Despite advancements in the management of cirrhosis, the prevalence of hepatocellular carcinoma (HCC) is increasing. Currently, HCC is the fifth most common cancer representing almost 6% of all newly diagnosed cancers globally. Moreover, HCC is one of the common causes of mortality in patients with cirrhosis (1-3). The prevalence of HCC varies geographically. However, up to 80% of HCC have been reported from South-East Asia and Africa (1, 3). Etiologically, Hepatitis B(HBV) and C(HCV) are the most important attributable factors for HCC especially in Asia (4). Due to diverse oncogenic pathways involved, the difference exists in natural history and outcome of HCC due to HBV and HCV (5-7). Hence, considering the fact that HBV has a more direct carcinogenic activity, most of HBV related HCC present at earlier stage of cirrhosis with greater aggressiveness as compared to HCV related HCC (8, 9).
Nonetheless, both hepatitis B and C negative HCC (NBNC-HCC) have also been increasingly recognized that are considered to be caused by alcoholic liver injury, autoimmune and metabolic liver diseases and nonalcoholic steatohepatitis (NASH) (5). Considering the involvement of distinct oncogenic pathways in development of HCC it is well expected that the difference exist in natural history and prognosis of HCC due to viral and non-viral etiologies (3, 10). There have been few reports regarding NBNC-HCC which is mostly based upon unselected or post surgical patients without stratification according to age, liver function, tumor stage and modality of cancer diagnosis(regular surveillance more likely detects slow growing tumors (length time bias) (9, 11). Furthermore, the data regarding HCC in the presence of HBV and hepatitis D(HDV) or HCV co-infection is limited(1). Hence, it is significant to address this issue on broader scale.
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Pakistan exist in â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦ Limited data is available from Pakistan regarding HCC that is mostly consisting of single center experience with small sample size and main emphasis on viral etiology. Based upon their results, a higher proportion of HCV (45%) related HCC as compared to HBV-related cases was found in Pakistan (1, 12-15).
Hence this study was conducted to estimate the prevalence and trends of viral marker negative HCC and to compare the clinico-pathological, radiological characteristics at diagnosis, applicability of treatments and initial treatment response/ prognosis among patients with viral marker negative and viral marker positive HCC visiting The Aga Khan university hospital, Karachi, Pakistan
Patients and methods:
This was a retrospective cross sectional study. Patients â‰¥18 years, already diagnosed to have HCC visiting the Gastroenterology ward, clinics of The Aga Khan University Hospital, Karachi, Pakistan during January 1998 to December 2009 were identified from our data base by using ICD code â€¦....The information was collected about the etiology of chronic liver disease, clinical, radiological, histological characteristics and stage of HCC at the time of diagnosis and the treatment provided. The cases were excluded where the required information about etiology, diagnosis, clinic-pathological characteristics and staging of HCC was incomplete.
Diagnosis of HCC and cirrhosis
The diagnosis of HCC was made by combination of elevated alfa feto protein (AFP) (>200ng/ml) with characteristic features of HCC on triple-phase computerized tomography (CT) scan/ magnetic resonance imaging (MRI) or in the absence of elevated AFP when the concurrent results were found on two imaging modalities with or without histological verification (16, 17). The presence of arterial enhancement, followed by washout of contrast on porto-venous and delayed phase were considered as typical characteristic features of HCC (16, 17). The diagnosis of cirrhosis was made either on liver biopsy or in the absence of liver biopsy by clinical and laboratory features of portal hypertension i.e. varices on upper gastrointestinal endoscopy, radiological features suggestive of cirrhosis including nodular liver margins, dilated portal vein, spleenomegaly and ascites(18). The Child-Pugh classification was used to define the severity of liver dysfunction (19).
Staging and classification of HCC:
The Milano criteria were used to define the stage of HCC (16, 20). The HCC was considered as "nonadvanced" (if the lesion was solitary â‰¤5 cm or plurifocal â‰¤3 lesions, with the largest diameter â‰¤3 cm, in the absence of vascular invasion and distant metastases) and "advanced," when the tumor exceeded these limits. Moreover, the HCC was also classified for macroscopic types as (i) solitary,( ii) paucifocal (â‰¤3 nodules), (iii) multifocal (>3 nodules), (iv) infiltrative (infiltrating pattern of HCC) and (v) massive
Always on Time
Marked to Standard
(huge mass with a diameter of > 10cm and an undefined boundries) (21). The tumor size of expanding nodules was also measured (with multinodular tumors, the largest one).
When possible, patients were also restaged according to the CLIP system (A new prognostic system for hepatocellular carcinoma: A retrospective study of 435 patients: The Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28:751-5).
Stage of HCC were evaluated according to the recently proposed CLIP9 and JIS10 scoring systems, and BCLC classification,11 which incorporate both tumor extension and liver function factors.
In patients aged â‰¤65, potential amenability to orthotopic liver transplantation (OLT) was evaluated according to the Milano criteria (17).
The criteria for considering patients amenable to hepatic resection, percutaneous ethanol injection (PEI), or radiofrequency thermoablation and transarterial chemoembolization (TACE) have been reported in detail elsewhere (6).
Vascular invasion was assessed by means of dynamic CT and angiography in cases in which pathologic evaluation had not been performed.
Modality of cancer diagnosis: Patients were was defined under "surveillance,"when HCC was detected during regular follow-up based on semiannual or annual US and alpha-fetoprotein (AFP) determination, "incidental," when an asymptomatic neoplasm was discovered outside any surveillance program or during diagnostic procedures performed for extrahepatic diseases, "symptomatic," when HCC was diagnosed because of symptom appearance.
Liver function tests i.e. total bilirubin, serumalanine aminotranspherase (ALT), serum albumin, prothrombin time (PT) and serum alpha-fetoprotein (AFP: normal values:â‰¤20 ng/mL)were determined by conventional methods. Hepatitis B virus markers were tested by radioimmunoassay or enzyme-linked immunosorbent assay(ELISAâ€¦â€¦.) and anti-HCV antibody was tested by ELISAâ€¦â€¦.
Main Outcome Measures and Putative Prognostic Factors
Patients were divided in to i) NBNC-HCC (those who have negative HBsAg and Anti-HCV antibody/ in whom HBV or HCV infection was not detected) and ii) viral HCC (those who have positive HBsAg or Anti-HCV antibody/ with viral HCC in whom HBV or HCV infection was detected) group. Patient's demographic features, clinical, biochemical, histological, radiological characteristics and initial treatment responses were compared between two groups. Clinical, laboratory parameters including demographic characteristics, body mass index (BMI), comorbid conditions, etiology of cirrhosis, duration from diagnosis of CLD to diagnosis of HCC, complications due to cirrhosis, Child-Turcotte-Pugh (CTP) score and class, AKUDA and CLIP score, mode of diagnosis, Alfa fetoprotein (AFP), total bilirubin, ALT, platelets count at baseline, histopathology, radiological features of HCC (location , size/median diameter, no of lesions), HCC stage, vascular invasion, metastasis, macroscopic types and treatment response were compared (as putative prognostic factors)between two groups.