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Singapore Med J
Singapore Med J
SMJ
Singapore Med J
Singapore Medical Journal
0037-5675
2737-5935
Wolters Kluwer - Medknow India

37171434
SMJ-65-444
10.4103/singaporemedj.SMJ-2021-283
Original Article
Prognostic impact of presenting symptoms of patients with hepatocellular carcinoma
Lim Samuel Jun Ming MBBS, MRCP 1
Hao Ying PhD 2
Goh George Boon Bee MBBS, MRCP 13
Chang Jason Pik Eu MBBS, MRCP 13
Tan Chee Kiat MBBS, FRCP 13
1 Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
2 National Public Health and Epidemiology Unit, National Centre for Infectious Diseases, Singapore
3 Duke-NUS Medical School, Singapore
Correspondence: Prof. Chee Kiat Tan, Senior Consultant, Department of Gastroenterology and Hepatology, Singapore General Hospital, Outram Road, 169608, Singapore. E-mail: tan.chee.kiat@singhealth.com.sg
8 2024
28 4 2023
65 8 444448
10 7 2021
07 1 2022
Copyright: © 2024 Singapore Medical Journal
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Introduction:

It is not known if the nature, number and duration of presenting symptoms at diagnosis of hepatocellular carcinoma impact on overall survival. This study examines whether the presenting symptoms of hepatocellular carcinoma have a significant impact on prognosis.

Methods:

The study cohort comprised 725 patients with symptomatic hepatocellular carcinoma seen in our department since October 1983. Another 545 patients were diagnosed on surveillance or from incidental findings. Presenting symptoms at diagnosis were documented. A survival census was performed on 31 October 2015 with the national registry of deaths. Presenting symptoms were examined for association with overall survival using multivariable Cox regression analysis. Survival analysis was done by Kaplan–Meier method with log-rank testing. Bivariate Pearson correlation was used to look for any association between duration of symptoms and overall survival.

Results:

Patients with symptomatic hepatocellular carcinoma had a significantly shorter survival than those diagnosed incidentally or on screening (94.0 vs. 786.0 days, P < 0.001). Survival was shorter in patients presenting with fluid retention (56.0 vs. 118.0 days, P < 0.001), jaundice (48.0 vs. 94.0 days, P = 0.017) and two or more symptoms (P = 0.010). Pain was associated with better survival (P < 0.001). On multivariable Cox regression analysis, only fluid retention (hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.30–1.87) and jaundice (HR 1.36, 95% CI 1.07–1.74) were independently associated with shorter survival. There was no significant relationship between the duration of symptoms and overall survival.

Conclusion:

Patients with hepatocellular carcinoma who present with fluid retention or jaundice have significantly shorter overall survival. This is useful in assessing patients at the time of diagnosis.

Carcinoma
hepatocellular
jaundice
oedema
prognosis
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pmcINTRODUCTION

Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide, and more than 800,000 patients are diagnosed annually. It generally has a poor prognosis and is the third leading cause of cancer-related mortality worldwide.[1]

It is difficult to accurately prognosticate as survival depends on multiple factors, including the stage of disease, tumour biology, liver function, the patient’s physical function and the choice of therapy.[2] A number of prognostication models exist, such as the Barcelona Clinic Liver Cancer (BCLC), Okuda, Cancer of the Liver Italian Program (CLIP), Chinese University Prognostic Index (CUPI) and French classifications.[3] The use of these models necessitates biochemical investigations and cross-sectional imaging. A tool for early prognostication, or in a setting where laboratory, radiological and therapeutic resources are limited, will be useful and can be based on clinical assessment.

It is well known that patients with symptomatic HCC have a poor prognosis compared to those diagnosed incidentally or on screening.[456] However, it is unclear how the nature, number and duration of presenting symptoms are associated with a poor prognosis.

This study examines how the presenting symptoms of HCC have a significant impact on a patient’s prognosis. We postulate that some symptoms have more impact on prognosis than others. It also stands to reason that a greater number and longer duration of symptoms may have more impact on prognosis. The presence of significant findings from this study can help in the early prognostication of HCC patients at the time of diagnosis, or where limited laboratory and radiological resources do not allow for the use of conventional prognostication models.

METHODS

The study cohort comprised 725 patients with symptomatic HCC seen in our department since October 1983. There were another 545 patients without symptoms who had HCC diagnosed on surveillance or from incidental findings during the same period. The diagnosis of HCC was based on criteria defined by the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD).[78]

Presenting symptoms of pain, fluid retention, loss of weight, loss of appetite, jaundice, palpable mass, lethargy, gastrointestinal bleeding, fever, shortness of breath and encephalopathy were documented at the time of diagnosis, and patients were followed up by our department. A survival census was performed on 31 October 2015 with the national registry of deaths. Our study included only patients who died from a liver-related cause, with reference being made to the cause of death documented in the registry.

