size within different higher TNM stages.Compared with TNM stage I tumors,there were no significant adjusted age differences for TNM stage II tumors smaller than 3 cm,IIIA tumors smaller than 3 cm or between 3-5 cm,IIIB tumors smaller than 3 cm or between 3-5 cm,or IIIC tumors smaller than 3 cm or between 3-5 cm.However,the adjusted average ages of patients with TNM stage II tumors ranging from 3-5 cm and larger than 5 cm,IIIA tumors larger than 5 cm,IIIB tumors larger than 5 cm,and IIIC tumors larger than 5 cm were all significantly younger than those of patients with TNM stage I HCC (by-0.21,-0.29,-0.25,-0.36,and -0.59 adjusted years,respectively,allP＜0.05;Table 6).

Table 5 Estimates from multiple linear regression models for age,adjusting for patient race,sex,marital status,and grade among patients with TNM stage I and II disease stratified by tumor size.

Table 6 Estimates from multiple linear regression models for age,adjusting for patient race,sex,marital status,and grade among patients with TNM stage I,II,or III disease stratified by tumor size.

Discussion

Evidence of HCC rapid progression through its clinical stages implicates that early-stage detection is critical to curative therapies.The surveillance of patients at risk of HCC using liver ul-trasound is recommended by the HCC management guidelines of many countries [9-11] .To avoid encountering late-stage cancers,early detection efforts should focus on very small subcentimeter HCC and cancerinsitu.Sala et al.[12] reported that the likelihood of cure after radiofrequency ablation is highest when HCC lesions are smaller than 2 cm,but that treatment efficacy drops substantially when lesions exceed 2 cm.The only randomized controlled trial of HCC screening showed that a 6-month screening interval enhanced survival [13],while Santi et al.also reported that 6-month screening intervals were associated with better survival compared with 12-month intervals [14] .

For the same HCC patient,it stands to reason that the age when tumors are at a high-stage must be older than that when tumors are at a low-stage.However,the relationship between age at diagnosis of HCC patients and tumors of different stages at diagnosis is unclear.In this study,we estimated differences in the average age at diagnosis of patients with HCC of different sizes and stages after adjusting for cofactors associated with age at diagnosis.As a representative example,we found that among patients diagnosed with localized or locally advanced disease,those diagnosed with T2,T3,or T4 HCC were younger at diagnosis compared with patients withT1 tumors.Notably,the adjusted average ages of patients with T1,T2,T3,or T4 tumors were gradually younger.

This results revealed an interesting and novel finding that an average estimated time for patients with stages T2,T3,and T4 at diagnosis taken from the tumor first developing to at diagnosis is shorter,compared with that of patients with stage T1 at diagnosis.The average progression time of patients with stage T1,T2,T3,and T4 was gradually shortening.In other words,there is an accelerated progression rate as stage T progressed.

Our results indicated that the more advanced the HCC stage at diagnosis,the younger patients at diagnosis and the faster the growth rate of HCC.There is a gradually accelerated progression rate as stage T and stage TNM,an average estimated time from carcinogenesis to stages II,IIIA,IIIB,and IIIC at diagnosis is shorter,compared with that of patients with stage I at diagnosis.This seems not logical because the HCC patients have to reach stage I first from oncogenesis and then progress to higher stage.We emphasized here that at the time of diagnosis,patients with higher stages are younger.In addition,when the age was adjusted,the time of oncogenesis are assumed to be at the equivalent age point.Notably,the average progression time from lower stage to next higher stage (I -II -IIIA -IIIB -IIIC) was also gradually shortening.In other words,there is a gradually accelerated progression rate as TNM stage progressed.This phenomenon was also analogously taken place in a comparison of the average adjusted age of patients with different TNM stage I and II stratified by tumor size.In addition,Table 5 also indicated a gradually accelerated progression rate as tumor size progressed.

At first glance,the findings shown in Table 6 do not support this phenomenon.However,when subgroups with small sample sizes (＜100 cases) were removed from Table 6,the data confirmed our earlier findings.Therefore,we proposed that patients with high-stage HCC at diagnosis likely represent a specific group having significant heterogeneity to patients with low-stage tumors at diagnosis.This subgroup appears to have more malignant biological behavior than those with low-stage tumors,leading to a significantly faster rate of progression.

