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Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinico-pathology and predictors of extrahepatic metastasis
Arab Journal of Gastroenterology xxx (xxxx) xxx
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Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Gastroenterology in Arab countries
Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinico-pathology and predictors of extrahepatic metastasis Walid Elmoghazy a,d,⇑, Khalid Ahmed a, Adarsh Vijay a, Yasser Kamel b, Ahmed Elaffandi a,e, Walid El-Ansari a,f, Rasul Kakil c, Hatem Khalaf a a
Department of Surgery, Hamad Medical Corporation, Doha, Qatar Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatar c National Center for Cancer Care and Research, Doha, Qatar d Department of Surgery, Sohag University, Sohag, Egypt e Department of Surgical Oncology, National Cancer Institute, Cairo University, Egypt f School of Health, University of Skövde, Skövde, Sweden b
a r t i c l e
i n f o
Article history: Received 26 April 2017 Accepted 25 January 2019 Available online xxxx Keywords: Hepatocellular carcinoma Incidence Metastasis Risk factors Prognosis Maximal tumour diameter Total tumour volume
a b s t r a c t Background and study aims: Hepatocellular carcinoma (HCC) with extrahepatic metastasis has been studied, however, data from the Middle East remain scarce. In this study, we assess epidemiology of HCC in Qatar, and identify predictors of the metastatic behaviour. Patients and methods: All newly-diagnosed HCC patients on top of liver cirrhosis between 2011 and 2015 were included in the study. Results: A total of 180 patients met our inclusion criteria. The mean age was 58.8 ± 10.5 years with a mean follow-up of 1.0 ± 1.1 years. There were 150 male patients and HCV was the most common cause of liver cirrhosis 108 (60%), and 22 (12.2%) patients were classified as Child-Pugh class C. The overall survival of 51.1%, and 47 (26%) had at least one extrahepatic metastasis at the time of diagnosis. Single site metastasis was diagnosed in 10 patients, whereas 37 patients had multiple sites metastases. We compared patients who had metastases with patients who did not have metastasis at the time of diagnosis of HCC regarding several variables, and analysis revealed that tumour diameter larger than 5 cm (OR = 6.10, 95% CI = 1.85–20.12) (p = 0.003), and bilobar liver involvement (OR = 5.49, 95% CI = 1.10–27.30) (p = 0.037) were independent predictors of metastatic behaviour of HCC. Conclusion: The incidence of HCC is rising in our population, extrahepatic metastasis is no longer rare and tumours larger than 5 cm and bilobar involvement are determinants of the extrahepatic metastasis. Ó 2019 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Hepatocellular carcinoma (HCC) is an aggressive tumour responsible for high mortality rates in both sexes [1]. In most cases it occurs in relation to chronic viral hepatitis and liver cirrhosis [2]. Over the last two decades, prognosis of HCC has improved due to the availability of several treatment options including radiofrequency ablation, chemo- and radio-embolization, liver resection and liver transplantation, in addition to improvements in diagnostic imaging and early detection of HCC [3]. Such progress in detection, diagnosis and treatment resulted in parallel improvement in ⇑ Corresponding author at: Weil-Cornell Medical College in Qatar, Hamad Medical Corporation (HMC), P.O. Box 3050, Doha, Qatar. E-mail address: [email protected] (W. Elmoghazy).
patient survival which resulted in increased detection of extrahepatic metastases from HCC [4]. Epidemiology of HCC in Qatar has been studied before [5,6], however, the publications narrowly addressed the epidemiological features of HCC, omitting the assessment of any clinicopathological aspects, patient survival or predictors of the metastatic behaviour. Moreover, they do not reflect the recent steeper increase of population [7], nor the increasing incidence of HCC we have observed over the last five years, based on our experience. Epidemiology of HCC and predictors of extrahepatic metastasis have been examined globally [4], but few studies assessed the aggressive HCC tumours that present with extrahepatic metastasis and data from the Middle Eastern Region remain scarce [5]. In addition, inflammatory markers such as neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have, to date, not
https://doi.org/10.1016/j.ajg.2019.01.006 1687-1979/Ó 2019 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
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W. Elmoghazy et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx
Therefore, we aimed to assess the epidemiology of HCC in Qatar, and identify predictors of the metastatic behaviour.
the variables significant in the initial bivariate analysis were included in the subsequent logistic regression. Multivariate logistic regression analysis assessed the independent predictors of metastatic HCC. SPSS statistical software (SPSS inc., US, version 20) was used for the analysis, with significance level set at P < 0.05.
Patients and methods
Results
The current research was conducted in Doha at our institute, the National Referral Center for cancer patients in Qatar. Between January 2011 – January 2015, all adult patients (18 years) newly diagnosed with hepatocellular carcinoma lesions on top of liver cirrhosis were included in the study. Patients with HCC related to non-cirrhotic liver, previously diagnosed HCC, secondary liver tumours and those with extrahepatic primary cancer were excluded from the study. Patients were identified from the Hepatobiliary Multi-disciplinary team database at our institution, and their records were reviewed retrospectively. This study was approved by the ethical research committee of our institute.
Characteristics of patients and HCC lesions
been assessed as potential risk factors in HCC metastasis [4,8], despite its importance as a predictor of HCC patient survival [9], and after liver resection [10].