The nature and number of presenting symptoms for each patient were examined for any association with overall survival using multivariable Cox regression analysis. Survival analysis was done by Kaplan–Meier method with log-rank testing, with hazard ratios (HRs) calculated using univariate Cox regression analysis. Bivariate Pearson correlation was used to look for any association between the duration of presenting symptoms and overall survival. Statistical analysis was done using IBM SPSS Statistics version 23.0 (IBM Corp, Armonk, NY, USA).

This study was supported by the hospital’s Institutional Review Board and carried out according to the principles set out in the 1964 Declaration of Helsinki and its later amendments.

RESULTS

The mean age of patients in the study cohort was 62.3 (±12.6) years. Majority of patients were male (84.8%), of Chinese ethnicity (88.6%) or had hepatitis B infection (74.2%). It is of note that 90% of patients in the study cohort were BCLC stage C and D, compared to just 36% in the group of asymptomatic patients. Similarly, 59% of patients in the study cohort were Child–Pugh B or C, compared to only 30% in the asymptomatic group. The demographics of both groups of patients are detailed in Table 1.

Table 1 Demographics of symptomatic (study cohort) and asymptomatic patients at diagnosis of hepatocellular carcinoma.

Demographic	n (%)	
	
Overall (n=1,270)	Symptomatic (n=725)	Asymptomatic (n=545)	P	
Agea(yr)	62.5±12.1	62.3±12.6	62.9±11.3	0.573*	
	
Male	1,047 (82.4)	615 (84.8)	432 (79.3)	0.012†	
Female	223 (17.6)	110 (15.2)	113 (20.7)		
	
Chinese	1,136 (89.4)	642 (88.6)	494 (90.6)	0.18†	
Non-chinese	114 (10.6)	83 (11.4)	51 (9.4)		
	
BCLC Stage 0	81 (6.4)	10 (1.4)	71 (13)	<0.001†	
BCLC Stage A	204 (16.1)	23 (3.2)	181 (33.2)		
BCLC Stage B	106 (8.3)	34 (4.7)	72 (13.2)		
BCLC Stage C	667 (52.5)	506 (69.8)	161 (29.5)		
BCLC Stage D	179 (14.1)	144 (19.9)	35 (6.4)		
BCLC unknown	33 (2.6)	8 (1.1)	25 (4.6)		
	
Child-Pugh A	578 (45.5)	249 (34.3)	329 (60.4)	<0.001†	
Child-Pugh B	422 (33.2)	287 (39.6)	135 (24.8)		
Child-Pugh C	171 (13.5)	142 (19.6)	29 (5.3)		
Child-Pugh unknown	99 (7.8)	47 (6.5)	52 (9.5)		
	
Hepatitis B infection	902 (71.0)	538 (74.2)	364 (66.8)	<0.001†	
No Hepatitis B infection	293 (23.1)	170 (23.4)	123 (22.6)		
Hepatitis B infection unknown	75 (5.9)	17 (2.3)	58 (10.6)		
	
Heavy alcohol consumptionb	220 (17.3)	127 (17.5)	93 (17.1)	0.892†	
No heavy alcohol consumption	1,050 (82.7)	598 (82.5)	452 (82.9)		
	
Hepatitis C infection	88 (6.9)	49 (6.8)	39 (7.2)	<0.001†	
No Hepatitis C infection	899 (70.8)	568 (78.3)	331 (60.7)		
Hepatitis C infection unknown	283 (22.3)	108 (14.9)	175 (32.1)		
aData presented as mean ± standard deviation. bHeavy alcohol consumption corresponds to >60 g of alcohol per day. *t-test. †Chi-square test. BCLC: Barcelona Clinic Liver Cancer

Patients in the study cohort had significantly shorter median overall survival compared to those who had HCC diagnosed on surveillance or from incidental findings (94.0 vs. 786.0 days, P < 0.001). The Kaplan–Meier survival curves are shown in Figure 1.

Figure 1 Kaplan–Meier survival curves of symptomatic (study cohort) and asymptomatic patients at diagnosis of hepatocellular carcinoma.

