Histopathological study of hepatobiliary malignancies and its correlation with clinical features

Objectives: The aim of the study is to analyze hepatobiliary malignant tumors histologically, histochemically, immunohistochemically wherever possible and compare with the clinical features and review the literature.Methods: It is a retrospective clinicopathologic study using routine and special histopathological methods with information from clinical recordsResults: The age of the patients ranged from 32 to 72 years with male predominance. There were 5 cases of metastatic tumours and 2 cases of primary tumours of liver without cirrhosis both being hepatocellular carcinomas (HCC) where one was fibrolamellar type with amyloid deposition. There were 4 cases of primary and one case of secondaries in the gall bladder with majority associated with cholelithiasis. Extrahepatic biliary system had one case of adenocarcinoma.Conclusions: The liver is the most common site of malignancy of hepatobiliary system where secondaries are dominating followed by gall bladder with the primary being most common. Fibrolamellar type of hepatocellular carcinoma is not uncommon but amyloid in the tumor tissue has not been reported in the literature. Least common site of hepatobiliary system cancer is extra hepatic bile duct.


Introduction
Hepatobiliary malignancies comprise a diverse group of tumors including hepatocellular carcinoma, variants such as fibrolamel lar HCC and cholangiocellular carcinoma, carcinoma of the gallbladder, carcinoma of extrahepatic bile ducts, cancers such as sarc oma, angiosarcoma, hepatoblastoma and metastatic tumours mainly in the liver. Hepatocellular carcinoma is a malignancy of worldwid e significance and has become increasingly important. HCC is the most common primary liver malignancy. Liver cirrhosis is acknow ledged as a premalignant condition for developing HCC. Hepatitis B and hepatitis C virus, alcohol use, and nonalcoholic fatty liver disease (NAFLD) ar e the most common causes of cirrhosis. Gallbladder cancer is a relatively uncommon cancer thought to be related to gall stones and more common in women in 6 th and 7 th decade. Extrahepatic bile duct cancer is very rare. Here we are reporting study on 13 cases of hepatobiliary malignancies.

Materials and Methods
13 cases of hepatobiliary carcinomas were studied over a period from June 2012 to December 2013 using routine histopathological, histochemical and immunohistochemical methods wherever indicated and possible. Paraffin blocks and haematoxylin and eosin sta ined slides from archives were reviewed for histopathological examination .Clinical details with results of imaging studies were collected and results were correlated with the pathological findings. Histochemistry and immunohistochemistry were performed as per the manufacturer's protocol (Novocastra TM ready to use mouse monoclonal antibody) in cases where they were necessary.

Figure (7, 8)-Acute leukaemic/lymphoma infiltration of liver-2738/09. Infiltration of portal triad by monotonous leukaemic blast cells.
Both cases of HCC occurred in 52 and 59 year old males without cirrhosis. Out of two cases of HCC, one was fibrolamellar type with amyloid deposits in the tumour stroma proved by histochemistry -Congo red staining with polarizing light microscopic examination. Immunohistochemistry for kappa and lambda light chains was negative (figure -9, 10, 11, 12). Second case of HCC was of moderately differentiated hepatocellular carcinoma. Next common site of hepatobilliary tumor was gall bladder (38.5%) where primary tumor was dominating (4/5-80.0%) and all were well differentiated adenocarcinomas with one case showing papillary pattern ( Table 2). Male to female ratio in gall bladder cancer including secondaries was 3:2. One of the cases of gall bladder adenocarcinomas was secondaries in the gall bladder in a calculous cholecystitis where tumor was seen as tumor emboli in the blood vessels ( figure-13, 14). Age range of primary carcinoma of gall bladder was 51 to 72 years with male to female ratio 3:1.Two cases had presented with chronic cholecystitis with cholelithiasis. All cases had increase in serum bilirubin and aminotransferases (AST and ALT) levels. There was one case of adenocarcinoma arising from common hepatic duct (klatskin tumour)(Table3) which is the least common site of cancer in this series(7.6 %) which occurred in a young , 32 years old female .This patient presented with history of pain and fever with obstructive jaundice.

