Sabato 27 ottobre 2012 - Pacini Editore

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techniques have resulted in the current classification of renal
epithelial neoplasms as outlined in the 2004 World Health Organization
(WHO) monograph. The common renal cell carcinomas
of clear cell, papillary and chromophobe types, account
for 85–90% of the renal tubular malignancies encountered in
routine practice. The remaining 10–15% includes a variety of
uncommon sporadic and familial carcinomas, some of which
have been recently described, along with a group of unclassified
carcinomas. Selected uncommon, recently described and
emerging forms of renal cell carcinoma are discussed in the
current Literature, in particular the mucinous tubular spindlecell
carcinoma, tubulocystic carcinoma, translocation carcinoma,
carcinoma in neuroblastoma survivors, dialysis associated
carcinoma, oncocytic papillary renal cell carcinoma, clear cell
papillary renal cell carcinoma, clear cell renal carcinoma with
prominent leiomyomatous proliferation.
At a molecular diagnostic level, cytogenetic studies have
shown that 3p deletions are linked to clear cell RCC, occurring
in 40-70% of tumors with this histological subtype. LOH
analyses with matched pairs of RCC tumor/normal kidney
DNA have detected losses of 3p sequences in about 80% of
clear cell RCCs. A very high prevalence of 3p deletions (98%)
has been reported in DNA extracted from tumor cell lines
after culture. This discrepancy suggests that there may be
intratumoral heterogeneity of 3p deletions in RCCs. Previous
molecular studies demonstrated that at least three separate regions
are critical in the development of RCCs, one coincident
with the VHL disease gene on 3p25.5, one at 3p21-22, and
one at 3pl3-14. The VHL gene on 3p25.5 is the most likely
candidate for a clear cell renal tumor suppressor gene because
somatic VHL gene mutations were identified in about 50% of
RCCs. It seems likely that VHL inactivation occurs even more
fre quently because hypermethylation of the VHL promoter
region, yet another mechanism for gene inactivation, has been
observed in an additional 20% of RCCs. Thus it is assumed
that the inactivation of one or more genes on 3p plays a role
in RCC initiation. Aiming at a potential diagnostic application
of genetic analyses, the extent of genetic heterogeneity that
involves potential marker alterations is of importance. At light
of emerging renal tumours with a clear cell-like morphology
but characterized by lack of 3p abnormalities and VHL mutation,
the knowledge of the heterogeneity in small and larger
tumours and the impact of routine molecular techniques in the
diagnostic practice need to be evaluated and the magnitude of
this pitfall be seized.
At a prognostication level, several algorithms and nomograms
for RCC survival or recurrence after nephrectomy have
been developed that incorporate multiple clinicopathological
prognostic factors such as TNM stage, Fuhrman grade, tumor
size, performance status. Accumulation of genetic aberrations
plays a pivotal role in the initiation and prognosis of RCC and
other cancers. Integration of genetic markers into traditional
approaches may allow a more accurate prediction of prognosis.
Conventional cytogenetic and gene expression profiling
identified a number of chromosome aberrations in development
ccRCC. Several chromosomal abnormalities, such as
deletions of 8p, 9p, and 14q, have all been suggested to correlate
with worse stage and grade, but only a minority of studies
included survival as an end point. Previous studies suggest
that gain of chromosome 5q is associated with improved overall
survival and that losses of 8p and 9p chromosomal material
predict poorer recurrence-free survival. The ultimate goal of a
cytogenetic stratification is to improve post-operative clinical
risk-stratification systems via the incorporation of cytogenetic
data, which may help to personalize therapy and surveillance.
CONGRESSO aNNualE di aNatOmia patOlOGiCa SiapEC – iap • fiRENzE, 25-27 OttOBRE 2012
Moreover, recent Literature focused on models developed to
predict survival of RCC patients. Two mathematical models
including clinical variables only (Yaycioglu, cI 0.651; Cindolo,
cI 0.672); 2 algorithms including also pathological variables
(SSIGN, cI 0.819; UISS, cI 0.79-0.84), 5 nomograms
(Kattan, cI 0.76-0.86; Sorbellini, cI 0.82; Kim 2004, cI 0.79,
Kim 2005, cI 0.68; Karakiewicz, cI 0.86); 2 algorithms for
patients with metastatic disease (Motzer, Leibovich).
One of the most applicable prognostic score among the most
common clear cell renal cell carcinoma treated with radical
nephrectomy is the SSIGN score. The SSIGN (Size, Staging,
Grading, Necrosis) score allows clinicians to assess the effects
of tumor characteristics on outcome, which can be used to
improve treatment, and develop and assess adjuvant therapies
for renal cell carcinoma. Many of common models focus on
metastatic renal cell carcinoma only and divided patients according
to risk.
The SSIGN is the most accurate algorithm for clear cell RCC,
while the UISS allowed the evaluation of patients regardless
of tumor histotype. The Sorbellini nomogram is applicable
only for patients with clear cell RCC, while the Kattan and
Karakiewicz nomograms also provide information for other
histotypes. Metastatic patients can be evaluated with Leibovich
and Motzer algorithms. Two models combine molecular
markers and clinical features (Kim 2004-2005).
Overall, these models do not include cytogenetic abnormalities.
Only recently, loss of chromosome 9, can provide additional
prognostic information to standard clinicopathologic
variables. Genetic information can provide important prognostic
information that augments standard clinicopathologic
analysis. The magnitude of this prognostic information has to
be validated.
Finally, at a molecular target level, there is substantial
evidence of an association between mutation on von Hippel-
Lindau (VHL) gene and the earliest stages of tumorigenesis
of RCC. The main consequence of VHL loss is the upregulation
of downstream proangiogenic factors leading to highly
vascular tumors. Overexpression of hypoxia inducible factor
(HIF) is also caused by the mammalian target of rapamycin
(mTOR), a key component of signaling pathways inside the
cell, involved in cell proliferation. The inhibition of proangiogenic
factors and mTOR was the main idea behind the
development of new targeted agents in advanced RCC. Since
December 2005, 3 targeted agents have been approved by the
U.S. Food and Drug Administration (FDA) for the treatment
of advanced RCC: sorafenib, sunitinib and temsirolimus. Sorafenib
and sunitinib are synthetic, orally active agents shown
to directly inhibit vascular endothelial growth factor receptors
-2 and -3 (VEGFR-2, VEGFR-3) and platelet-derived growth
factor receptor beta (PDGFR-beta), while temsirolimus is an
mTOR inhibitor.
MGMT evaluation in patientes whit glioblastoma
and high grade glioma
F. Castiglione1 , A.M. Buccoliero2 , I. Aguzzi3 , D. Moncini1
, M. Panfili3 , P. Pretelli1 , B. Detti, G. Peruzzi1 , G. Rossi
Degl’Innocenti1 , G.L. Taddei1 1 Università di Firenze Dipartimento di Area Critica Medico- Chirurgica.
Sezione di Anatomia Patologica; 2 Azienda Ospedaliro, Universitaria
Meyer; 3 Quiagen Italia
Introduction. Glioblastoma is the most common and most
aggressive brain tumor that had an average survival of an
year from the diagnosis. Standard therapy consists in sur-