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Original Articles
Cervical Cancer Incidence and Trends among Nationals of the Gulf Cooperation Council States, 1998-2012 .....................................06Eman Alkhalawi, Amal Al-Madouj, Ali Al-Zahrani
Vitamin D Receptor and Role of Vitamin D Supplementation in Advanced Gallbladder Cancer: A Prospective Study from Northern India ..................................................................................................................................................13Sanchit Mittal, Akshay Anand, Aarthi Vijayashankar, Abhinay Arun Sonkar, Nuzhat Husain, Abhijit Chandra
Total Parenteral Nutrition in Middle Eastern Cancer Patients at End of Life: Is it Justified? ..................................................................20Elie Rassy, Tarek Assi, Ziad Bakouny, Rachel Ferkh, May Fakhoury, Hanine Elias, Aline Tohme, Fadi El Karak, Fadi Farhat,
Georges Chahine, Fadi Nasr, Marwan Ghosn, Joseph Kattan
Implementation and Evaluation of Phantomless Intensity Modulated Radiotherapy Delivery Verification Using FractionCHECK .......25Buchapudi Rekha Reddy, Manickam Ravikumar, Chandraraj Varatharaj, Nathan Childress, Tirupattur Rajendran Vivek
Gastric Adenocarcinoma in a Moroccan Population: First Report on Survival Data................................................................................35N. Lahmidani, S. Miry, H. Abid, M. El Yousfi, D. Benajah , A. Ibrahimi, M. El Abkari, A. Najdi
Trends and Patterns of Primary Hepatic Carcinoma in Saudi Arabia .......................................................................................................40Fazal Hussain, Shazia Anjum, Njoud Alrshoud, Asif Mehmood, Shouki Bazarbashi, Aneela N. Hussain, Naeem Chaudhri
Trend and Characteristics of Endometrial Cancer in Lagos, Nigeria ........................................................................................................51Adeyemi Adebola Okunowo, Morakinyo Abiodun Alakaloko, Ephraim Okwudiri Ohazurike, Kehinde Sharafadeen Okunade, Rose Ihuoma Anorlu
Open Nephron Sparing Surgery for T1a Renal Tumors: Clinical Experience in an Emerging Country ....................................................59A. Fetahu, Xh. Çuni, I. Haxhiu, R. Dervishi, L. Ҫuni, S. Manxhuka, L. Shahini
Consumption Coagulopathy in Paediatric Solid Tumours: A Retrospective Analysis and Review of Literature ....................................65Yamini Krishnan, Smitha B, Sreedharan P. S.
Case Reports
Clinicoradiological Discrepancy in Multisystem Langerhans Cell Histiocytosis with Central Nervous System Involvement ...............71Hussein Algahtani, Bader Shirah, Mohammed Bajunaid, Ahmad Subahi, Hatim Al-Maghraby
Primary Ewing’s Sarcoma of Maxillary sinus: A Case Report ..................................................................................................................77Chauhan Richa, Trivedi Vinita, Kumari Nishi, Rani Rita, Singh Usha
A Diagnostic Dilemma of Sinonasal T Cell Lymphoma: Report of A Unique Case and Literature Review ..............................................82Selvamalar V, S.P. Thamby, Mohammad Ahmed Issa Al-Hatamleh, Rohimah Mohamud, Baharudin Abdullah
Conference Highlights/Scientific Contributions
• BookReview-IARCHandbooksonCancerPrevention,Volume17ColorectalCancerScreening ...................................................89
• NewsNotes ............................................................................................................................................................................................91
• ScientificeventsintheGCCandtheArabWorldfor2019 ..................................................................................................................95
41
Corresponding author: Fazal Hussain, MD, MPH, Oncology Centre, King Faisal Specialist Hospital & Research Centre, PO Box 3354, MBC-64, Riyadh
11211, Saudi Arabia, Tel no: 966-1-4647272 Ext. 80768, Fax: 966-11-4647272 ext. 80768,
Email: [email protected]
Abstract
Background: Primary hepatic carcinoma (PHC) is the 4th most common malignancy among males at King Faisal Specialist Hospital and Research center (KFSH & RC) and in Saudi Arabia. There has been a steady increase in the number of PHC cases since 1975 at KFSH & RC and the burden of hepatic carcinomas is growing in Saudi Arabia. The aim of this study is to explore the changing trends and patterns of PHCs at KFSH & RC and conduct a comparative analysis with local, regional and global trends.
Materials and Methods: Cancer incidence data was obtained from the King Faisal Specialist Hospital and Research Center Tumor Registry program as per the American College of Surgeons standards. Clinical-epidemiological data of 1174 liver cancer patients from KFSH & RC during 2000 to 2014 and Saudi Cancer Registry (SCR) between 2001-2015 with total of 5,796 cases was reviewed. Trends, patterns of occurrence and other prognostic factors of interest were sub-stratified by gender, age, stage, and grade.