Discussion
The liver, gallbladder, bile ducts, and pancreas have a common embryologic origin. Cancers that arise from these sites share a similar spectrum of histologic types. 1 On the whole males are affected more than females in the ratio 8:5. In all four sites, greater than 95% are carcinomas. 2 Primary cancers of the liver are uncommon in United States but are common in other parts of the world, especially in Africa and southeast Asia 3 . In the present study of total 13 cases of hepatobiliary malignancies 53.8% were those of liver with metastases constituting( 71.4%.) Cholangiocarcinoma is much less common than HCC compared to other sites of hepatobiliary system as found in our study.
It is increasingly recognized that morphologic subtypes of liver carcinoma exist beyond the obvious broad distinctions of hepatocellular and cholangiocarcinoma. Commonly accepted subtypes are fibrolamellar HCC (FL HCC), scirrhous HCC, sarcomatoid HCC, and the so-called inflammatory HCC. 4 In our study we have reported one case of fibrolamellar type of HCC with amyloid stroma.
Gallbladder Carcinoma (GBC) is a rare but highly lethal disease. In many patients, the disease is not suspected clinically and is found at an advanced stage, often during surgery for cholelithiasis. The associated survival rates are very low, similar to those s een for pancreatic and lung cancer. 5,6,7 The mean age of patients is 65 years. In the present study most of the patients were males (60%), and had cholelithiasis. Gallbladder carcinomas are associated with gallstones in 80%, porcelain gallbladder 10-20%, and abnormal choledochopancreatic duct junction. Gallbladder carcinoma usually produces asymmetric thickening of the gallbladder wall with infiltration to surrounding structures. As described by Campbell et al 8 most cancers originate in the gallbladder fundus. As the tumour progresses, the gallbladder may fill with tumour or may contain pus, mucus, or stones. Early carcinomas can appear as a mucosal plaque, a polypoid or papillary outgrowth, or discrete thickening of the wall. There are papillary and nodular forms of GBC. Papillary tumours are less likely to invade the liver directly and have lower incidence of lymph-node metastasis. [9][10][11][12] In our study one case (20%) showed papillary pattern of adenocarcinoma. Most carcinomas of the gallbladder are adenocarcinomas (80-95%) as in the present study, and can be papillary, tubular, mucinous, or signet cell type. Less common types of GBC are undifferentiated or anaplastic carcinoma (2-7%), squamous cell carcinoma (1-6%), and adenosquamous carcinoma (1-4%). Clear cell adenocarcinoma of the gallbladder is composed of cords, sheets, nests, and trabeculae of clear cells with well -defined cytoplasmic borders and may be confused histologically with metastatic renal cell carcinoma. In our study 66.6 %( 2 cases of primaries and one case of secondaries) patients had cholelithiasis. Size of the gallstones may also be a risk factor, as patients with stones larger than 3 cm have a significantly greater risk of developing carcinoma. 13 Recently, clinical and epidemiological studies have suggested a link between gallstone disease GBC as well as other hepatobiliary diseases and previous infection with Helicobacter species . 14,15 Cholangiocarcinoma intrahepatic or extrahepatic are less common .They are slightly more common in males, not associated with lithiasis and have poor outcome because of low rate of resectability, and occurrence in older age group. Cancers of the extrahepatic bile ducts are less common than those of the gallbladder. The same major histologic types can be found in both sites, but slight differences are seen in the frequency of certain subtypes. 99% of cases were carcinomas, and the most frequently reported subtype was adenocarcinoma not otherwise specified (NOS).Papillary carcinomas accounted for a higher percentage of carcinomas in the extrahepatic bile ducts than in the gallbladder. 16,17 In our study we had one case of common hepatic duct adenocarcinoma which was moderately differentiated. Bile duct carcinomas are often small and have not metastasized when detected but patient outcome remains poor. An important factor in the prognosis is the location of the tumor within the biliary tree. 18 Tumors in the lower third of the bile duct can be resected more successfully than those from other location but the majority of tumors are located within the upper third of the bile duct system as in the present study -at the confluence of the hepatic ducts at the hilum as a single mass (MRI). Bile duct tumors can be diffusely infiltrative or multifocal also [17][18][19][20][21][22]

Conclusion
The liver is the most common site of malignancy of hepatobiliary system where secondaries are dominating. Fibrolamellar type of hepatocellular carcinoma which is not uncommon but amyloid in the tumor tissue is not reported in the literature. Primary carcinoma of Gall bladder is more common than secondary in the gall bladder and found to be more common in older age with male predominance. Least common site of hepatobiliary system cancer is extra hepatic bile duct cancer and is seen in younger age. Secondaries can be seen only as tumo r emboli in the vessels as in the gall bladder secondaries in the present study which has not been reported in the literature.