Diagnosis of hepatocellular carcinoma The diagnosis of HCC was based on 4-phase multi-detector computed tomography (CT) scan or contrast-enhanced magnetic resonance imaging (MRI). The typical hepatocellular carcinoma pattern is arterial hypervascularity with washout in portal or delayed phase [11]. Atypical lesions on imaging were biopsied under sonography or CT guidance. Abdominal and pulmonary metastases were diagnosed with contrast enhanced CT/MRI. Bone scans, Positron emission tomography-computed tomography (PET-CT), and brain MRI/CT were only performed in patients symptomatic for an extrahepatic spread, or in cases of unexplained elevated alpha-fetoprotein (AFP) levels. Macro-vascular invasion of portal vein, hepatic vein, or inferior vena cava was determined radiologically with contrast enhanced CT/MRI evidence, it was defined in patients with HCC lesions in close proximity to a partially or complete occlusion of the vein, and enhancement of the thrombus in the arterial phase. Metastatic work-up is not a routine practice at our institute, chest X-ray is done routinely at time of admission to the hospital. At our institute, we follow the BCLC algorithm [12] for management of HCC, and selection of patients for liver transplantation is limited to patients within Milan criteria [13]. Data collection Data were retrieved from patient charts and included patients’ demographics, performance status, aetiology of cirrhosis, comorbidities, serology, AFP, viral load, Child-Pugh score [14], Model for end-stage liver disease (MELD) score [15], APRI score [16], HCV genotype, presence/absence of ascites, history of variceal bleeding, or encephalopathy before or at time of diagnosis of HCC. In line with others, the liver lesions were characterised at the time of diagnosis based on their size, site, and number, presence of vascular invasion, portal vein thrombosis, and total tumour volume [17]. The extrahepatic metastases were further detailed based on their location/s and multiplicity at the time of diagnosis. Statistical analysis Data were summarised as mean ± standard deviation (SD) for continuous variables, and frequency (percentage) for categorical variables. Univariate analysis was undertaken to identify potential predictors of metastatic HCC using Chi-square (v2) test (categorical variables) and student’s t-test (continuous variables). Only
A total of 180 patients met our inclusion criteria. The mean age at the time of diagnosis was 58.8 (range: 31–82) years. There were 150 male patients, with male to female ratio of 5:1. Across our sample, HCV was the most common cause of liver cirrhosis 108 patients (60%), followed by HBV 42 (23.3%), co-infection of HBV and HCV in 7 patients (3.9%), and co-infection of HBV, HCV and HDV in one (0.6%) patient. Chronic alcoholism was the aetiology of cirrhosis in 5 (2.8%) cases, and 17 (9.4%) patients had cirrhosis of unknown aetiology. Cryptogenic cirrhosis or cirrhosis of unknown aetiology was a diagnosis of exclusion after extensive clinical, serological, and pathological work-up has been done. Ethnicity had close relation to the aetiology of liver disease, 97 (90%) patients were Middle Eastern (68 (63%) Egyptian patients, 20 (19%) Qatari patients, and 9 (8%) patients from other Arab countries) while 22 (52%) of HBV had come from East Asian countries. A total of 128 (71.1%) patients with liver disease related to viral hepatitis (HBV, HDV, and HCV) were treated; however, control of the disease with evidence of non-replicating virus was achieved in 52 (28.9%) patients only. Comorbidities across our cohort included diabetes mellitus (38%), hypertension (32%) and coronary artery disease (4%). Mean MELD score was 11.6 ± 4.7 (range: 6–32), and 22 (12.2%) patients were classified as class C according to Child-Pugh criteria (Table 1). The follow up of patients ranged from 0.1 to 4.4 years (mean = 1.0 ± 1.1 years). However, as 29 patients (16%) left Qatar to return back to their home country after diagnosis of HCC and were hence lost to follow-up, these patients were excluded from the analysis. During the follow-up period, 80 patients died with an overall survival of 51.1% (Fig. 1). Fig. 2 shows that the population in Qatar increased from 1.7 to 2.3 million between 2011 and 2015, and during the same period, the incidence of HCC cases surged in parallel to the increase in population [7]. As for the tumour characteristics, maximal tumour diameter was 5.1 ± 3.9 cm (range: 1–22), and the total tumour volume was 250.1 ± 705.5 cm3. Hepatocellular carcinoma was diagnosed based on imaging in 153 (85%) patients while 27 (15%) patients has atypical lesions and required biopsy to establish diagnosis. Solitary liver lesions were detected in 83 (46%) patients, while 97 (54%) patients had multiple liver lesions. HCC lesions were limited to one liver lobe in 112 (62%) patients, while 68 (38%) patients had bilobar involvement. A total of 53 (29.4%) patients had portal vein thrombosis, and 50 (27.8%) patients were diagnosed with macrovascular invasion. Extrahepatic metastasis Of the 180 patients included in the study, 47 (26%) had at least one extrahepatic metastatic lesion at the time of diagnosis. Single site metastasis was diagnosed in 10 patients, whereas 37 patients had metastases in multiple sites. The location of the first metastasis included abdominal sites in 24 (51%) patients, thoracic in 13 (27.7%), bone in 7 (14.9%), and unusual sites (e.g. nasopharynx) in 3 (6.4%) patients. Patients with extrahepatic metastasis at time
Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
W. Elmoghazy et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx Table 1 Characteristics of 180 patients at time of HCC diagnosis. Variable
Summary
Age (years) (range) Male: female, n (%)
58.8 ± 10.5 (31–82) 150:30 (5:1)
Underlying liver etiology, n (%) HCV HBV HCV/HBV HCV/HBV/HDV Alcoholic cirrhosis Cryptogenic cirrhosis
108 (60) 42 (23.3) 7 (3.9) 1 (0.6) 5 (2.8) 17 (9.4)
Performance status, n (%) 0 1 2 3 4
71 (39.4) 36 (20) 27 (15) 15 (8.3) 5 (2.8)
Child-Pugh grade, n (%) A B C Model for end-stage liver disease [M ± SD (range)] Laboratory at time of diagnosis [M ± SD (range)] Haemoglobin White blood cells Platelets Total bilirubin Albumin AST ALT ALP INR Creatinine Alfa-foetoprotein APRI score
76 (42.2) 82 (45.6) 22 (12.2) 11.6 ± 4.7 (6–32)
12.7 ± 2.2 (6–18) 6.7 ± 3.9 (2.0–27.3) 139.2 ± 85.7 (22–494) 35.3 ± 50.1 (3–512) 31.9 ± 7.4 (14–46) 95.3 ± 75.9 (14–682) 66.8 ± 56.2 (5–445) 154.2 ± 97.1 (46–637) 1.3 ± 0.3 (0.9–4.6) 86.1 ± 45.8 (23–379) 1584.9 ± 3707.6 (1– 17117) 2.6 ± 2.3 (0.1–13.9)
Abbreviations: INR, International normalised ratio; Hb, haemoglobin; WBCs, white blood corpuscles; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; AFP, alpha-fetoprotein; APRI score, AST to Platelet Ratio Index; MELD score, Model for end-stage liver disease.