Results: Temporal trends indicated a rising incidence of PHC from 2001 to 2014 in Saudi Arabia; from 323 cases in 2001 to 376 cases in 2015 as per SCR. A total of 2,779 new cases of PHC were seen at KFSH & RC between
1975 and 2014; the rate of PHC increased from 60 cases in 2004 to 80 cases in 2014. Majority of liver cancers were hepatocellular carcinomas (79.3%) followed by cholangiocarcinoma (11%), and hepatoblastoma (4.7%) with significantly higher incidence among males with a male to female ratio of 2:1 (p <0.01). The highest incidence by age was at 6th and 7th decade of life. Majority of patients were diagnosed in localized stage (44.6%) and had a past medical history (28.2%) of hepatitis (p < 0.001). The most common treatment for liver cancer at KFSH & RC was surgery (26.7%) followed by transplant (9.5%).
Conclusion: Despite improvement in preventive measures, incidence rates of PHC has increased during the last decade with marked regional variation. Etiology of this escalating trend is multifactorial; predominantly, chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), heavy alcohol consumption, obesity, diabetes, and tobacco smoking. This exponential increase may also be due to early detection and diagnosis due to expanding health care delivery in the Kingdom. Further studies are indicated to comprehend the rising trends at the molecular and genetic levels.
Keywords: Primary hepatic carcinoma (PHC), Hepatocellular Carcinoma (HCC), age distribution, trends and patterns in Saudi Arabia
Original Article
Trends and Patterns of Primary Hepatic Carcinoma in Saudi Arabia
Fazal Hussain1, Shazia Anjum1, Njoud Alrshoud1, Asif Mehmood1, Shouki Bazarbashi2, Aneela N. Hussain3, Naeem Chaudhri1
1 Oncology Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia 2 Saudi Cancer Registry, Ministry of Health, Riyadh, Saudi Arabia
3 Department of Family Medicine and Polyclinic, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
Introduction: Primary hepatic carcinoma (PHC) is a malignancy of
the hepatocyte, generally leading to death within 6-20 months (1). Tumors are multifocal within the liver 75% of the time. Late in the disease, metastases may develop in the lung, portal vein, periportal nodes, bone, or brain. The most common histological subtype of PHC is hepatocellular carcinoma (HCC) which frequently arises in the setting
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Trends and Patterns of Primary Hepatic Carcinoma in Saudi Arabia, Fazal Hussain, et. al.,
of cirrhosis, appearing 20-30 years following the initial insult to the liver. About 25% of patients have no history or risk factors for the development of cirrhosis. The extent of hepatic dysfunction limits treatment options, and as many patients die of liver failure as from tumor progression. It accounts for 85% of all PHC cases. Cholangiocarcinoma (CC) is the second most common type of PHC responsible for about 20% cases (2).
In the United States liver cancers comprise 3% of all malignancies. PHC is 3 times more common in males than in females. The burden of liver cancer is rapidly growing in the United States. From 2002 to 2012 the incidence rate of Hepatic carcinoma has increased by 2.78 per year
(3, 4). Liver cancer cases increased from 2016 to 2017 by 3.7% (5).
Worldwide, PHC is ranked the 5th most common cancer among males and 9th among females. In the year 2012 about 782,000 new liver cancer cases were diagnosed worldwide. Liver cancer also claimed 745,500 lives during the same year (6). Worldwide there has been an increase in incidence of PHC in areas that had historically low rates like Oceania, Western Europe and North America. During the same time there has been a decrease in hepatic carcinomas in geographic locations that previously had high rates like China and Japan (7). In Europe in 2012 there were 52,000 new cases of liver cancer and approximately 48,000 deaths occurred due to liver cancer (6).
In comparison with Eastern Mediterranean Countries, liver cancer incidence in 2015 were 24,568 cases. Syria, Jordan and Lebanon had the lowest age standardized rates of liver cancer with 2.4/100,000, 2.7/100,000, 3.1/100,000 respectively. Egypt had the highest burden with 12.9/100,000 (8).
In Gulf Cooperation Council (GCC) countries primary hepatic carcinoma is the 6th most common type of carcinoma. There were 6071 newly diagnosed cases of liver cancer between 1998 and 2013. The overall Age Standardized Incidence Rate (ASR) for liver cancer for all GCC states was 7.1/100,000 for males and 2.9/100,000 for females. In all GCC countries males had a significantly higher incidence of liver cancer. Qatar has the highest burden of liver cancer with ASR 13.1/100,000 for males followed by Kuwait and KSA (9).
Four hundred and ninety five new (495) cases of PHC were reported in 2013 by the Saudi Cancer Registry, accounting for 4.3% of all cancer diagnoses. Liver cancer is the fourth most common cancer among males, and ninth most common cancer among females in the Saudi Arabia. In the Kingdom there were 344 (72.6%) male and 130 (27.4%) female cases of liver cancer in 2012. The male to female ratio was 2.64:1. The Age Standardized Incidence
rates (ASR) was 6.3/ 100,000 for males and 2.3/100,000 for females. The PHC rates varied significantly across different regions of Saudi Arabia. Riyadh had highest incidence of PHC with ASR (11/100,000), followed by Tabuk (8.5/100,000), Najran and Asir (2.9/100,000), Madinah (2.7/100,000) and Makkah and Eastern region (1.8/100,000). The median age at the time of diagnosis was 68 years for males and 66 years for females. Hepatocellular carcinoma (HCC) is the most common type of PHC in Saudi Arabia. In 2013, 78.8% of all male and 67.3% of all female liver carcinomas were HCC (10).