Variations in tumor growth rate and HCC progression have been reported previously [15-17],and may reflect heterogeneity with respect to angiogenesis,the extracellular matrix,the immune microenvironment,and tumor cells [18] .Ebara et al.[15] analyzed tumor volume doubling times for HCC smaller than 3 cm without specific treatment.They showed that the speed of tumor growth is not always constant.Tumor grows faster as disease progresses.Indeed,Okazaki et al.[16] reported that the tumor volume doubling time is from 41 to 305 days in HCC smaller than 4.5 cm in diameter before the initiation of a specific treatment.Barbara et al.[17] also reported that tumor volume doubling time is from 27.2 to 605.6 days within HCC ≤5 cm in diameter.The fastest growing rate is 22 times higher than that of the slowest.These findings support our theory that patients diagnosed with high-stage HCC represent a group with a faster growth rate than those diagnosed at a low-stage HCC.

Our results showed that in most cases,an average estimated time from carcinogenesis to the diagnosis was shorter in patients with high-stage tumors than in those with low-stage tumors.This phenomenon can be explained by our hypothesis that high-stage tumors at diagnosis have a faster rate of progression than low-stage tumors at diagnosis.We observed that the age at diagnosis between high-and low-stage tumors was not different.This is because the gap between these two specified stages is too short to embody the advantage of the growth rate of progression in patients with high-stage tumors at diagnosis.The positive values without significance in Table 6 may be caused by the small number of patients available for analysis(type II error).

Few studies have investigated factors predictive of the HCC growth rate,and these have not yet been identified.Only changes in serum alpha-fetoprotein (levels over time) were somewhat positively associated with changes in HCC tumor size in patients in the Far East [15,19],but not in Caucasians [20] .The identification of other specific factors predictive of the HCC growth rate would help formulate optimal therapeutic strategies [21] .

It is unclear whether the etiology of liver disease affects the age of developing HCC.Unfortunately,there is a limitation that the SEER database does not provide the etiology data of liver disease.Whether the etiology of liver disease affects the age of developing HCC is required to be explored in future study.In a retrospective study of liver cancer [6],we reanalyzed the data of SEER database and found patients aged ≤35 years had a higher proportion of distant metastasis than those aged 36 to 45 years.This means that distant metastasis is significantly associated with the younger age,which is basically in line with our conclusion.

There are several limitations in our study.First,although patient age at diagnosis was adjusted for associated cofactors,this cannot be done for some risk factors for HCC carcinogenesis that interfere with the timing of HCC progression not in the SEER database,including different fibrosis etiologies and tumor capsules.This may reduce the reliability of estimates of average age at diagnosis.Second,the factors such as the contribution of tumor stroma to tumor size and deficiencies of tumor size measurements of resection margin-positive cancers were not taken into account when tumor size was used to estimate HCC progression.Third,in the SEER database,only the AJCC Cancer Staging system is recorded for HCC staging.

In conclusion,our study suggests that the more advanced the HCC stage at diagnosis,the younger the patient age at diagnosis and the faster the HCC growth leading to the shorter time from the oncogenesis to the diagnosis.There is a gradually accelerated progression rate as TNM stage progressed at diagnosis.Therefore,there should be an HCC screening program for the young population who have chronic liver diseases.

Acknowledgments

None.

CRediTauthorshipcontributionstatement

Tian-MingGao:Conceptualization,Methodology,Data curation,Writing -original draft.Dou-ShengBai:Conceptualization,Methodology,Writing -original draft.Jian-JunQian:Formal analysis,Writing -original draft.ChiZhang:Formal analysis,Writing-original draft.Sheng-JieJin:Formal analysis,Writing -original draft.Guo-QingJiang:Conceptualization,Funding acquisition,Supervision,Writing -review &editing.

Funding

This study was supported by grants from the Scientific Research Subject of Jiangsu Province Health Department (H201661)and the Project of Invigorating Health Care through Science,Technology and Education:Jiangsu Provincial Medical Youth Talent(QNRC2016331).

Ethicalapproval

This study was approved by the Ethics Committee of our hospital.This study has been permitted to obtain the data from Surveillance,Epidemiology,and End Results (SEER) database (10778-Nov2018).

Competinginterest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.