Background
Cholangiocarcinoma (CCA) is a rare and aggressive cancer that arises from the epithelium of the intrahepatic or the extrahepatic bile ducts. CCA can also arise from hepatic progenitor cells [
1]. Globally, the incidence of cholangiocarcinoma varies from as high as 113 per 100,000 in Northern Thailand, 5.7/100,000 in Southern Thailand, 2.2/100,000 in UK, 1.1/100,000 in USA and 0.3/100,000 in Israel [
2]. In both males and females, the incidence rises at age 60 to 70 years, rarely diagnosed before age 40 years, with a higher incidence and mortality in men compared to women [
2‐
4]. Little is known of CCA in Africa. Patients with CCA can present with jaundice pruritus, acholic stool and steatorrhea depending on tumor location and stage of presentation, but they can also present with abdominal pain and weight loss. Some patients have their CCAs detected as incidentalomas during cross sectional imaging for abdominal symptoms, or during hepatoma screening in those with underlying cirrhosis. Screening programs exist for detection of gall bladder or biliary cholangiocarcinoma in patients with underlying primary sclerosing cholangitis (PSC) using MRCP and CA19-9 [
5]. The management of CCA is dependent on anatomical location of tumor, staging and histology [
6].
Anatomically CCA are classified as: Intrahepatic cholangiocarcinoma (iCCA) if the tumor is located proximal to the secondary branches of the right and left hepatic ducts, perihilar cholangiocarcinoma (pCCA) if located between the secondary branches of the right and left hepatic ducts and the common hepatic duct proximal to the origin of the cystic duct, and distal cholangiocarcinoma (dCCA) if involving the common bile duct but not the ampulla of Vater [
2,
7]. Surgical resection is curative in early iCCA and if R0 resection is achieved, can give up to 36 months disease specific survival. There is a risk of recurrence in up to 62.2% of patients [
8]. Surgical resection is also curative in dCCA early stage disease for R0 resection which entails a Whipple’s procedure, although the risk of recurrence is high with 5-year survival of 27% [
9]. Surgical resection is the treatment of choice for early stage Bismuth-Corlette pCCA, although liver transplantation is emerging as the preferred treatment option with up to 76% 5-year survival with neoadjuvant chemoradiotherapy [
10]. Neoadjuvant and adjuvant chemotherapy does improve survival in all types of CCA. Hyperbilirubinemia due to biliary obstruction results in a pro-inflammatory state that negatively impacts the post-operative outcomes [
11]. Hyperbilirubinemia due to biliary obstruction results in a pro-inflammatory state that negatively impacts the post-operative outcomes [
11]. Endoscopic Retrograde Cholangiopancreatography (ERCP) and percutaneous transhepatic biliary drainage (PTBD) are the procedures most commonly used for biliary drainage; in both the curative (preoperative) and palliative setting. PTBD is considered to be more advantageous in the preoperative setting, for better priming for surgery, and there is a lower risk of postprocedural complications such as cholangitis. In the palliative setting, either technique can be used depending on the expertise of the operators, however in cases where the bilirubin is very high, the stenosis is lengthy, or in the presence of cholangitis, ERCP failure, or altered biliary anatomy—PTBD is recommended over ERCP [
12].
Many patients present with unresectable or metastatic disease; as such the median survival rate is as low as 3 to 6 months in the USA [
13].
Risk factors for developing CCA include occupation, which can be due to chemical exposure, chronic biliary inflammation, chronic hepatic inflammation, and cirrhosis of any cause and congenital and acquired causes of cholestasis leading to biliary inflammation. Nonetheless, risk factors are not identifiable in 50% of cases [
2]. CCA has been documented in workers at printing companies in Japan exposed to high concentrations of 1,2-dichloropropane (1,2-DCP) and dichloromethane [
14]. CCA has been shown to develop decades after administration of the radiologic contrast medium thorotrast, that was used for cerebral angiography in the 1950s [
15]. Autoimmune conditions, especially PSC have been associated with increased risk of cholangiocarcinoma in elderly patients in the USA [
16]. Heavy infestation by liver flukes
Clonorchis sinensis and
Opisthorchis viverrini due to eating raw fish is a known cause of CCA in Asian countries where these flukes are endemic, including Korea, China, Taiwan, and Vietnam [
17]. Other liver flukes
Fasciola hepatica and
Fasciola gigantica, cause fascioliasis in sheep and cattle, and can infest other herbivores, are a known zoonotic cause of human fasciolasis from eating water cress and drinking water with Lymnaeidae snails, that are intermediate hosts, can cause chronic cholestasis [
18]. Unlike the
Clonorchis sinensis and
Opisthorchis viverrini, there is no direct causal like between
Fasciola hepatica and
Fasciola gigantica, to CCA [
18]. Chronic intrahepatic cholestasis due to pigment stones can occur to due chronic hemolysis associated with hemolytic conditions such as sickle cell disease, thalassemia and red blood cell enzyme disorders such as G6PD deficiency. Although hepatolithiasis is a known risk factor for CCA, a direct link between hemolytic anemia and CCA has not been established [
19]. Bacterial infections with
Helicobacter species causing chronic cholangitis and cholecystitis have been implicated in the etiological role in biliary cancers [
20] Obesity has been associated with the increased risk of cholangiocarcinoma [
21]. The use of GLP-1 analogues, used in treatment of diabetes is associated with an increased risk of bile duct and gallbladder disease requiring hospital admission including cholelithiasis, cholecystitis, cholangitis. Over the long term as inflammation and cholestasis are associated with CCA, there is a possibility that use of these medications could pose a risk to development of CCA [
22]. In a recent review of risk factors for CCA in Eastern and Western countries, choledochal cysts, cirrhosis, choledocholithiasis, hepatitis B virus infection have been found to be associated with CCA [
2].