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of HCC diagnosis had significantly lower survival compared to patients with no metastasis (42.6% vs. 54.1%, p < 0.001) (Fig. 3). Predictors of the HCC metastatic behaviour We then compared patients with metastases to patients who did not have metastasis regarding several factors (Table 2). Univariate analysis revealed that multiple liver lesions, bilobar liver involvement, vascular invasion, tumours with diameter >5 cm, bigger total tumour volume, and higher platelets to lymphocyte ratio (PLR) were associated with extrahepatic metastasis (p < 0.05). Other factors including underlying liver disease, presence of multiple HCC lesions, neutrophil to lymphocyte ratio, APRI score, AFP, ALP, and the remaining biochemical markers did not show association with the metastatic behaviour of HCC (p > 0.05) (Table 2). Significant variables were entered into the multivariate regression analysis that revealed tumour diameter larger than 5 cm (OR = 6.10, 95% CI = 1.85–20.12) (p = 0.003), and bilobar liver involvement (OR = 5.49, 95% CI = 1.10–27.30) (p = 0.037) were independent predictors of metastatic behaviour of HCC (Table 3).
Discussion We summarised the status of hepatocellular carcinoma in a rapidly growing community, related mainly to male immigrant workers, where we observed a parallel increase in the number of newly diagnosed HCC cases related to liver cirrhosis. Over a period of 12 years, (2004–2015), the population of Qatar has increased steadily from 0.4 to 2.4 million [7]. Over the first 8 years, there were 150 newly diagnosed HCC cases [6] while the last 4 years were accompanied by diagnosis of 180 cases. Hence, the incidence of HCC almost doubled between 2011 and 2015, despite the fact that most of the immigrant workers are young adults. Such increase in the number of newly diagnosed cases might reflect the instigation of a regular six-monthly surveillance
Fig. 1. Survival of the HCC patients over the follow-up period.
Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
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Fig. 2. Increases in population of Qatar and newly-diagnosed HCC.
Fig. 3. Survival of patients by presence or absence of metastasis.
program for high risk groups that could be identifying higher numbers of new HCC. In terms of age, the mean age of diagnosis we observed was 58.8 years, which is in agreement with previous research in Qatar [5]. Likewise, our mean age of diagnosis is similar to the Asian average age of HCC at presentation (around 60 years) [4], and also similar to neighboring Eastern Mediterranean Region countries [18,19] as well as the United States, Canada and United Kingdom, where the mean age of HCC at diagnosis tends to be >65 years [20]. In connection with gender, our male to female ratio (5:1) was more than the ratio published earlier by Rasul et al [6] in Qatar in the period 2004–2010 (3:1). Such increase in gender ratio might reflect the further rapid change in the structure of the general population of Qatar, where there is a dominance of males over females due to the sharp increase in the number of male expatriate workforce in the country. Indeed immigrants comprise a staggering 94%
of Qatar’s workforce, and 70% of its total population, and the male to female ratio in Qatar is 3: 1, closely paralleling the HCC male to female ratio [7]. Concerning aetiology, HBV and HCV viruses as well as the consumption of alcohol are major risk factors of HCC development globally with regional variations [20]. Across our sample, chronic HCV infection remains the major risk factor for developing HCC among, in agreement with other countries such as Egypt [21] and Japan [22], but in contrast to other countries e.g. Taiwan, where chronic HBV infection is the dominant risk factor [1]. However, in the United States, 15–55% of HCC patients had no established risk factors [20]. Nevertheless, HCV was responsible for 64.4% of our observed HCC, which is double the worldwide rate of 30% [23]. Such doubling of HCV as an etiological cause for HCC seen in Qatar might be due to the fact that most of our patients are from countries of known high HCV prevalence (e.g. Egypt, Pakistan and
Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
W. Elmoghazy et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx Table 2 Univariate analysis of HCC patients with and without extrahepatic metastasis. Variable
Age* Gender** Male Female Child-Pugh score** A B C Total bilirubin* Albumin* INR* Hb* WBCs* Platelets* AST* ALP* AFP* APRI score* NLR* PLR* MELD score* Maximal tumour diameter (cm)* Total tumour volume (cm3)* Single vs. multiple** Single Multiple Unilobar vs. Bilobar** Unilobar Bilobar Vascular invasion** Yes No
Patients
p
Metastasis
No metastasis
57.8 ± 10.1
59.2 ± 10.6
41 (87.2) 6 (12.8)
109 (82) 24 (18)
16 (22.8%) 23 (29.9) 6 (28.6%) 35.7 ± 46.5 32.6 ± 7. 2 1.3 ± 0.5 12.8 ± 2.4 7.3 ± 3.2 170.7 ± 96.2 100.2 ± 63.3 170.6 ± 105.0 2472.4 ± 4100.0 2.1 ± 1.6 3.1 ± 2.8 93.8 ± 63.9 11.6 ± 5.3 4.5 ± 3.6
56 (78.2%) 54 (70.1%) 15 (71.4%) 35.1 ± 51.5 31.7 ± 7.5 1.2 ± 0.2 12.7 ± 2.1 6.5 ± 4.1 128.1 ± 79.1 93.53 ± 80.1 148.4 ± 93.8 1268.8 ± 3520.3 2.7 ± 2.5 4.1 ± 4.2 134.1 ± 104.6 11.5 ± 4.5 6.5 ± 4.3
536.5 ± 959.2
177.8 ± 610.7
14 (16.9) 33 (34)
69 (83.1) 64 (66)
20 (17.9) 27 (39.7)
92 (82.1) 41 (60.3)
20 (40.0) 27 (20.8)
30 (60.0) 103 (71.2)
0.423 0.404
0.556
0.943 0.473 0.109 0.903 0.279 0.003 0.607 0.179 0.056 0.142 0.161 0.016 0.917 0.002 0.020 0.009
0.001
0.009
*
Data summarised as mean ± SD. Data summarised as number (percent); INR: International normalised ratio; Hb: haemoglobin; WBCs, white blood corpuscles; AST: aspartate aminotransferase; ALP: alkaline phosphatase; GGT: gamma-glutamyl transferase; AFP: alpha-foetoprotein; APRI score: AST to Platelet Ratio Index; NLR: Neutrophil to lymphocyte ratio; PLR: Platelets to lymphocyte ratio; MELD score: Model for end-stage liver disease. **
Table 3 Predictors of extrahepatic metastasis of HCC. Variable
EXP (B)
95% confidence interval
p-value
Platelets Platelets to lymphocyte ratio Single vs. multiple Unilobar vs. Bilobar Vascular Invasion Total tumour volume Tumour diameter >5 cm
0.999 1.005 0.905 5.490 2.443 1.000 6.094
0.990–1.007 0.996–1.014 0.183–4.468 1.104–27.297 0.742–8.041 0.999–1.001 1.846–20.120
0.776 0.321 0.903 0.037 0.142 0.921 0.003
Note: Multivariate regression analysis.
