الفهرس 
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Abstract
Sixty four cases of hepatic focal lesion(s) have been diagnosed as adenocarcinoma including 3 cases as extrahepatic cholangiocarcinoma (by clinical and radiological means) and 61 cases of intrahepatic adenocarcinoma . After exclusion the extrahepatic cholangiocarcinoma cases the rest of cases are evaluated with CK19 ,c-Kit immunohistochemistry ; It has been found that CK19 status ( as positive/ negative) alone statistically doesn’t help the differential diagnosis of primary hepatic adenocarcinomas from the metastatic adenocarcinomas to liver. Comparing the clinical history of metastasis with the CK19 score we find that the score of CK19 can efficiently differentiate the primary vs the metastatic adenocarcinoma that all the cases with known metastatic are negative or weak in intensity and focal positive , around the cut off value of CK19 positivity (5%) ;score 1 has been excluded from further evaluation and accordingly the use of a combination of c-Kit &CK19 score 2,3 can be used as a primary step to exclude the metastatic adenocarcinoma until prove it by metastatic work or rather more importantly to select the primary liver adenocarcinomas and examine them for targeted therapy.
CK18 has to be used to confirm this selection as adenocarcinomas of primary hepatic progenitor cell origin as long as progenitor cells can differentiate into hepatocytes and cholangiocytes, which in turn can give rise to hepatocellular carcinoma/cholangiocellular carcinoma. All of the selected cases CK19 &c-Kit score 2,3 ;each has been found expressing CK18.
Eight cases have been stained with CD133 . It has been found that not all the primary intrahepatic adenocarcinomas of progenitor cell origin) express CD133 .Only 62.5% of our cases CK19+ve /c-Kit +ve/ CK18 +ve primary intrahepatic adenocarcinomas (of progenitor cell origin) express CD133 ie; of Cancer Stem Cell Phenotype .
Special category : Hepatocellular carcinoma (HCC) with progenitor cell features:
Among the cases histologically diagnosed as HCC by H&E , there is a group of HCC are expressing CK19 (n=8) . 75% of the HCCs expressing CK19 (n=6) is CK19 score 1 ( > 5% ; the cut off positive value and of focal weak intensity in comparison to only two cases are of score 3 ,with statistically significant value ( P value < 0.5) which unlike the staining pattern of CC (moderate and diffuse ).
Florescent In Situ Hybridization (FISH) (using The Vysis LSI 4q12 Tri-Color Rearrangement Probe
Vysis LSI 4q12 Tri-Color Rearrangement Probe through Fluorescent In Situ Hybridization (FISH) test has been used to estimate the c-Kit gene expression aberrations /rearrangements among the five hepatic adenocarcinomas of cancer stem cell origin cases (CK19 +ve/c-Kit +ve /CK18 +ve /CD133 +ve cases).
from data analysis it has been found that the c-Kit amplification or aberrant gene patterns whether separate or combined together or combined with abnormal one tricolor gene expression are the most common aberration /rearrangement . This finding is coming with the strong and moderate immunohistochemistry expression of c-Kit and CD133 in those five hepatic adenocarcinomas of cancer stem cell origin cases (CK19 +ve/c-Kit +ve /CK18 +ve /CD133 +ve cases .
CONCLUSIONS
1) CK19 status alone cannot differentiate primary liver adencarcinomas from the metastatic however using a combination of c-Kit &CK19 can be used as a primary step to exclude the metastatic adenocarcinoma until proving it by metastatic work up .
2) Taking into consideration the CK19 score (specially scores 2,3 ) together with c-Kit positivity and patient history as well will significantly aid this differential diagnosis and can be used as an essential step to exclude the metastatic cases or rather more importantly to select the primary liver adenocarcinomas of progenitor cell origin and examine them for targeted therapy.
3) Clinical history and data are of high important guidance values .
4) The combined immunostaining with CK 18 , CK 19 & c-Kit (as stem cell marker) is useful for the characterization of PLC (primary liver carcinomas) (primary adenocarcinoma of hepatobiliary origin /intrahepatic cholangiocarcinomas). It helps to differentiate primary adenocarcinoma of hepatobiliary origin / intrahepatic cholangiocarcinoma from metastatic adenocarcinomas to liver .Combined positivity for both hepatocellular (CK18) and biliary (CK19) markers which supports the biphenotypic differentiation in these tumors.
5) The identification of tumorigenic liver CD 133 +ve CSCs could provide new insight into the primary liver tumorigenic process and possibly bear great therapeutic implications.
6) Not all the primary liver adencarcinomas of progenitor cell origin (CK19+ve/c-Kit +ve/ CK18 +ve ) express CD133 (ie; being as cancer stem cells CSCs) which makes their identification a goal for a targeted anti CD133 therapy.
7) Cases positive for CDD133,c-Kit (specially score 2-3), CK19(score 2-3)& CK18 all together is the targeted group for targeted therapy in which specific CSCs-targeted therapies which recognize only CSCs and not the normal stem cells which allowing avoiding the ‘wrong’ target.
8) HCC expressing CK19 , primary liver adenocarcinomas , cholangiocarcinomas and CHCs are different from pure hepatocellular carcinoma, as these tumors follow an aggressive clinical course, poor survival and rapid recurrence and accordingly this group should be identified and directed to selective type of therapy depending on targeting the cell of origin as these tumors could have different biological behavior and respond differently to therapy.
9) Hepatic adenocarcinomas of cancer stem cell origin cases (CK19 +ve/c-Kit +ve /CK18 +ve /CD133 +ve predominantly exhibited mixed variable abnormal pattern of the Vysis 4q12 Tri-Color Rearrangement Probe through using Florescent In Situ Hybridization (FISH)
10) Aberrant c-Kit gene amplification /rearrangement patterns by Florescent In Situ Hybridization (FISH) is one of the most common aberrations /rearrangements in hepatic adenocarcinomas of cancer stem cell origin cases (CK19 +ve /c-Kit +ve /CK18 +ve /CD133 +ve which comes with the strong and moderate immunohistochemistry expression of c-Kit and CD133 in those cases which makes it a target for targeted molecular therapies.
11) Florescent In Situ Hybridization (FISH) is an important tool for identification of genetic molecular aberrations of the gene 4q12 as well as for determination the molecular targets for targeted therapy .