To date, no systematic review or meta-analysis of studies on CCA in Africa has been conducted. We address this gap by conducting a comprehensive systematic review on the epidemiology, management, and outcomes of CCA in Africa.
Discussion
This is the first systematic review to assess risk factors, epidemiology, and management of cholangiocarcinoma in Africa. We have not identified a comprehensive study on the incidence of CCA across the whole continent of Africa. An Egyptian study has identified male gender (1.7:1), farming and rural residency, cirrhosis, hepatitis C infection (54%), Schistosomiasis (66.5%), chronic typhoid infection (52%) and gallstone disease as possible risk factors for hilar cholangiocarcinoma [
35]. However, in a retrospective study done by Babatunde et al. in Nigeria, 37 patients had biliary tract carcinomas (representing 0.18% of all cancers in Ibadan), with more female than male patients (26 versus 11) [
24]. Twenty females and four males had gallbladder carcinoma, while 6 females and 7 males had cholangiocarcinoma (p = 0.02). Gallstones (33%) and dysplasia (42%) were also risk factors for developing biliary type cancers [
24].
CCAs express different types of mucin as a marker of differentiation and probable metastatic potential. MUC1, MUC1 core, MUC2, MUC3, MUC4, MUC5AC, and MUC6, were studied [
36]. Extensive MUC3 expression was significantly associated with well-differentiated tumors, while there was an approaching significance between the extensive expression of MUC1 and metastasis in CCA [
36]. Depot‐medroxyprogesterone acetate (DMPA) is not a risk factor for the development of either hepatocellular carcinoma or cholangiocarcinoma according to a study conducted in Thailand and Kenya [
37]. PSC, a major risk factor in the west, is rare especially in sub-Saharan Africa as is ulcerative colitis. A study on PSC has been conducted in South Africa, with a total of 69 patients attending Charlotte Maxeke Johannesburg Academic Hospital of which 22 were black [
38]. The risk of CCA among this population in Johannesburg has not been stated. 3 out of 4 Afro Caribbean women on the UC database at St Bartholomew’s Hospital in London developed of PSC [
39]. Segal reported a series of the first 46 patients treated at Baragwanath Hospital with ulcerative colitis which is a known risk factor for PSC [
40].
We have not seen any published evidence of risk of PSC and CCA in Africa. Fish borne zoonotic liver flukes
Clonorchis sinensis and
Opisthorchis viverrini are not a problem in Africa. There is a case report of infestation among Egyptian family who had the practice of consumption of imported fish from the Far East [
41]. Morsy et al. describe liver flukes in an Egyptian family, however this is a case report and describes an infestation among the Egyptian family who had the practice of consumption of imported fish from the Far East and not a larger Africa population [
41]. Whereas, this is not a risk factor among native Africans, it will be an increasing risk with Chinese migration onto the continent of Africa. It is estimated up to 12.5 million Chinese are infected by
Clonorchis sinensis [
42].
Other liver flukes causing fasciolasis affect cows and sheep in almost all countries in Africa [
43]. Although there is a similar lifecycle and pathogenesis with
Clonorchis sinensis and
Opisthorchis viverrini, there is not definite causal effect for CCA. Gall stones have been identified as a risk factor for CCA. However, no direct cause link has been attributed to hemolytic anemias which causes pigment stones. Recent and innovative studies have explored the role of organoids as models for studying cholangiocarcinoma [
45]. Sato et al. describe the use of 3D cell culture models to create an environment that contributes towards the understanding cholangiopathies including cholangiocarcinoma [
45]. Wang et al. also delineate the impact of the microenvironment in liver carcinogenesis [
46]. Exploring the role of microenvironment and developing models for the study of cholangiocarcinoma are channels to explore in understanding the epidemiology and risk factors [
46].
Eleven studies report on the management of CCA in Africa, 6 in Egypt, 2 in South Africa, 2 in Tunisia and 1 in Senegal. Although liver transplantation is emerging as treatment of choice in localized hilar CCA (hCCA), this has not been reported in Africa. Six Egyptian and 2 Tunisian studies have reported on surgical resection of CCA with curative intent. In Egypt, Wahab reported that major hepatectomy with excision of the extrahepatic bile duct system and caudate lobe resection may be recommended for the surgical treatment of central cholangiocarcinoma in selected cases [
32].