India). However, we observed other etiological factors among our HCC sample including HBV (23.3%), alcoholism (2.8%), and cryptogenic cirrhosis (9.4%). Such etiological pattern is the same configuration previously documented in Qatar [6] and in the region [5]. Regarding metastasis, extrahepatic spread of HCC seems to be frequently seen nowadays, and is expected to increase in the future due to regular follow-up of HCC patients, and the availability of different treatment options that resulted in prolonged patient survival enough to develop extrahepatic metastasis. Globally, extrahepatic metastasis ranges between 15% and 42% [4]; in our cohort, 26% of the patients had extrahepatic metastasis, in agreement with the international rates. Whilst globally, lung is usually the commonest site of metastasis [4], however among our patients,
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half of the lesions were in the abdomen (mainly in lymph nodes), followed by the lungs (28% of metastases). Bone is an uncommon site of HCC metastasis, with 3%-20% incidence [4,24]; in agreement, bone was involved in only 4% of the metastases we observed. As regards the predictors of metastases, we analysed the variables that could potentially predict the metastatic behaviour of HCC, and found that tumours larger than 5 cm, and bilobar liver lesions were the main predictors of the metastasis. We found that tumour diameters 5 cm were associated with a 6-fold increase in the risk of metastasis compared to patients with smaller tumours <5 cm. This finding agrees with other published results from Turkey [19], and several assumptions have been postulated. One explanation is that the tumour biology changes beyond a certain mass, as the tumour cannot grow without neovascularization. A second hypothesis suggests that tumour cells could gain more aggressive traits in response to the hypo-oxygenation that is associated with the tumour expansion. A third assumption that was put forward is that the tumour stem cells that are responsible for the aggressive biology of the tumour including tumour expansion and large tumour volume are also simultaneously responsible for the metastatic behaviour of the tumour[8 24]. Interestingly, we observed that bilobar tumour involvement was positively associated with the metastatic behaviour of HCC, with a 5-fold higher risk of metastasis among patients with HCC lesions involving both lobes of the liver when compared with malignancy confined to a single lobe of the liver. To the best of our knowledge, such finding has not been reported before. The published literature suggests that the multiplicity of HCC lesions is a contributing factor to metastasis, regardless of the location of HCC lesions (whether uni- or bilobar) [8]. Bilobar HCC could be a better indicator of metastasis generally. Whilst Bilobar HCC could be viewed as intrahepatic metastasis of the primary tumour, hence reflecting a more aggressive tumour behaviour with a higher risk of consequent spread outside the liver; however, multi-focal HCC cannot be confidently excluded in bilobar HCC. Thus differentiation between intrahepatic metastasis and multi-focal HCC remains difficult [25]. Globally, routine metastatic work-up is not undertaken for all HCC patients [22], and thus the predictor findings of this study highlight the importance of such routine work-up, as the one quarter of our patients were found to have extrahepatic metastasis at time of diagnosis. As for other potential predictors of metastasis we examined, surprisingly across our cohort, serum AFP, vascular invasion, and portal vein thrombosis were potential risk factors in the univariate analysis, but did not prove to be actual determinants of the HCC metastatic behaviour when entered in the multivariate analysis. This could possibly be related to the time of analysis, as we assessed the behaviour of HCC metastasis at time of diagnosis. Perhaps a survival analysis undertaken at a longer follow-up time might uncover any potential relationships between these variables and the metastatic behaviour. Over the last decade, inflammatory markers such as neutrophil to lymphocyte and platelet to lymphocyte ratios have gained attention as predictors of tumour progression and metastasis [26–28]. On the one hand, neutrophils accelerate tumour progression and metastasis by promoting angiogenesis through several factors e.g. vascular endothelial growth factor. Conversely, lymphocytes act as a barrier against tumour spread through generating a cellular immune response [28]. However, we did not find a relationship between NLR nor PLR, and the metastatic behaviour of HCC. Two points are worth to consider here. First, the time of the NLR and PLR reading, as it could be that values of the inflammatory markers before diagnosis of metastasis reflect the prepared microenvironment for spread of the tumour. Second, trends of the inflammatory markers prior to the diagnosis might be a more pertinent prognostic factor than the actual NLR value at the time of
Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
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established diagnosis of metastasis. So, our Future research in our centre will be focused on these points. This study has limitations that include the short follow-up period and deficient metastatic work-up that might underestimate the percentage of extrahepatic disease in this cohort. Future research could benefit from studying the prognostic value of the inflammatory markers in predicting extrahepatic metastasis. In conclusion, the incidence of hepatocellular carcinoma is rising among our population; extrahepatic metastasis is no longer rare; and tumours larger than 5 cm and bilobar involvement are significant determinants of the extrahepatic metastasis in HCC patients. Considering the high percentage of metastasis, metastatic work-up should be done routinely.
