Discussion
APC somatic mutations are not generally found in sporadic MBL, but this
tumor may be associated with patients harboring the APC germline
pathogenic mutations that cause FAP syndrome17. APC
gene mutations generally start from a KRAS proto-oncogene point mutation
with DNA hypomethylation activating the proto-oncogene. This is followed
by a loss of the APC alleles that serve as a tumor suppressor gene. MBL
associated with FAP syndrome comes from neural stem cells containing the
homozygous APC mutation18.
MBL accounts for 80% of the brain tumors found in patients with FAP, a
condition associated with a 7-fold relative lifetime risk of any brain
tumor, and with a 90 times higher risk of MBL19.
The molecular subtype in the context of FAP is Wnt/Wg. APC mutations are
involved in around 7% of Wnt/Wg molecular subtype
MBL20-25. It is noticeable that in our series, some
cases despite APC germline mutations do not show nuclear β‐catenin
accumulation, but it must be underlined that there are some limits of
immunohistochemistry which make the technique not always reliable26-27.. These patients’ radiological features were
superimposable on those reported by Patay in the context of Wnt
molecular subgroup MBL14 and later confirmed by other
authors28. There are no guidelines for brain tumor
surveillance in the context of FAP, probably because there are still no
registries available to consult that reliably show how many people with
inherited or sporadic colorectal cancer develop MBL, or vice
versa29. In members of a family with FAP who do not
yet have polyposis, neurological symptoms should prompt radiological
examination of the CNS because brain tumors manifest before the
polyposis is diagnosed in more than one in two FAP
patients30. This was also the case in two of our six
patients. A major effort by the SIOP to move in this direction is in
progress as part of the PNET5 trial12, with the
creation of a registry for all patients with MBL harboring
constitutional genetic mutations, including APC.
What we are still lacking, however, is therapeutic guidelines that take
into account both the good outcomes reported in a handful of more recent
papers15 and the genetic fragility of these patients.
They spontaneously develop many different types of tumor and are
obviously more susceptible to secondary tumors after adjuvant treatment
for MBL. It is sadly remarkable that the only death of a patient, in the
series recently reported by a cooperative French
group15, was due to a triton tumor 14 years after MBL
had been diagnosed.
As already underlined, patients with Wnt-MBL are currently treated with
de-escalating protocols aiming at maintaining good outcome with reduced
late effects12-13. This FAP patient subgroup is even
more fragile, deserving special attention in their disease story. It is
moreover to note that a very recent paper has reported a meta-analysis
on Wnt -MBL relapses showing the usefulness of adjuvant cyclofosfamide
in reducing relapses31.
In our smaller but single-institution series, apart from desmoid and
thyroid tumors, three patients developed other three tumors possibly
unrelated to FAP, despite having received lower doses of CSI than the
French series, and standard chemotherapy.
Few data characterize the cognitive abilities of individuals with FAP
but the role of the APC protein in the development of the central
nervous system is well known32 and a very recent paper
has underlined the significantly lower performance on IQ and in a
variety of neurocognitive functions in a population of 24 subjects
compared to non-FAP pairs33. The results of our small
series in term of cognitive performances, FIQ and social life are
therefore not only to be attributed to MBL and its treatment but also to
the persasive activity of FAp 33
Collecting these now better-defined cases of MBL in patients with FAP
will broaden our understanding of their MBL outcome and hopefully enable
their better-tailored treatment and rehabilitation.
Disclosure statement . No relevant interest to be disclosed