|
HEPATOBILIOPANCREATIC DISEASES AND MULTITUMORAL
SYNDROMES (P.I. Francesco Cetta) |
|
1)Morphologic
and genetic analysis of non virus- and/or cirrhosis-related primary liver
tumors.
Background and Aims. The vast majority of
primary liver cancers develop in cirrhotic livers and are usually
associated with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or both
(1). Nevertheless, a small percentage (10-20%) of primary liver tumors
occur in the absence of viral infection and/or overt cirrhosis (1,2). In
particular, these neoplasms may develop in young people «3» (less than 40
years old) and even in the pediatric age (4). In the latter case HB is the
most frequent one but also HCC may occur. The aim of the present research
has been to study Hepatocellular Carcinoma (HCC) and Hepatoblastoma (HB)
in different settings. Both may in fact occur either as a part of an
inherited multitumoral syndrome «Familial Adenomatous Polyposis (FAP),
Beckwith-Wiedemann Syndrome (BWS)» or as «sporadic» tumors. Particularly,
both morphological and genetic analysis have been performed. Methods. The
less frequent «non virus-related primary liver tumors» were compared with
the more frequent «cirrhosis-associated liver tumors» in order to see what
is different and what is common between these two types of tumors. HBs and
HCCs were also studied in two different «settings» (genetically–induced
and sporadic) to detect whether they have some carcinogenetic steps which
are common or they follow different carcinogenetic pathways. In fact, rare
inherited diseases can give the clue for a better knowledge of the
pathogenesis of the more common sporadic counterpart. Between 1994 and
1999, 49 patients (39 M and 10 F) had preoperative diagnosis of single HCC
larger than 4 cm not associated with a preoperative diagnosis of cirrhosis,
whereas 145 patients had HCCs (single or multiple) associated with evident
cirrhosis. All patients underwent complete removal of their tumors.
Results. HCCs involved the right lobe in 44 of the 49 patients of the
former group (88.2%), but only in 66 of 104 patients of the latter group,
who had segmental liver resection (excluding “wedge resection”) (63,4%) (p
= 0,001). In the former group tumors were almost always capsulated and
well differentiated and satellite nodules were present in only 4 of the 49
patients. In particular, 17 of the 49 patients (34%) despite large size (9
of them were >5 cm in size, range 5.5 to 20 cm) had neither macroscopic
nor microscopic involvement of the portal vein. 15 of 17 tumors had a
complete capsule. Only 19 of the 49 were positive for HBV or HCV infection
vs 105 of 112 patients with evident cirrhosis, who had this analysis (p <
0,001). Ten of 49, but only one of the 17 without portal vein involvement,
had recurrence 6 months to 5 years after surgery. Conclusions. We think
that this clinical, morphological and molecular approach to the study of
primary liver neoplasms could be useful to select new cancer screening
programs and give a better insight into the knowledge of carcinogenetic
processes in the liver tissue.
|
|
2)
Primary
liver tumors in patients with Familial Adenomatous Polyposis.
INTRODUCTION: Germline
mutations of the Adenomatous Polyposis Coli (APC) gene, the earliest
genetic alterations in Familial Adenomatous Polyposis (FAP), can
predispose to a wide range of primary liver tumors such as hepatoblastoma
(HB), hepatocellular adenoma (HA), hepatocellular and fibrolamellar
carcinoma (HCC, FLC). AIMS OF THE RESEARCH: The specific aims of the
present study have been: 1) to evaluate genotype-phenotype correlation in
FAP patients with liver tumors; 2) to determine whether germline APC
mutations are scattered throughout the entire gene or tend to cluster in a
defined genomic area; 3) to evaluate cooperation among genes and tissue
specific cooperation; 4) to detect loss of heterozigosity (LOH) for APC
and p53 mutations in the liver tumoral tissue. PATIENTS AND METHODS: As a
part of a larger European project we have collected 102 patients (pts)
with primary liver tumors. The following pts had already some types of
genetic analysis: 16 pts with FAP associated HB, 4 with sporadic HB and 18
with primary liver tumors other than HB. Genetic analysis included: 1)
analysis of germline and somatic mutation of the APC gene; 2) detection of
p53 mutations; 3) detection of ret/PTC activation. RESULTS: All pts with
FAP associated HB had their mutations out of the mutation cluster region (MCR,
codons 1286-1513). Ten pts had their mutation in the genomic area (codons
463-1387) that is usually associated with congenital hypertrophy of the
retinal pigment epithelium (CHRPE). On the contrary, pts with HA and HCC
or FLC had mutations 3’ to codon 1444, in association with desmoids. Three
kindreds with germline mutation at codon 1061, in addition to HB, also had
papillary thyroid carcinoma (PTC) in one member of the kindred. Fifteen
pts with FAP associated PTC had germline APC mutations in exon 15, in the
CHRPE genomic area. The wild type allele was never lost in 6 out of 6 FAP
associated PTC. Four out of 5 pts had ret-PTC activation. On the contrary
a LOH was observed in one patient with FAP associated HB. Interestingly, a
p53 mutation at codon 175 was found in the child with HA. Three of the 4
pts with sporadic HB showed somatic mutations in the APC gene.
CONCLUSIONS: Mutations around codon 1061 are more related with HB, PTC and
CHRPE whereas mutations located in the desmoid associated area 3’ to codon
1444 could be more frequently associated with primary liver tumors other
than HB. p53 overexpression may be involved in tumor progression,
determining the dedifferentiation and the proliferative activity of HCC.
APC gene is involved in the tumorigenesis of sporadic HB and some pts with
sporadic HBs are index cases of undiagnosed FAP.
|
|
|
|
|
|
|
|