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Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
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Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Gastroenterology in Arab countries
Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinico-pathology and predictors of extrahepatic metastasis Walid Elmoghazy a,d,⇑, Khalid Ahmed a, Adarsh Vijay a, Yasser Kamel b, Ahmed Elaffandi a,e, Walid El-Ansari a,f, Rasul Kakil c, Hatem Khalaf a a
Department of Surgery, Hamad Medical Corporation, Doha, Qatar Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatar c National Center for Cancer Care and Research, Doha, Qatar d Department of Surgery, Sohag University, Sohag, Egypt e Department of Surgical Oncology, National Cancer Institute, Cairo University, Egypt f School of Health, University of Skövde, Skövde, Sweden b
a r t i c l e
i n f o
Article history: Received 26 April 2017 Accepted 25 January 2019 Available online xxxx Keywords: Hepatocellular carcinoma Incidence Metastasis Risk factors Prognosis Maximal tumour diameter Total tumour volume
a b s t r a c t Background and study aims: Hepatocellular carcinoma (HCC) with extrahepatic metastasis has been studied, however, data from the Middle East remain scarce. In this study, we assess epidemiology of HCC in Qatar, and identify predictors of the metastatic behaviour. Patients and methods: All newly-diagnosed HCC patients on top of liver cirrhosis between 2011 and 2015 were included in the study. Results: A total of 180 patients met our inclusion criteria. The mean age was 58.8 ± 10.5 years with a mean follow-up of 1.0 ± 1.1 years. There were 150 male patients and HCV was the most common cause of liver cirrhosis 108 (60%), and 22 (12.2%) patients were classified as Child-Pugh class C. The overall survival of 51.1%, and 47 (26%) had at least one extrahepatic metastasis at the time of diagnosis. Single site metastasis was diagnosed in 10 patients, whereas 37 patients had multiple sites metastases. We compared patients who had metastases with patients who did not have metastasis at the time of diagnosis of HCC regarding several variables, and analysis revealed that tumour diameter larger than 5 cm (OR = 6.10, 95% CI = 1.85–20.12) (p = 0.003), and bilobar liver involvement (OR = 5.49, 95% CI = 1.10–27.30) (p = 0.037) were independent predictors of metastatic behaviour of HCC. Conclusion: The incidence of HCC is rising in our population, extrahepatic metastasis is no longer rare and tumours larger than 5 cm and bilobar involvement are determinants of the extrahepatic metastasis. Ó 2019 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Hepatocellular carcinoma (HCC) is an aggressive tumour responsible for high mortality rates in both sexes [1]. In most cases it occurs in relation to chronic viral hepatitis and liver cirrhosis [2]. Over the last two decades, prognosis of HCC has improved due to the availability of several treatment options including radiofrequency ablation, chemo- and radio-embolization, liver resection and liver transplantation, in addition to improvements in diagnostic imaging and early detection of HCC [3]. Such progress in detection, diagnosis and treatment resulted in parallel improvement in ⇑ Corresponding author at: Weil-Cornell Medical College in Qatar, Hamad Medical Corporation (HMC), P.O. Box 3050, Doha, Qatar. E-mail address: [email protected] (W. Elmoghazy).
patient survival which resulted in increased detection of extrahepatic metastases from HCC [4]. Epidemiology of HCC in Qatar has been studied before [5,6], however, the publications narrowly addressed the epidemiological features of HCC, omitting the assessment of any clinicopathological aspects, patient survival or predictors of the metastatic behaviour. Moreover, they do not reflect the recent steeper increase of population [7], nor the increasing incidence of HCC we have observed over the last five years, based on our experience. Epidemiology of HCC and predictors of extrahepatic metastasis have been examined globally [4], but few studies assessed the aggressive HCC tumours that present with extrahepatic metastasis and data from the Middle Eastern Region remain scarce [5]. In addition, inflammatory markers such as neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have, to date, not
https://doi.org/10.1016/j.ajg.2019.01.006 1687-1979/Ó 2019 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
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W. Elmoghazy et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx
Therefore, we aimed to assess the epidemiology of HCC in Qatar, and identify predictors of the metastatic behaviour.
the variables significant in the initial bivariate analysis were included in the subsequent logistic regression. Multivariate logistic regression analysis assessed the independent predictors of metastatic HCC. SPSS statistical software (SPSS inc., US, version 20) was used for the analysis, with significance level set at P < 0.05.
Patients and methods
Results
The current research was conducted in Doha at our institute, the National Referral Center for cancer patients in Qatar. Between January 2011 – January 2015, all adult patients (18 years) newly diagnosed with hepatocellular carcinoma lesions on top of liver cirrhosis were included in the study. Patients with HCC related to non-cirrhotic liver, previously diagnosed HCC, secondary liver tumours and those with extrahepatic primary cancer were excluded from the study. Patients were identified from the Hepatobiliary Multi-disciplinary team database at our institution, and their records were reviewed retrospectively. This study was approved by the ethical research committee of our institute.
Characteristics of patients and HCC lesions
been assessed as potential risk factors in HCC metastasis [4,8], despite its importance as a predictor of HCC patient survival [9], and after liver resection [10].