Pain was present in 294 (40.8%), fluid retention in 232 (32.2%), loss of weight in 159 (22.1%), loss of appetite in 143 (19.9%), jaundice in 79 (11.0%), palpable mass in 50 (6.9%), lethargy in 24 (3.3%), gastrointestinal bleeding in 21 (2.9%), fever in 20 (2.8%), shortness of breath in 17 (2.4%) and encephalopathy in five (0.7%) patients. Overall, 491 (68.2%) patients had one, 143 (19.9%) had two and 86 (11.9%) had three or more symptoms at the time of HCC diagnosis.

Within the study cohort, the median overall survival was significantly shorter in patients presenting with fluid retention compared to those without fluid retention (56.0 vs. 118.0 days, P < 0.001), as well as in patients with jaundice compared to those without jaundice (48.0 vs. 94.0 days, P = 0.017). Patients presenting with two or more symptoms also had a significantly shorter median overall survival compared to those who presented with one symptom (80.0 vs. 96.0 days, P = 0.010). Patients who had pain at the time of diagnosis had a significantly better median overall survival compared to those without pain (117.0 vs. 76.0 days, P < 0.001). There was no significant difference in overall survival for patients presenting with other symptoms, as detailed in Table 2.

Table 2 Median overall survival of study cohort (N=725), stratified by presenting symptoms.

Symptom	n (%)	Median OS if present (day)	Median OS if absent (day)	HR* (95% CI)	P †	
Pain	294 (40.8)	117.0	76.0	0.754 (0.647–0.878)	<0.001	
	
Fluid retention	232 (32.2)	56.0	118.0	1.614 (1.375–1.894)	<0.001	
	
Loss of weight	159 (22.1)	89.0	89.0	1.120 (0.935–1.341)	0.220	
	
Loss of appetite	143 (19.9)	81.0	90.0	1.100 (0.911–1.329)	0.322	
	
Jaundice	79 (11.0)	48.0	94.0	1.334 (1.051–1.694)	0.018	
	
Palpable mass	50 (6.9)	153.0	87.0	0.856 (0.640–1.144)	0.293	
	
Lethargy	24 (3.3)	109.0	88.0	0.897 (0.591–1.359)	0.607	
	
Gastrointestinal bleeding	21 (2.9)	229.0	88.0	0.664 (0.426–1.036)	0.071	
	
Fever	20 (2.8)	71.0	89.0	1.208 (0.765–1.907)	0.417	
	
Shortness of breath	17 (2.4)	56.0	90.0	1.315 (0.812–2.130)	0.266	
	
Encephalopathy	5 (0.7)	418.0	88.0	0.598 (0.248–1.443)	0.253	
	
≥2 symptoms	229 (31.8)	80.0	96.0	1.233 (1.050–1.448)	0.011	
*HR was calculated using univariate Cox regression analysis. †P values were calculated using Kaplan-Meier method with log-rank testing. CI: confidence interval, HR: hazards ratio, OS: overall survival

The proportion of patients with fluid retention was significantly smaller in patients who presented with pain compared to those without pain (8.0% vs. 49.8%, P < 0.001). Similarly, the proportion of patients with jaundice was also smaller in patients who presented with pain (6.0% vs. 14.2%, P = 0.001).

Patients with fluid retention were more likely to be Child–Pugh B or C compared to those without fluid retention (87.7% vs. 45.5%, P < 0.001). They were also more likely to be BCLC stage D (38.3% vs. 11.0%, P < 0.001). The same trend was observed in patients with jaundice when considering Child–Pugh B or C (79.5% vs. 56.7%, P < 0.001) or BCLC stage D (42.3% vs. 17.2%, P < 0.001). Patients with pain were less likely to be Child–Pugh B or C (41.6% vs. 71.7%, P < 0.001) or BCLC stage D (10.0% vs. 26.9%, P < 0.001).

Fluid retention, jaundice and pain were selected for multivariable Cox regression analysis [Table 3] as presenting symptoms that were significant on univariate analysis. Given the wide age range within the study cohort, age was also included as a variable. Only fluid retention (HR 1.56, 95% confidence interval [CI] 1.30–1.87) and jaundice (HR 1.36, 95% CI 1.07–1.74) were independently associated with shorter overall survival. Age was not a confounder.

Table 3 Hazard ratios with multivariable Cox regression analysis.

Variable*	Hazard ratio	95% confidence interval	P	
Fluid retention	1.56	1.30–1.87	<0.001	
	
Jaundice	1.36	1.07–1.74	0.012	
	
Pain	0.913	0.77–1.09	0.302	
	
Age	1.00	1.00–1.01	0.759	
*Symptoms significant on univariate analysis and age (as a potential confounder) were selected as variables for multivariable analysis.

The mean duration of presenting symptoms before diagnosis of HCC was 5.40 ± 17.1 weeks. There was no significant association between the duration of presenting symptoms and overall survival (r = −0.006, P = 0.873).

