Issue 4 - August 2010 - Pacini Editore

142
line LS mutation had a higher FIGO grade and more frequent
vascular invasion than their sporadic counterparts. In our series
we also identified 2 cases of Malignant Mixed Mullerian
Tumor in 2 MSH2-mutated sisters, a finding that has also been
recently reported in a MLH1-mutated patient
Regarding the FIGO grade, 46.1% of the LS women with
EECA in our study had a grade III tumor, a frequency appreciably
higher than that seen in the control group.
As far as the FIGO Stage is concerned, Boks et al. and Broaddus
et al. had commented on the relatively high number of
Stage III tumors they found in their series of LS-related EC,
especially in view of the relatively young age of the patients;
regrettably, no information was provided on the stage distribution
according to histologic type. In our group of patients,
the tumor stage distribution at presentation of both EECA and
N-EECA paralleled those observed in their sporadic counterparts,
with the majority of EECA presenting at stage I and
most N-EECA (with or without an endometrioid component)
presenting at higher stages.
The overall survival of our patients at the end of the followup
was lower than that reported in previous studies and was
strongly influenced by histologic type and tumor stage, as
shown by the fact that 4 of the 5 patients who died of EC had
a N-EECA. By contrast, the EECA were characterized by
a uniformly favourable outcome, with only a tumor-related
death in a 67-year-old woman who had a grade III, stage IIB
tumor.
LS associated ovarian carcinomas account for 10-15% of
hereditary ovarian carcinomas. Histologically, they tend to be
more frequently of endometrioid and clear cell types. Findings
from a study by Crijnen et al. on 26 patients with LS associated
ovarian cancer showed that the survival rate for ovarian
cancer was not significantly different between these patients
and controls with sporadic ovarian cancer.
references
Boks DE, Trujillo AP, Voogd AC, et al. Survival analysis of endometrial
carcinoma associated with hereditary nonpolyposis colorectal cancer.
Int J Cancer 2002;102:198-200.
Broaddus RR, Lynch HT, Chen LM, et al. Pathologic features of endometrial
carcinoma associated with HNPCC: a comparison with sporadic
endometrial carcinoma. Cancer 2006;106:87-94.
Carcangiu ML, Radice P, Casalini P, et al. Lynch syndrome--related
endometrial carcinomas show a high frequency of non-endometrioid
types and of high FIGO grade endometrioid types. Int J Surg Pathol
2010;18:21-6.
Crijnen ThEM, Janssen-Heijnen MLG, Gelderblom H, et al. Survival of
patients with ovarian cancer due to a mismatch repair defect. Fam
Cancer 2005;4:301-305.
Lynch HT, Casey MJ, Snyder CL, et al. Hereditary ovarian carcinoma:
heterogeneity, molecular genetics, pathology, and management. Mol
Oncol 2009;3:97-137.
Molecular and immunohistochemical features
of endometrial carcinoma in HNPCC/lS
C. Riva
Dept of Human Morphology, University of Insubria, Varese
Endometrial carcinoma (EC) is the most common extracolonic
neoplasia in HNPCC/Lynch Syndrome (LS) patients.
Men with LS have a 74% lifetime risk of colorectal cancer
(CRC), in women the risk is over 30%, but more than 40% to
50% will develop EC.
LS is characterized by germline mutations of DNA MMR
genes. The MMR system repairs DNA replications errors
that are not immediately corrected by DNA polymerase and,
therefore, it plays a crucial role in DNA replication accuracy.
5 th triennial congress of the italian society of anatomic Pathology and diagnostic cytoPathology
Human (h) MMR genes and corresponding proteins include
hMSH2, hMSH6, hMLH1, and hPMS2.
Functional inactivation of MMR genes by mutations or epigenetic
changes leads to the accumulation of insertions/deletions.
These are easily identified in short DNA tandem repeat
sequences (microsatellites) and this phenotype is known
as microsatellites instability (MSI). MSI can be present in
tumors from LS patients but it is also observed in a fraction
(15-25%) of various sporadic neoplasms, including EC.
Among germline mutations are recognized 1) truncating mutations
leading either to a loss or to a easily degradable protein
and allowing to a negative immunohistochemical (IHC) staining
of MMR protein and 2) missense point mutations leading
to an amino acid substitution, affecting chemical stability or
functionality; in point mutations often MMR protein is still
immunoreactive and atypical clinical scenarios are observed.
Analysis for germline mutations in MMR genes is confirmatory
for LS diagnosis. Mutational analysis is very expensive
and time consuming, therefore pre-selection of high risk
patients for mutation search is very important. This purpose
can be achieved by employing MSI tumor DNA analysis (by
PCR), IHC for 4 MMR proteins (hMLH1, hMSH2, hMSH6
and PMS2) and methylation assays.
An epigenetic (sporadic) cause of MSI is more common than
LS. Most of sporadic MSI CRCs and ECs arise via hMLH1
promoter methylation, therefore methylation analysis seems
useful to distinguish between sporadic and heritable cases.
MSI analysis is performed using the NCI panel of 5 PCR
microsatellite markers (BAT-25, BAT-26, D2S123, D5S346
and D17S250). Tumors are classified as MSI-H (two or more
markers show MSI), MSI-L (one marker shows MSI) and
MSS (none marker shows MSI). Not all LS associated ECs are
MSI-H, while most MSI-H ECs are sporadic tumors, therefore
MSI analysis may fail to detect a number of ECs arising in a
hereditary setting.
DNA-MMR protein IHC is an effective method to detect MSI
and it is useful as a screening of LS. Infact MLH1, MSH2,
MSH6 and PMS2 are lacking in tumor cell nuclei by IHC in
up 1/3 of ECs; this derives in most cases from MLH1 promoter
ipermethylation, while mutations accounts for the rest. IHC
interpretation can be problematic: in general only a complete
loss of expression in the setting af a positive internal control
(endometrial stroma, normal glands, lymphocytes, etc) seems
to be reliable. In rare cases with inconclusive IHC results and a
clinical LS suspicion, an alternative test should be performed.
IHC with MLH1, MSH2 and MSH6 antibodies shows an high
sensitivity (91%) and a specificity of only 83%, due to lack of
correlation between loss of MSH6 and MSI-H. In fact LS-associated
EC is fivefold more frequently associated with MSH6
mutations compared to CRC and these mutations usually do
not leave to MSI-H. The positive predictive value of IHC for
detect a germline mutation, especially with absence of MSH2
and MSH6 is very high.Therefore it has been suggested that
IHC loss of these proteins may be a sufficient evidence of LS.
On the other hand, IHC can be easy performed in the majority
of pathology laboratories, is a convenient test and, in addition,
it can address specific genes sequencing.
Since LS detection methods cannot be applied routinely to every
EC, various screening algorithms have been proposed. In
particular some data suggest the application of IHC for DNA
MMR proteins in ECs patients with strong personal or family
history, age of onset less than 50 years, lower uterine segment
localisation, a synchronous ovarian clear cell carcinoma and,
finally, morphological features characterized by peritumoral
or tumor infiltrating lymphocytes and tumor heterogeneity
including dedifferentiated areas.