Diagnosis of hepatocellular carcinoma The diagnosis of HCC was based on 4-phase multi-detector computed tomography (CT) scan or contrast-enhanced magnetic resonance imaging (MRI). The typical hepatocellular carcinoma pattern is arterial hypervascularity with washout in portal or delayed phase [11]. Atypical lesions on imaging were biopsied under sonography or CT guidance. Abdominal and pulmonary metastases were diagnosed with contrast enhanced CT/MRI. Bone scans, Positron emission tomography-computed tomography (PET-CT), and brain MRI/CT were only performed in patients symptomatic for an extrahepatic spread, or in cases of unexplained elevated alpha-fetoprotein (AFP) levels. Macro-vascular invasion of portal vein, hepatic vein, or inferior vena cava was determined radiologically with contrast enhanced CT/MRI evidence, it was defined in patients with HCC lesions in close proximity to a partially or complete occlusion of the vein, and enhancement of the thrombus in the arterial phase. Metastatic work-up is not a routine practice at our institute, chest X-ray is done routinely at time of admission to the hospital. At our institute, we follow the BCLC algorithm [12] for management of HCC, and selection of patients for liver transplantation is limited to patients within Milan criteria [13]. Data collection Data were retrieved from patient charts and included patients’ demographics, performance status, aetiology of cirrhosis, comorbidities, serology, AFP, viral load, Child-Pugh score [14], Model for end-stage liver disease (MELD) score [15], APRI score [16], HCV genotype, presence/absence of ascites, history of variceal bleeding, or encephalopathy before or at time of diagnosis of HCC. In line with others, the liver lesions were characterised at the time of diagnosis based on their size, site, and number, presence of vascular invasion, portal vein thrombosis, and total tumour volume [17]. The extrahepatic metastases were further detailed based on their location/s and multiplicity at the time of diagnosis. Statistical analysis Data were summarised as mean ± standard deviation (SD) for continuous variables, and frequency (percentage) for categorical variables. Univariate analysis was undertaken to identify potential predictors of metastatic HCC using Chi-square (v2) test (categorical variables) and student’s t-test (continuous variables). Only
A total of 180 patients met our inclusion criteria. The mean age at the time of diagnosis was 58.8 (range: 31–82) years. There were 150 male patients, with male to female ratio of 5:1. Across our sample, HCV was the most common cause of liver cirrhosis 108 patients (60%), followed by HBV 42 (23.3%), co-infection of HBV and HCV in 7 patients (3.9%), and co-infection of HBV, HCV and HDV in one (0.6%) patient. Chronic alcoholism was the aetiology of cirrhosis in 5 (2.8%) cases, and 17 (9.4%) patients had cirrhosis of unknown aetiology. Cryptogenic cirrhosis or cirrhosis of unknown aetiology was a diagnosis of exclusion after extensive clinical, serological, and pathological work-up has been done. Ethnicity had close relation to the aetiology of liver disease, 97 (90%) patients were Middle Eastern (68 (63%) Egyptian patients, 20 (19%) Qatari patients, and 9 (8%) patients from other Arab countries) while 22 (52%) of HBV had come from East Asian countries. A total of 128 (71.1%) patients with liver disease related to viral hepatitis (HBV, HDV, and HCV) were treated; however, control of the disease with evidence of non-replicating virus was achieved in 52 (28.9%) patients only. Comorbidities across our cohort included diabetes mellitus (38%), hypertension (32%) and coronary artery disease (4%). Mean MELD score was 11.6 ± 4.7 (range: 6–32), and 22 (12.2%) patients were classified as class C according to Child-Pugh criteria (Table 1). The follow up of patients ranged from 0.1 to 4.4 years (mean = 1.0 ± 1.1 years). However, as 29 patients (16%) left Qatar to return back to their home country after diagnosis of HCC and were hence lost to follow-up, these patients were excluded from the analysis. During the follow-up period, 80 patients died with an overall survival of 51.1% (Fig. 1). Fig. 2 shows that the population in Qatar increased from 1.7 to 2.3 million between 2011 and 2015, and during the same period, the incidence of HCC cases surged in parallel to the increase in population [7]. As for the tumour characteristics, maximal tumour diameter was 5.1 ± 3.9 cm (range: 1–22), and the total tumour volume was 250.1 ± 705.5 cm3. Hepatocellular carcinoma was diagnosed based on imaging in 153 (85%) patients while 27 (15%) patients has atypical lesions and required biopsy to establish diagnosis. Solitary liver lesions were detected in 83 (46%) patients, while 97 (54%) patients had multiple liver lesions. HCC lesions were limited to one liver lobe in 112 (62%) patients, while 68 (38%) patients had bilobar involvement. A total of 53 (29.4%) patients had portal vein thrombosis, and 50 (27.8%) patients were diagnosed with macrovascular invasion. Extrahepatic metastasis Of the 180 patients included in the study, 47 (26%) had at least one extrahepatic metastatic lesion at the time of diagnosis. Single site metastasis was diagnosed in 10 patients, whereas 37 patients had metastases in multiple sites. The location of the first metastasis included abdominal sites in 24 (51%) patients, thoracic in 13 (27.7%), bone in 7 (14.9%), and unusual sites (e.g. nasopharynx) in 3 (6.4%) patients. Patients with extrahepatic metastasis at time
Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
W. Elmoghazy et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx Table 1 Characteristics of 180 patients at time of HCC diagnosis. Variable
Summary
Age (years) (range) Male: female, n (%)
58.8 ± 10.5 (31–82) 150:30 (5:1)
Underlying liver etiology, n (%) HCV HBV HCV/HBV HCV/HBV/HDV Alcoholic cirrhosis Cryptogenic cirrhosis
108 (60) 42 (23.3) 7 (3.9) 1 (0.6) 5 (2.8) 17 (9.4)
Performance status, n (%) 0 1 2 3 4
71 (39.4) 36 (20) 27 (15) 15 (8.3) 5 (2.8)
Child-Pugh grade, n (%) A B C Model for end-stage liver disease [M ± SD (range)] Laboratory at time of diagnosis [M ± SD (range)] Haemoglobin White blood cells Platelets Total bilirubin Albumin AST ALT ALP INR Creatinine Alfa-foetoprotein APRI score
76 (42.2) 82 (45.6) 22 (12.2) 11.6 ± 4.7 (6–32)
12.7 ± 2.2 (6–18) 6.7 ± 3.9 (2.0–27.3) 139.2 ± 85.7 (22–494) 35.3 ± 50.1 (3–512) 31.9 ± 7.4 (14–46) 95.3 ± 75.9 (14–682) 66.8 ± 56.2 (5–445) 154.2 ± 97.1 (46–637) 1.3 ± 0.3 (0.9–4.6) 86.1 ± 45.8 (23–379) 1584.9 ± 3707.6 (1– 17117) 2.6 ± 2.3 (0.1–13.9)
Abbreviations: INR, International normalised ratio; Hb, haemoglobin; WBCs, white blood corpuscles; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; AFP, alpha-fetoprotein; APRI score, AST to Platelet Ratio Index; MELD score, Model for end-stage liver disease.