PHC is the fourth most common cancer in men in King Faisal Specialist Hospital & Research Center (KFSH & RC). PHC accounts for 3.4% of all cancers and 2.3% of all male cancers at KFSH & RC. Occurrence of PHC is significantly more common in men than in women. The male to female ratio is 1.6:1 (11).
Materials and Methods:We retrospectively analyzed data of 1174 primary
hepatic carcinoma patients treated at KFSH & RC from 2000 to 2014. Demographic data including sex, age, nationality, region, histological tumor type, smoking and alcohol use history and TNM staging were analyzed. SEER summary staging criteria were used to stage the carcinomas. Stratification and sub stratification of prognostic factors were performed. Cross tabs were run between variables of interest. The data were analyzed using SPSS version 20. Data of 4,786 patients diagnosed with primary hepatic carcinoma between 2001 and 2012 were extracted from Saudi Cancer Registry, Cancer Incidence Reports. Age Standardized Incidence Rates calculated using World Health Organization (WHO) standard population were used to examine changing trends in incidence of liver cancer over time in Saudi Arabia
ResultsAs per Saudi Cancer Registry Cancer Incidence report
2015, liver cancer is the fifth most common cancer among Saudi males and accounted for 3.1 % of all cancer cases in Saudi nationals. Liver cancer affected 72.9 % males and 27.1% females with a male to female ratio of 2.6:1.0. The ASR was 4.0/100,000 for males and 1.5/100,000 for females.
Three hundred and seventy six new cases of PHC were reported in 2015 by the Saudi Cancer Registry, accounting for 3.1% of all cancer diagnoses. Liver cancer is the ninth most common cancer among adults, and fifth most common cancer among males in the Saudi Arabia. In the Kingdom there were 274 (72.9%) male and 102 (27.1%) female cases of liver cancer in 2015. The male to female
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G. J. O. Issue 31, 2019
cases was in the year 2011, while the lowest incidence (6.1 %) was in 2005. The incidence of PHC was more than two fold in men than in women from 2001 to 2012 with a male: female ratio 2.4:1. (Table 1 & Fig. 1)
The Age Standardized Incidence Rate (ASR) has increased from 5.9 per 100,000 in 2001 to 6.3 per 100,000 in 2012 in Saudi Arabia. The percent change observed over the time period from 2001 to 2012 was 0.068%. In females the Age Standardized Rates have remained relatively static, with an ASR of 2.2 per 100,000 in 2001 and 2.3 per 100,000 in 2012. The highest ASR for males 8.3 per 100,000 was in 2006. In females the highest ASR 3.3 per 100,000 was observed in 2003 and 2006. The lowest ASR 5.9 per 100,000 in males in 2013 and 2.3 per 100,000 females was seen in 2012. (Table 2 & Fig. 2). Temporal trends show that the overall incidence of primary hepatic carcinoma at KFSH & RC has increased
ratio was 2.64:1. The Age Standardized Incidence rates (ASR) was 4.0/ 100,000 for males and 1.5/100,000 for females. The highest ASR for males were Riyadh region at (6.7/100,000), followed by Tabuk and Eastern region both at (4.6/100,000), Najran (4.3/100,000), Makkah (3.7/100,000). In females Riyadh had highest incidence of PHC with ASR (2.5/100,000), followed by Eastern region (2.3/100,000), then Hail and Jouf both at (2.1/100,000) and Tabuk (2.0/100,000). The median age at the time of diagnosis was 68 years for males (range 0-99 yrs) and 64 years for females (range 0-102 yrs). Hepatocellular carcinoma (HCC) is the most common type of PHC in Saudi Arabia. In 2015, 74.5% of all male and 76.5% of all female liver carcinomas were HCC). At KFSH & RC from 2000-2014, 1174 patients of liver cancer were treated, 66.7% were males and 33.3% were females. PHC was significantly more common in males (p < 0.01), with a male: female ratio 2.00:1.0.