DISCUSSION

Our study further confirms current literature, which shows that patients with symptomatic HCC have a poorer prognosis compared to those who are asymptomatic at the time of diagnosis.[456] However, further analysis on the nature, number and duration of presenting symptoms as possible prognostic indicators has not been done before. To achieve this, our study focused on directly correlating presenting symptoms and overall survival. We hope that our findings can help to shed new light on this area and allow it to serve as a tool for early prognostication. It can also be useful in situations where medical resources are limited, since the prognostication models for HCC necessitate biochemical investigations and cross-sectional imaging.

Early prognostication and subsequent alignment of expectations allow patients to address end of life issues in a timely manner, and this is all the more crucial when the expected survival is short. In our study, patients with symptomatic HCC had a short median overall survival of 3 months from the time of diagnosis. One study found that more than 80% of patients with advanced gastrointestinal cancers felt it was highly important to know about their prognosis and also showed that patients with a better understanding of their prognosis were more likely to have realistic goals of care.[9] This helps clinicians and patients mutually agree on the need and urgency for further investigations and treatment.

A study of 1,051 patients in Italy comparing symptomatic and asymptomatic HCC showed that the median overall survival of patients with symptomatic HCC was 14 months, which was significantly shorter than that of those with asymptomatic HCC (36 months).[4] Another study of 306 patients in Hong Kong showed that patients who presented with symptomatic HCC had a significantly shorter median overall survival of 5 months compared to 22 months for those diagnosed on screening.[5] A study of 91 patients in Hawaii evaluating the survival benefit with screening for HCC found that patients who were symptomatic on presentation had a median overall survival of 234 days compared to 1,399 days for those who were asymptomatic and diagnosed on screening.[6] Our study showed similar statistics. This trend can be explained by the likelihood of advanced disease and known poor prognostic factors in patients with symptomatic HCC, such as tumour size, multifocal disease, portal vein thrombosis, lymphadenopathy, distant metastasis, elevated prothrombin time and high bilirubin.[451011] These patients not only suffer from the negative physiological impact of advanced disease, but are also often found unsuitable for treatment options such as surgical resection, liver transplantation, ablation or transarterial chemoembolisation.[45]

In our study, the presenting symptoms of fluid retention and jaundice were shown to be independently associated with a significantly shorter median overall survival in patients diagnosed with HCC. Fluid retention and jaundice were also significantly associated with poor BCLC and Child–Pugh statuses. This is consistent with commonly used prognostication models that include factors related to tumour stage and liver function, such as tumour size (Okuda, CLIP), portal vein invasion (BCLC, CLIP, French), bilirubin level (BCLC, Okuda, French, CUPI) and the presence of ascites (Okuda, CUPI).[12]

Conversely, the presence of pain at the time of diagnosis was associated with better median overall survival on univariate analysis. We postulate that patients presenting with pain seek medical attention more urgently and present earlier in the course of disease. This is further supported by better BCLC and Child–Pugh statuses, as well as a lower likelihood of fluid retention or jaundice in patients presenting with pain. Peripherally located HCC that may cause pain from capsular involvement is more accessible and not likely to involve major vasculature, and thus more likely to be amenable to resection and ablative therapy compared to HCC in deeper locations of the liver. However, on multivariable analysis, pain was not found to be a significant factor affecting survival.

The number or duration of presenting symptoms did not independently affect a patient’s survival. This affirms that the clinical implications of individual symptoms differ greatly between each other. Hence, the nature of presenting symptoms, rather than the number or duration, is of primary significance.

Our study has a number of strengths and limitations. It had one of the largest study cohorts compared to other similar studies mentioned earlier. Our study cohort also comprised patients who were all cared for by a single department. Data on the nature, number and duration of presenting symptoms were collected prospectively for every patient with newly diagnosed HCC. Unfortunately, we were unable to completely detail tumour characteristics or treatment given for every patient.

Data on the study endpoint of overall survival was complete and accurate, as it is a legislated requirement in our country that all deaths and the cause of death be reported to the national registry of deaths. Though we could not account for every comorbid condition in our study cohort, we have mitigated this by including only patients who died from a liver-related cause in our survival analysis.

In conclusion, patients who present with fluid retention or jaundice at the time of diagnosis of HCC have a significantly shorter overall survival. This can serve as a tool for early prognostication and allow timely decisions for further investigations and treatment, especially in situations where medical resources are limited.

Financial support and sponsorship

Nil.

Conflicts of interest

Goh GBB is a member of the SMJ Editorial Board, and was not involved in the peer review and publication decisions of this article.
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