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of HCC diagnosis had significantly lower survival compared to patients with no metastasis (42.6% vs. 54.1%, p < 0.001) (Fig. 3). Predictors of the HCC metastatic behaviour We then compared patients with metastases to patients who did not have metastasis regarding several factors (Table 2). Univariate analysis revealed that multiple liver lesions, bilobar liver involvement, vascular invasion, tumours with diameter >5 cm, bigger total tumour volume, and higher platelets to lymphocyte ratio (PLR) were associated with extrahepatic metastasis (p < 0.05). Other factors including underlying liver disease, presence of multiple HCC lesions, neutrophil to lymphocyte ratio, APRI score, AFP, ALP, and the remaining biochemical markers did not show association with the metastatic behaviour of HCC (p > 0.05) (Table 2). Significant variables were entered into the multivariate regression analysis that revealed tumour diameter larger than 5 cm (OR = 6.10, 95% CI = 1.85–20.12) (p = 0.003), and bilobar liver involvement (OR = 5.49, 95% CI = 1.10–27.30) (p = 0.037) were independent predictors of metastatic behaviour of HCC (Table 3).
Discussion We summarised the status of hepatocellular carcinoma in a rapidly growing community, related mainly to male immigrant workers, where we observed a parallel increase in the number of newly diagnosed HCC cases related to liver cirrhosis. Over a period of 12 years, (2004–2015), the population of Qatar has increased steadily from 0.4 to 2.4 million [7]. Over the first 8 years, there were 150 newly diagnosed HCC cases [6] while the last 4 years were accompanied by diagnosis of 180 cases. Hence, the incidence of HCC almost doubled between 2011 and 2015, despite the fact that most of the immigrant workers are young adults. Such increase in the number of newly diagnosed cases might reflect the instigation of a regular six-monthly surveillance
Fig. 1. Survival of the HCC patients over the follow-up period.
Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
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W. Elmoghazy et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx
Fig. 2. Increases in population of Qatar and newly-diagnosed HCC.
Fig. 3. Survival of patients by presence or absence of metastasis.
program for high risk groups that could be identifying higher numbers of new HCC. In terms of age, the mean age of diagnosis we observed was 58.8 years, which is in agreement with previous research in Qatar [5]. Likewise, our mean age of diagnosis is similar to the Asian average age of HCC at presentation (around 60 years) [4], and also similar to neighboring Eastern Mediterranean Region countries [18,19] as well as the United States, Canada and United Kingdom, where the mean age of HCC at diagnosis tends to be >65 years [20]. In connection with gender, our male to female ratio (5:1) was more than the ratio published earlier by Rasul et al [6] in Qatar in the period 2004–2010 (3:1). Such increase in gender ratio might reflect the further rapid change in the structure of the general population of Qatar, where there is a dominance of males over females due to the sharp increase in the number of male expatriate workforce in the country. Indeed immigrants comprise a staggering 94%
of Qatar’s workforce, and 70% of its total population, and the male to female ratio in Qatar is 3: 1, closely paralleling the HCC male to female ratio [7]. Concerning aetiology, HBV and HCV viruses as well as the consumption of alcohol are major risk factors of HCC development globally with regional variations [20]. Across our sample, chronic HCV infection remains the major risk factor for developing HCC among, in agreement with other countries such as Egypt [21] and Japan [22], but in contrast to other countries e.g. Taiwan, where chronic HBV infection is the dominant risk factor [1]. However, in the United States, 15–55% of HCC patients had no established risk factors [20]. Nevertheless, HCV was responsible for 64.4% of our observed HCC, which is double the worldwide rate of 30% [23]. Such doubling of HCV as an etiological cause for HCC seen in Qatar might be due to the fact that most of our patients are from countries of known high HCV prevalence (e.g. Egypt, Pakistan and
Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
W. Elmoghazy et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx Table 2 Univariate analysis of HCC patients with and without extrahepatic metastasis. Variable
Age* Gender** Male Female Child-Pugh score** A B C Total bilirubin* Albumin* INR* Hb* WBCs* Platelets* AST* ALP* AFP* APRI score* NLR* PLR* MELD score* Maximal tumour diameter (cm)* Total tumour volume (cm3)* Single vs. multiple** Single Multiple Unilobar vs. Bilobar** Unilobar Bilobar Vascular invasion** Yes No
Patients
p
Metastasis
No metastasis
57.8 ± 10.1
59.2 ± 10.6
41 (87.2) 6 (12.8)
109 (82) 24 (18)
16 (22.8%) 23 (29.9) 6 (28.6%) 35.7 ± 46.5 32.6 ± 7. 2 1.3 ± 0.5 12.8 ± 2.4 7.3 ± 3.2 170.7 ± 96.2 100.2 ± 63.3 170.6 ± 105.0 2472.4 ± 4100.0 2.1 ± 1.6 3.1 ± 2.8 93.8 ± 63.9 11.6 ± 5.3 4.5 ± 3.6
56 (78.2%) 54 (70.1%) 15 (71.4%) 35.1 ± 51.5 31.7 ± 7.5 1.2 ± 0.2 12.7 ± 2.1 6.5 ± 4.1 128.1 ± 79.1 93.53 ± 80.1 148.4 ± 93.8 1268.8 ± 3520.3 2.7 ± 2.5 4.1 ± 4.2 134.1 ± 104.6 11.5 ± 4.5 6.5 ± 4.3
536.5 ± 959.2
177.8 ± 610.7
14 (16.9) 33 (34)
69 (83.1) 64 (66)
20 (17.9) 27 (39.7)
92 (82.1) 41 (60.3)
20 (40.0) 27 (20.8)
30 (60.0) 103 (71.2)
0.423 0.404
0.556
0.943 0.473 0.109 0.903 0.279 0.003 0.607 0.179 0.056 0.142 0.161 0.016 0.917 0.002 0.020 0.009
0.001
0.009
*
Data summarised as mean ± SD. Data summarised as number (percent); INR: International normalised ratio; Hb: haemoglobin; WBCs, white blood corpuscles; AST: aspartate aminotransferase; ALP: alkaline phosphatase; GGT: gamma-glutamyl transferase; AFP: alpha-foetoprotein; APRI score: AST to Platelet Ratio Index; NLR: Neutrophil to lymphocyte ratio; PLR: Platelets to lymphocyte ratio; MELD score: Model for end-stage liver disease. **
Table 3 Predictors of extrahepatic metastasis of HCC. Variable
EXP (B)
95% confidence interval
p-value
Platelets Platelets to lymphocyte ratio Single vs. multiple Unilobar vs. Bilobar Vascular Invasion Total tumour volume Tumour diameter >5 cm
0.999 1.005 0.905 5.490 2.443 1.000 6.094
0.990–1.007 0.996–1.014 0.183–4.468 1.104–27.297 0.742–8.041 0.999–1.001 1.846–20.120
0.776 0.321 0.903 0.037 0.142 0.921 0.003
Note: Multivariate regression analysis.