In Saudi Arabia the incidence of liver cancer has increased from 2001 to 2012. In 2001, 7.2% males were diagnosed with primary hepatic carcinoma compared to 10.2% of the total in 2012. In females an increase in incidence of PHC was also observed over time; 5.8% females were diagnosed with PHC in 2001 compared to 9.3% of the total in 2012. For males and females combined the highest incidence of PHC (10.2%) of total
Table 1. Frequency Incidence of Liver Cancer in Saudi Arabia, 2001-2013
Figure 1. Incidence of PHC in Saudi Arabia 2001-2013
Table 2. Age Standardized Incidence Rates of liver cancer and Annual Percentage Change in Saudi Arabia, 2001-2013
Number of new cases diagnosed per year
N (% of total liver cancer during 2001-2013)
Male: Female Ratio
Male Female Total
2001 274 (6.72%) 101 (5.86%) 375 (6.47%) 2.71:1
2002 292 (7.16%) 116 (6.74%) 408 (7.04%) 2.51:1
2003 283 (6.94%) 129 (7.49%) 412 (7.11%) 2.19:1
2004 277 (6.79%) 120 (6.97%) 397 (6.85%) 2.30:1
2005 289 (7.09%) 114 (6.62%) 403 (6.95%) 2.53:1
2006 319 (7.82%) 137 (7.96%) 456 (7.87%) 2.32:1
2007 333 (8.17%) 130 (7.55%) 463 (7.99%) 2.56:1
2008 338 (8.29%) 126 (7.32%) 464 (8.01%) 2.62:1
2009 328 (8.04%) 150 (8.17%) 478 (8.25%) 2.18:1
2010 329 (8.07%) 154 (8.94%) 483 (8.33%) 2.13:1
2011 330 (8.09%) 158 (9.18%) 488 (8.42%) 2.08:1
2012 344 (8.44%) 130 (7.55%) 474 (8.18%) 2.64:1
2013 339 (8.31%) 156 (9.06%) 495 (8.54%) 2.17:1
Total 4075 1721 5796 2.37:1
Year of Diagnosis
ASR per 100,000 population
Annual Percentage Change (APC)
Males Females Males Females
2001 7.3 2.7
2002 7.1 2.8 -.03 .04
2003 7.1 3.3 0 .178
2004 6.6 2.9 -.07 -.12
2005 6.8 2.6 .03 -.10
2006 8.3 3.3 .22 .27
2007 7.2 2.8 -.13 -.15
2008 6.9 2.6 -.04 -.07
2009 6.6 3 -.04 .154
2010 6.4 3.1 -.03 .033
2011 6.1 2.9 -.047 -.064
2012 6.3 2.3 .033 -.206
2013 5.9 2.6 -.063 .130
0
100
200
300
400
500
600
Num
ber o
f new
lver
can
cer
case
s
Year of diagnosis
Female
Male
Total
0
1
2
3
4
5
6
7
8
9
ASR
per
100
,000
pop
ulat
ion
Yars of diagnosis
Female
Male
44
Trends and Patterns of Primary Hepatic Carcinoma in Saudi Arabia, Fazal Hussain, et. al.,
of 1174 cases of primary hepatic carcinoma treated at KFSH & RC between 2000 and 2014; about 79.3% cases were hepatocellular carcinoma (HCC) with a male:female ratio of 2.18:1; 11% cases were cholangiocarcinoma (CC) with a male:female ratio of 1.28:1, (4.7%) cases of hepatoblastoma (HB) with a male: female ratio of 2.1:1 and (4.9%) other malignancies. (Table 4 & Fig. 4)
Age:
The peak incidence of PHC in Saudi Arabia was between the sixth and seventh decade of life. The median age for
Figure 2. Trends in Age Standardized Incidence Rates (per 100,000) population in Saudi Arabia 2001-2013
Figure 3. Incidence of PHC at KFSH & RC 2000-2014
Figure 4. Distribution of primary liver cancer by histological type at KFSH & RC
0
100
200
300
400
500
600
Num
ber o
f new
lver
can
cer
case
s
Year of diagnosis
Female
Male
Total
0
1
2
3
4
5
6
7
8
9 A
SR p
er 1
00,0
00 p
opul
atio
n
Yars of diagnosis
Female
Male
0 20 40 60 80
100 120
Incidence of PHC at KFSH&RC 2000-2014
Female Male
0 100 200 300 400 500 600 700 800 900
1000
Histological types at KFSH&RC
Female Male
0 20 40 60 80
100 120
Incidence of PHC at KFSH&RC 2000-2014
Female Male
0 100 200 300 400 500 600 700 800 900
1000
Histological types at KFSH&RC
Female Male
Table 3. Frequency of Liver Cancer at KFSH & RC, 2000-2014
Incidence of liver cancer at KFSH & RC 2000-2014
N (% of total liver cancer during 2001-2014)
Male Female Total
2000 61 (7.79%) 24 (6.13%) 85 (7.24%)
2001 72 (9.19%) 19 (4.85%) 91 (7.75%)
2002 46 (5.87%) 27 (6.90%) 73 (6.21%)
2003 43 (5.49%) 27 (6.90%) 70 (5.96%)
2004 44 (5.61%) 16 (4.09%) 60 (5.11%)
2005 23 (2.93%) 14 (3.58%) 37 (3.15%)
2006 47 (6.00%) 21 (5.37%) 68 (5.79%)
2007 27 (3.44%) 22 (6.19%) 49 (4.17%)
2008 47 (6.00%) 24 (6.13%) 71 (6.04%)
2009 54 (6.89%) 35 (8.95%) 89 (7.58%)
2010 67 (8.55%) 27 (6.90%) 94 (8.00%)
2011 74 (9.45%) 36 (9.20%) 110 (9.36%)
2012 74 (9.45%) 27 (6.90%) 101 (8.60%)
2013 60 (7.66%) 36 (9.20%) 96 (8.17%)
2014 44 (5.61%) 36 (9.20%) 80 (6.81%)
Total 783 391 1174
Table 4. Histological Diagnosis and Number of Cases
Male Female Total Percent Male: Female
Hepatocellular 638 293 931 79.3% 2.18:1
Cholangiocarcinoma 73 57 130 11.1% 1.28:1