In a study published in 2012 Wahab concluded that caudate lobe resection in combination with major hepatectomy did not affect operative or postoperative morbidity and mortality but led to higher rates of margin-negative resections and significantly improved survival [
33].
El- Hanafy et al. found that preoperative biliary drainage by PTC and ERCP in selected patients with cholangitis and long-standing jaundice increased morbidity, transfusion requirements and hospital stay [
29]. However biliary drainage was associated with better outcomes in patients with malnutrition and renal impairment prior to liver resection in hCCA. But in these patients, there was higher complication risk including bile leak and collections, increased transfusion requirement, wound infection and pneumonia. In another study El Wahab et al. treated 243 patients with hCCA with resection of which 173 were with curative intent [
30].
There was a 14% five-year survival. Factors influencing survival were young age at diagnosis, resection with caudate lobe resection, well differentiated tumor, negative resection margins, negative nodal metastases, and absence of cirrhosis. A bilirubin of less than 10 mg/dL and HCV negative status in a non-cirrhotic liver predicted a better prognosis in resection on hCCA [
44].
Of the two Tunisian studies, the treatments were multimodal with different tumor locations. Romdhane et al., [
25] treated 17 patients: 41% gall bladder, 35.5% pHCCA, 23.5% dCCA. Five patients were treated with curative intent, of which 3 had adjuvant chemotherapy (the subtype of CCA is not described), with rest treated with chemotherapy. Median survival for surgical resection was 10 months and 9 months for the chemotherapy group. Labidi S et al. also reports of treatment outcomes of 51 patients in Tunisia: 45% gall bladder, 22% hCCA, 20% iCCA 14.5% dCCA [
26]. Of these, 9 were treated with curative resection 5 of whom also had adjuvant chemotherapy (subtype unclear). Again, the outcome was 12 months median survival for surgical resection with curative intent group, and 9 months in the chemotherapy only group.
Two South African studies report on palliative management of obstructing hCCA [
27,
28], Clarke DL et al. report on a total of 36 deeply jaundiced patients with hilar obstruction [
27]. Twenty-two had surgical biliary bypass, and 14 had PTC, the surgical group had higher morbidity, but both had good symptomatic relief of jaundice. There was no significant benefit of survival in the 2 groups, concluding that PTC would be treatment of choice in this group of patients. Lawson AJ et al. evaluated the use of PTC self-expanding metal stents to palliate malignant biliary obstruction as an alternative to surgical bypass or when ERCP is not feasible [
28]. This study involved 50 patients. Although the mortality rate was high in this very high-risk group of patients, PTC placed SEMS achieved satisfactory palliation [
28].
While the risk factors exist across the continent, it is unlikely that these data can be extrapolated across the whole of Africa. The changing demographics on the African continent with changing migration from the Far East should increase the awareness of Clonorchis sinensis and Opisthorchis viverrini as risk factors for CCA. The prevalence of PSC in Africa is unknown, as it is the only condition that warrants surveillance elsewhere in the world. Research is also required to determine if Fasciola.hepatica and Fasciola.gigantica are indeed not a risk factor for CCA, as they have a similar life cycle and cause cholestatic disease as do Clonorchis sinensis and Opisthorchis viverrini.
CCA remains a late presenting disease in Africa. The best median survival outcome of 36 months were for patients who had undergone hepatectomy with caudate lobectomy. Outcomes were improved when patients
did not undergo preoperative biliary drainage. Where surgical resection with curative intent was planned, the data does not show that was based on modern radiological staging techniques and preoperative histology, and this may explain the poor 5-year survival. In a single high-volume center in Egypt, curative surgery results in 14% 5-year survival. At this center, factors positively influencing survival were identified as: caudate lobe resection, bilirubin of less than 10 mg/dL, absence of cirrhosis and young age. There are no obvious risk factors on which to formulate surveillance programs in Africa. PTC based SEMS can be used to palliate jaundice in obstructing tumors as can ERCP stenting of dCCA. This would require investment in expertise and equipment in those African countries lacking such equipment. Chemotherapy was used for palliative intent in most studies, except a select group from the Tunisian studies when it was neoadjuvant to curative resection [
25,
26].
The earlier studies were Gemcitabine based, either with Oxaliplatin (GEMOX) or Cisplatin (GEMCIS). The Folfirinox (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) regime has also been used. The numbers in these study groups were small and there was not significant survival advantage in those who received chemotherapy and neoadjuvant chemotherapy.
Our Study limitations include the few numbers of included studies; inability to rule duplicate publication as similar author’s group published a few of the included studies and the data reviewed is reported from 4 countries only. Given the small number of studies, our review highlights the need for more research to understand epidemiology and aid with development of management strategies.
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