India). However, we observed other etiological factors among our HCC sample including HBV (23.3%), alcoholism (2.8%), and cryptogenic cirrhosis (9.4%). Such etiological pattern is the same configuration previously documented in Qatar [6] and in the region [5]. Regarding metastasis, extrahepatic spread of HCC seems to be frequently seen nowadays, and is expected to increase in the future due to regular follow-up of HCC patients, and the availability of different treatment options that resulted in prolonged patient survival enough to develop extrahepatic metastasis. Globally, extrahepatic metastasis ranges between 15% and 42% [4]; in our cohort, 26% of the patients had extrahepatic metastasis, in agreement with the international rates. Whilst globally, lung is usually the commonest site of metastasis [4], however among our patients,
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half of the lesions were in the abdomen (mainly in lymph nodes), followed by the lungs (28% of metastases). Bone is an uncommon site of HCC metastasis, with 3%-20% incidence [4,24]; in agreement, bone was involved in only 4% of the metastases we observed. As regards the predictors of metastases, we analysed the variables that could potentially predict the metastatic behaviour of HCC, and found that tumours larger than 5 cm, and bilobar liver lesions were the main predictors of the metastasis. We found that tumour diameters 5 cm were associated with a 6-fold increase in the risk of metastasis compared to patients with smaller tumours <5 cm. This finding agrees with other published results from Turkey [19], and several assumptions have been postulated. One explanation is that the tumour biology changes beyond a certain mass, as the tumour cannot grow without neovascularization. A second hypothesis suggests that tumour cells could gain more aggressive traits in response to the hypo-oxygenation that is associated with the tumour expansion. A third assumption that was put forward is that the tumour stem cells that are responsible for the aggressive biology of the tumour including tumour expansion and large tumour volume are also simultaneously responsible for the metastatic behaviour of the tumour[8 24]. Interestingly, we observed that bilobar tumour involvement was positively associated with the metastatic behaviour of HCC, with a 5-fold higher risk of metastasis among patients with HCC lesions involving both lobes of the liver when compared with malignancy confined to a single lobe of the liver. To the best of our knowledge, such finding has not been reported before. The published literature suggests that the multiplicity of HCC lesions is a contributing factor to metastasis, regardless of the location of HCC lesions (whether uni- or bilobar) [8]. Bilobar HCC could be a better indicator of metastasis generally. Whilst Bilobar HCC could be viewed as intrahepatic metastasis of the primary tumour, hence reflecting a more aggressive tumour behaviour with a higher risk of consequent spread outside the liver; however, multi-focal HCC cannot be confidently excluded in bilobar HCC. Thus differentiation between intrahepatic metastasis and multi-focal HCC remains difficult [25]. Globally, routine metastatic work-up is not undertaken for all HCC patients [22], and thus the predictor findings of this study highlight the importance of such routine work-up, as the one quarter of our patients were found to have extrahepatic metastasis at time of diagnosis. As for other potential predictors of metastasis we examined, surprisingly across our cohort, serum AFP, vascular invasion, and portal vein thrombosis were potential risk factors in the univariate analysis, but did not prove to be actual determinants of the HCC metastatic behaviour when entered in the multivariate analysis. This could possibly be related to the time of analysis, as we assessed the behaviour of HCC metastasis at time of diagnosis. Perhaps a survival analysis undertaken at a longer follow-up time might uncover any potential relationships between these variables and the metastatic behaviour. Over the last decade, inflammatory markers such as neutrophil to lymphocyte and platelet to lymphocyte ratios have gained attention as predictors of tumour progression and metastasis [26–28]. On the one hand, neutrophils accelerate tumour progression and metastasis by promoting angiogenesis through several factors e.g. vascular endothelial growth factor. Conversely, lymphocytes act as a barrier against tumour spread through generating a cellular immune response [28]. However, we did not find a relationship between NLR nor PLR, and the metastatic behaviour of HCC. Two points are worth to consider here. First, the time of the NLR and PLR reading, as it could be that values of the inflammatory markers before diagnosis of metastasis reflect the prepared microenvironment for spread of the tumour. Second, trends of the inflammatory markers prior to the diagnosis might be a more pertinent prognostic factor than the actual NLR value at the time of
Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006
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established diagnosis of metastasis. So, our Future research in our centre will be focused on these points. This study has limitations that include the short follow-up period and deficient metastatic work-up that might underestimate the percentage of extrahepatic disease in this cohort. Future research could benefit from studying the prognostic value of the inflammatory markers in predicting extrahepatic metastasis. In conclusion, the incidence of hepatocellular carcinoma is rising among our population; extrahepatic metastasis is no longer rare; and tumours larger than 5 cm and bilobar involvement are significant determinants of the extrahepatic metastasis in HCC patients. Considering the high percentage of metastasis, metastatic work-up should be done routinely.
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Please cite this article as: W. Elmoghazy, K. Ahmed, A. Vijay et al., Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinicopathology and predictors of extrahepatic metastasis, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.01.006