Hepatoblastoma 38 18 56 4.7% 2.1:1
Others 34 23 57 4.9% 1.48:1
Total 783 391 1174 100% 2.00:1
from 7.8% of total in 2000 to 8.8% in 2013. The highest incidence (10.05%) was in 2011 and lowest incidence (3.38%) was in 2005. (Table 3 & Fig. 3)
Histopathology:
In Saudi Arabia, as per Saudi Cancer Registry Report 2015 the most common type of primary hepatic carcinoma was HCC 74.5% of males and 76.5% of females, followed by Cholangiocarcinoma (6.9%) in males and (5.9%) in females, then Tumor cells malignant was accounted for 4.4% in males and 4.9% in females. A total
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G. J. O. Issue 31, 2019
Table 4. Histological Diagnosis and Number of Cases
diagnosis was 68 years in males and 64 years in females. (Fig.5). At KFSH & RC from 2000 to 2014 the highest incidence of primary hepatic carcinoma in both males and females was among the age group 60-69 years (32%). The median age of diagnosis was 62 yrs (SD 18.5). The age distribution by histological tumor type is given in (Table 5 & Fig. 6.1 and 6.2). The highest incidence of both HCC and CC was in the age group 60-69. The peak incidence of HB was between 0 to 9 years with 98% of cases occurring in this age group. The mean age of diagnosis of HCC was 61.4 years, for CC was 58 years and for HB was 2.9 years.
Stage:
Primary hepatic carcinomas were staged according to the International Union Against Cancer (UICC) TNM staging and American Joint Commission on Cancer (AJCC) system. The most common stage of liver cancer observed in Saudi Arabia was localized stage with 43.1% followed by distant stage with 26.3%. About 15.7% of the patients presented with regional stage (Fig. 7). In the USA, 43% of the liver cancer cases were localized. About 27% had regional stage and 18% had distant stage (12). At KFSH & RC between the years 2000 to 2014, out of total 1174 patients 44.6% were diagnosed in localized stage. About 20% had distant metastasis and 12% had regional metastasis. (Table 6 & Fig 8.1 and 8.2).
History of Hepatitis:
As per available literature,(4) 28.2% of all liver cancer patients had a history of hepatitis. 18.3% had Hepatitis C, 9.1% had Hepatitis B and 0.7% had Hepatitis not specified. 71% of the cases presented with no history of hepatitis (Table 7). About 50% of HCC patients from USA had history of hepatitis C, and 10% presented with hepatitis B. Past history of hepatitis was present in 34.3% of HCC patients and in only 5% of CC patients. There was a statistically significant association between hepatocellular carcinoma (HCC) and past history of hepatitis (Chi square (df=3) = 77.8, p < 0.001) (Table. 8 & Fig.9).
Treatment
Of the total 1174 study participants, 16.6% patients received surgery alone, 3.9% received surgery combined with chemotherapy, and 8.4% were administered just chemotherapy. A large number of patients (55.7%) had no treatment. A total of 104 patients were registered for transplant. Among these 5.11% had surgery with transplant, 3.47% had transplant alone, 0.5% received a combination of surgery, radiation and transplant and 0.2% had surgery combined with radiation and transplant and 0.18% had transplant with radiation. (Table. 9 &10). In comparison with UK between 2013-2014, 23% of liver cancer patients
Table 5. Age Distribution
Figure 6.1 Distribution of PHC by age at KFSH & RC
Figure 6.2 Distribution of PHC by age at KFSH&RC(peakage60-69yrs.)
HCC CC HB Others
Age (n=872) (n=121) (n=48) (n=57)
0-9 5 0 48 5
10 -19 10 0 1 3
20-29 14 4 0 1
30-39 14 11 0 8
40-49 71 20 0 7
50-59 220 22 0 11
60-69 310 32 0 8
70-79 184 26 0 8
80-89 41 4 0 1
90-99 3 2 0 5
Mean 61.4 58 2.9 48.2
Figure 5. Age Specific Incidence Rate (AIR) for Liver Cancer in Saudi Arabia (Source: SCR Cancer Incidence Report 2015)
0
50
100
150
200
250
300
350
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
Male
Female
0
50
100
150
200
250
300
350
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
Male
Female
0
50
100
150
200
250
300
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
Female
Male
46
Trends and Patterns of Primary Hepatic Carcinoma in Saudi Arabia, Fazal Hussain, et. al.,
received a chemotherapy and 20% were treated with surgery. Only 4% of the patients received radiotherapy (13).
