pag. 216-318 - Siapec

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COMUNICAZIONI E POSTER
Tab. I. Prevalenza di lesioni esofagee e/o gastriche in pazienti con MIG ed in controlli.
Lesioni associate Prevalenza in casi con MIG Prevalenza in casi senza MIG p
Lesioni esofagee 46,1% (42/91) 34,8% (137/394) 0,053
Lesioni gastriche 13,2% (12/91) 17,2% (68/394) 0,93
Lesioni esofagee + gastriche 36,3% (33/91) 23,9% (94/394) 0,017
Esofago e stomaco normali 4,4% (4/91) 24,1% (95/394) < 0,0001
APC promoter methylation and 5q21
deletions are peculiar to gastric and
duodenal endocrine tumours
S. Pizzi, C. Azzoni, L. Bottarelli, T. D’Adda, C. Pasquali
* , G. Rindi, C. Bordi
Dipartimento di Patologia e Medicina di Laboratorio, Sezione
Anatomia Patologica, Università di Parma, Parma, Italia;
*
Dipartimento di Scienze Mediche e Chirurgiche, Semeiotica
Chirurgica, Università di Padova, Padova, Italia
Background
The role of the Wnt pathway in the pathogenesis of digestive
endocrine tumors is still under debate. Mutations of β-catenin
and E-cadherin have been found in gastrointestinal carcinoids,
but not in pancreatic endocrine tumours (PETs), and generally
very rare APC (adenomatous poliposis coli) mutations have
been detected. The aim of the present work was to systematically
investigate alterations (deletion and/or promoter methylation)
of the APC locus in a series of gastroenteropancreatic endocrine
neoplasms, with special emphasis to the site of origin,
the level of differentiation and the clinical behaviour.
Methods
Sixty cases were analyzed including 38 foregut (stomach,
n = 24; pancreas, n = 10; duodenum, n = 4), 14 midgut
(ileum-caecum, n = 8; appendix, n = 6) and 8 hindgut
(large bowel, n = 4; rectum, n = 4) tumours. According to
the WHO classification, the neoplasms were further subdivided
in three categories: poorly differentiated endocrine
carcinomas (PDECs, n = 11), well differentiated endocrine
carcinomas (WDECs, n = 27) and well differentiated endocrine
tumours (WDETs, n = 22). Deletions at APC locus
at 5q21 were detected by loss of heterozygosity (LOH)
analysis using the microsatellite marker D5S346. The
methylation status of APC promoter was analyzed by
methylation-specific PCR.
Results
APC promoter methylation was found in 30% of cases and
was restricted to foregut tumours (58%, P < 0.0001), independently
of the behaviour or the differentiation. Among
foregut neoplasms methylation was striking more frequent
in the stomach and duodenum (75%) than in pancreas
(11%, P < 0.01). LOH at APC locus was found in 37% of
cases, in particular in tumours from the stomach (36%),
duodenum (50%), colon (100%) and rectum (25%), but was
absent in pancreas, ileum and appendix. Indeed, 5q21 LOH
was more frequently detected in PDECs, from both the
stomach (83% of cases) and the colon (100% of cases) than
in well differentiated neoplasms, either benign or malignant
(P < 0.01).
Conclusions
Inactivation of the Wnt pathway has previously been shown
to represent a frequent and early event in gastrointestinal, but
not in pancreatic, endocrine neoplasms, on the basis of immunohistochemical
and mutational studies on β-catenin. Our
data are in agreement with this observation and indicate APC
methylation as a major mechanism for Wnt pathway inactivation
in gastric and duodenal endocrine tumours.
Differential involvement of the p16-Rb
pathway and alterations of the CDKN2 locus
in gastroenteropancreatic endocrine
tumours
S. Pizzi, C. Azzoni, L. Bottarelli, N. Campanini, T. D’Adda,
G. Rindi, C. Bordi
Dipartimento di Patologia e Medicina di Laboratorio, Sezione
Anatomia Patologica, Università di Parma, Parma, Italia
Background
Alterations of the p16-Rb pathway appear to be implicated in
the pathogenesis of gastroenteropancreatic (GEP) endocrine
tumours. Previous data from our laboratory indicate that loss
of p16 and/or Rb expression are frequent events in gastrointestinal
endocrine carcinomas, either well (WDECs) or poorly
differentiated (PDECs) 1 . The aim of the present work is to
further analyze the expression of p16, Rb and cyclinD1 and
the related alterations at the 9p21 CDKN2 locus (harbouring
the p16, p15 and p14 genes) in different subtypes of GEP endocrine
tumours, subdivided according to the site of origin,
the biological behaviour and the level of differentiation.
Methods
Sixty cases were analyzed including 38 foregut (stomach, n
= 24; pancreas, n = 10; duodenum, n = 4), 14 midgut (ileumcaecum,
n = 8; appendix, n = 6) and 8 hindgut (large bowel,
n = 4; rectum, n = 4) tumours. According to the WHO classification,
neoplasms were further subdivided in 11 PDECs, 27
WDECs and 22 well differentiated endocrine tumours
(WDETs). The p16, Rb, cyclinD1 proteins were analyzed by
immunohistochemisty (IHC). Deletions at CDKN2 locus
were detected by loss of heterozygosity (LOH) analysis using
two 9p21 microsatellite markers (D9S157, D9S171). The
promoter status of p16, p15 and p14 genes was analyzed by
methylation-specific PCR.
Results
Loss of p16 and Rb expression and hyperexpression of cyclinD1
were found in 37%, 58% and 53% of cases, respectively.
Significant differences were found between PDECs
(characterized by absence of both p16 loss and cyclinD1 accumulation)
and well differentiated neoplasms (P < 0.01).
Moreover among well differentiated tumours, the pattern of
expression of the three proteins varied according to the sites
of origin. LOH at 9p21 was frequently (> 75% of cases)
found only in PDECs and in well differentiated gastric neoplasms,
either WDETs or WDECs. Promoter methylation at