DiscussionHepatocellular carcinoma (HCC) is the 5th most
common solid tumor and 3rd most common cause of cancer mortality globally, resulting in an estimated 600,000 deaths yearly. Although HCC is less common in North America, the incidence has increased from 1.4 to 2.4 per 100,000 over the past twenty years, and it is expected to continue to rise in parallel to the increasing incidence of Hepatitis C. Cirrhosis, due to alcohol, viral hepatitis, autoimmune hepatitis, hemochromatosis, or nonalcoholic steatohepatitis (NASH) increases the risk of HCC. Patients with Hepatitis C cirrhosis have a 5-20% 5-year cumulative incidence of HCC, and even in the absence of cirrhosis, hepatitis B infection is associated with a 15% risk of HCC. Many patients with cirrhosis have impaired liver function, and the degree of impairment impacts HCC prognosis and treatment options. The most commonly used measure of liver function is the Child-Pugh classification, based on the presence or absence of ascites and encephalopathy as well as bilirubin, albumin, and INR levels, with worse survival in Child Pugh class C and best in Child-Pugh class A, even in the absence of HCC. The Model for End-Stage Liver Disease, or MELD, is a scoring system for assessing the severity of chronic liver disease and is useful in determining prognosis and prioritizing patients for receipt of a liver transplant. More recently it has been suggested to be useful in predicting survival in HCC patients (Huo 2007). The Barcelona Clinic Liver Cancer (BCLC) staging and treatment allocation system is commonly used to describe HCC patients (Llovet JNCI 2008). This system includes Child Pugh class in addition to tumor factors.
This clinical epidemiological study has explored temporal trends of primary hepatic carcinoma in the Kingdom of Saudi Arabia. Incidence rates of liver cancer have continued to rise in the past two decades. The most common histological type of PHC at KFSH & RC was hepatocellular carcinoma (HCC) and constituted
0
50
100
150
200
250
300
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
Female
Male
Figure 7. Stage distribution of Liver Cancer in Saudi Arabia (Source: SCR Cancer Incidence Annual Report, 2015)
Table 6. Frequency of Hepatitis at KFSH & RC
Type of Hepatitis n %
Hepatitis Not Otherwise Specified.
8 0.73%
Hepatitis B 100 9.14%
Hepatitis C 201 18.37%
No Hepatitis 780 71,29%
Unknown 5 0.45%
Total 1094 100%
Figure 8.1. Distribution by SEER staging at KFSH & RC: Combined overall
Localized 44%
Regional 16%
Distant Metastasis
20%
Unknown 20%
0 50 100 150 200 250 300 350
Localized
Regional
Distant Metastasis
Unknown
Female Male Figure 8.2. Distribution by SEER staging at KFSH & RC by gender
Localized 44%
Regional 16%
Distant Metastasis
20%
Unknown 20%
0 50 100 150 200 250 300 350
Localized
Regional
Distant Metastasis
Unknown
Female Male
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G. J. O. Issue 31, 2019
of the liver include Hepatitis B and C virus, cirrhosis, Non Alcoholic Fatty Liver Disease (NAFLD), Diabetes Mellitus, excessive alcohol intake, smoking, consumption of Aflatoxin contaminated food and Liver Fluke Infestation (15).
The rates of liver cancer in males were more than two-fold than in females at KFSH & RC. The higher rates of hepatic cancer in males may be due to difference in exposure to risk factors. Men are more at risk of getting HBV and HCV infection and more likely to smoke and consume alcohol (16).
More than one fourth of our study participants at KFSH & RC had a history of hepatitis. One third of patients with hepatitis had Hepatitis B and two thirds had Hepatitis C. Chronic Hepatitis B virus (HBV) and Chronic Hepatitis C virus (HCV) infections are responsible for more than 80% cases of HCC worldwide (17). About 400 million people are currently infected with HBV around the world. Each year more than 780,000 deaths are attributed to HBV infections
Table 8. Frequency Past History of Hepatitis (KFSH & RC Cancer Registry)
Figure 9. Cross tab between history of hepatitis and histology (Chi square=77.79, p<0.001) (KFSH & RC Cancer Registry)
Table 7. SEER Summary Stage Distribution of Liver Cancers in KFSH & RCᵃRegional Direct Extension ᵇRegional Lymph Nodes ᵉRegional Lymph Nodes and Direct Extension ᵏMetastases
Past History of hepatitis
Yes No
HCC 299 (34.4 %) 570 (65.5%)
CC 6 (5%) 113 (95%)
HB 0 (0%) 49 (100%)
Others 4 (7.7%) 48 (92.3%)
Stage N %
Localized 524 44.6%
Reg Dir Extᵃ 144 12.3%
Reg LNᵇ 18 1.5%
Reg LN& Extᵉ 22 1.9%
Distant Metsᵏ 233 19.8%
Unknown 233 19.8%
Table 9. Definitive Treatment Administered for Hepatocellular carcinoma at KFSH & RC Between 2000 and 2013
Table 10. Transplants registered in PHC patients diagnosed at KFSH & RC between 2000-2013
Treatment type n %
Surg/Chemo/Rad 2 0.2%
Surg/Chemo 37 3.38%
Surgery 182 16.63%
Surg/Rad 7 0.63%
Rad/Chemo 3 0.3%
None 609 55.7%
Rad 36 3.2%
Chemo 92 8.4%
Immunotherapy 2 0.18%
Palliative 3 0.027%
Surgery/Chemo/Transplant 2 0.2%
Surgery/Rad/Transplant 6 0.5%
Surgey/Transplant 56 5.11%
Transplant/Rad 2 0.18%
Transplant 38 3.47%
Others 17 1.55%
Total 1094 100%
Transplants registered n %
Transplants at KFSH & RC 102 98.07%
Transplants performed abroad 2 1.92%
Total Liver transplants 104 100%
0
100
200
300
400
500
600
700
800
900
HCC CC HB Others
No Hepatitis
History of Hepatitis
about 80% of all the liver cancers. It generally developed in patients with chronic liver diseases and cirrhosis. In contrast approximately 75% of primary liver cancer was HCC in US (5). Worldwide, HCC accounts for 7.5% of all male and 3.5% of all female cancers respectively. HCC is a disease with poor prognosis and high mortality. Five-year survival rate of HCC is less than 20%. Globally HCC is the third most common cause of cancer related deaths (7, 14).
PHC is a significant contributor to disease burden, morbidity, mortality and health related costs in Saudi Arabia. Observing current trends of increase in hepatic carcinoma in Saudi Arabia it is predicted that the rates will continue to increase. Established risk factors for cancers
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Trends and Patterns of Primary Hepatic Carcinoma in Saudi Arabia, Fazal Hussain, et. al.,
globally (18). Chronic Hepatitis B virus infections are the leading cause of cirrhosis and Hepatocellular Carcinoma (HCC) worldwide (17). Hepatitis B virus infection causes significant morbidity and mortality in the Kingdom of Saudi Arabia. There has been a steady decline in Hepatitis B infection prevalence since the Saudi Ministry of Health mandated HBV vaccine for infants in 1990. HBV was highly endemic in Saudi Arabia and most cases occurred due to horizontal transmission during birth. In addition to the routine infant vaccination for HBV, mandatory vaccine for health care personnel and availability of vaccine for high risk groups has contributed to reduce the prevalence of liver cancer. Despite lower rates of HBV infection in younger population the prevalence in older generations remains a health concern. Prevalence of HBV in Saudi Arabia is 7.4% to 17% (14, 19). Gender is an important risk factor for HBV infection; men have 1.8 times greater likelihood of HBV infection than females (20, 21).
Hepatitis C virus (HCV) infection is a major contributor to end stage liver disease and Hepatocellular Carcinoma (HCC). HCV infection is a great public health concern with 140-170 million people infected globally and 3-4 million new people getting infected each year. The prevalence of HCV infection is considerably higher among people born between 1945 and 1965 as before early 1990’s HCV preventive measures and screening of donor blood for HCV were not available (4). In Saudi Arabia, HCV infection was usually acquired by transfusion of infected blood products. The incidence has remarkably declined after the implementation of blood donation screening programs for HCV in the early 1990’s. Despite the reported decline in HCV infection in KSA during the past decade it still remains a major public health problem in the country, the incidence of HCV infection from 2000-2007 was 78.9 per 100,000 population. In Saudi Arabia the prevalence of HCV is 6.8% (14). Prevalence of HCV is high among hemodialysis patients and intravenous drug users (22). Prevalence of HCV infection is also higher in adult population over 35 years of age in Saudi Arabia. Currently no vaccine is available for HCV therefore prevention depends on improved hygiene, infection control, sterilization and screening of blood products in health care setting. Diagnosis and treatment of HCV infection at an early stage can result in 75% reduction in risk of liver cancer (4, 20, 23, 24).
Cirrhosis results in late stage scarring and fibrosis of the liver (25). Development of Cirrhosis caused by chronic inflammation from HBV and HCV infections or excessive alcohol intake is a major risk factor for HCC (26). Approximately 70% to 90% patients of HCC have chronic liver disease and cirrhosis (27). The annual rate of developing HCC in patients with cirrhosis is 1% to 7% (28).
About two thirds of patients with HCC at KFSH & RC did not have a history of hepatitis. With rising rates of obesity and diabetes in Saudi Arabia, Non-Alcoholic Fatty Liver Disease (NAFLD) may be a causative risk factor for HCC in Saudi Arabia. Worldwide rates of Obesity, Diabetes and Metabolic Syndrome are rising. Both Obesity and Diabetes are related to NAFLD. A cohort study in Taiwan with large number of recruiters infected with hepatitis followed up for 14 years found that obesity and diabetes are independent predictors of HCC (29). Moreover, American study concluded that 33% of HCC patients were diabetic (30). Results of recent research studies have shown Non-Alcoholic Fatty liver Disease (NAFLD) and Non Alcoholic Steatohepatitis (NASH) as rapidly growing risk factor for Hepatocellular Carcinoma (HCC) (31). Prevalence rates of Non-Alcoholic Fatty Liver Disease (NAFLD) were between 18% and 54% in Southwestern region of Saudi Arabia. The rates of fatty liver were higher compared with those in other regions of the Kingdom and also in comparison with Western and Asian countries (32). In United Kingdom, NAFLD was found as an increased risk of HCC by more than 10-fold (33).
Further research is indicated in this area to explore the link of NAFLD with HCC in Saudi Arabia. Alcoholism is a major risk factor for Hepatocellular carcinoma worldwide. Alcoholic liver disease (ALD) causes accumulation of lipids and inflammation of liver leading to cirrhosis and increases the risk of Hepatocellular Carcinoma (34). Patients with ALD often have other risk factors which cause simultaneous injury to liver like NAFLD and viral hepatitis (35). About 30-40% patients with Alcoholic liver disease are infected with HCV and 70% of individuals with HCV are heavy alcohol consumers (36). However, such data is not available and the problem has not been quantified in the Middle East.
The International Agency for Research on Cancer (IARC) lists smoking tobacco a risk factor for hepatic carcinoma. Results of a European study showed that smoking caused almost 50% of HCC cases (7, 37). In Saudi Arabia the prevalence of smoking in males ranges from 13% to 38% (median 26.9%). Smoking is a major public health problem in Saudi Arabia and a cause of considerable disease burden. Research is also needed to estimate the proportion of HCC cases attributed to smoking in the country (38).
Aflatoxins are highly toxic metabolites produced by fungi Apergillus flavus and Apergillus parasiticus. Chronic exposure to Aflatoxins leads to liver cancer. Aflatoxins are food contaminants common in tropical developing countries, which are produced in maize, ground nuts, wheat and other grains stored in warm and damp conditions.(39) Aflatoxin contamination of wheat and other grains has been detected in KSA(40). Further research is needed to estimate the magnitude of the problem (41).
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Infection with parasitic liver fluke Opisthorchis viverrini predisposes individuals to development of Cholangiocarcinoma (CCA) which is cancer of the bile duct epithelium. The International Agency for Research on Cancer (IARC) classifies Opisthorchis viverrini as a group 1 carcinogen (42). Humans and animals may contract infection by eating raw watercress or other aquatic plants with liver fluke contamination. Infection in humans may also occur by consumption of contaminated water or ingesting undercooked sheep or goat liver (43). In Saudi Arabia liver fluke infestation with Fasciolosis and Dicrocoeliasis strains has been detected in slaughtered animals. Better field control and screening is needed to prevent transmission by consumption of infected animal liver (44).
Exposure to arsenic in drinking water is associated with hepatitis, cirrhosis and liver cancer (45). In Al Kharj geothermal fields of Saudi Arabia 92.5% of aquifers had arsenic concentrations above the World Health Organization (WHO) permissible 10 µg/L (46). Further research needs to be conducted to estimate arsenic contamination in water and its potential harmful health effects in Saudi Arabia.
Due to increase in life expectancy many populations are experiencing a rise in number of cancer cases as old age is a high risk factor for developing cancer (46). Liver cancer is a cancer of old age and is usually diagnosed between the sixth and seventh decade of life. The median age of diagnosis of PHC among Saudi men in 2012 was 68 years (10). In United States, the highest incidence of PHC was observed among the age group (80-84 years) (4). While in UK, 44% of the liver cancer patients were aged 75 years and above (47). Life expectancy in Saudi Arabia has increased from 52 years in 1970 to 75 years in 2012 (48). The rise in number of cancer cases is contributed by the increase in aging population. Robust public health initiatives to encourage healthy eating and physical activity can reduce obesity, diabetes, fatty liver and in turn liver cancer attributed to these factors. Reducing smoking rates by raising awareness and implementing effective control measures can help reduce the rising incidence of liver cancer (51, 52).
ConclusionThere is a steady increase in the incidence of
primary hepatic carcinoma in Saudi Arabia. Advances in diagnosis and screening resulting in early detection have contributed significantly in this changing trend. Despite various preventive measures implemented, incidence and prevalence of chronic Hepatitis B and C virus infections remain high. Increasing life span, aging, dietary habits, diabetes, obesity, smoking, and rising NAFLD rates are other noteworthy risk factors. Large scale primary
prevention efforts, augmented HBV and HCV infection control measures, public awareness, vaccination for hepatitis B virus (HBV) infection, screening and treatment for hepatitis C virus (HCV) infections, and reduction of alcoholic liver disease can result in significant reduction in the incidence of hepatocellular carcinoma. However, this desired end state may not be evident for several years due to long latency period from hepatic damage to hepatocellular carcinoma. Further studies are recommended to explore this alarmingly trend and to find culturally sensitive preventive strategies for primary hepatic cancer.
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