Discussion
In certain cases of congenital fetal neck tumors, establishing a
definite prenatal diagnosis might be challenging or even impossible.
Despite all advances in imaging techniques available today it remains
challenging to delineate the underlying cause of such etiologically
heterogeneous tumors in utero. Both, the infant and physicians, as well
as the parents, will benefit from the most accurate clinical and, if
possible, molecular pathological classification of the etiology of the
tumor in order to be able to plan further interdisciplinary treatment.
If the final diagnosis in this case presented had been known earlier, a
number of therapeutic approaches could have been avoided.
During fetal life tumors of the neck tend to impair fetal swallowing,
often resulting in polyhydramnios.8 Another serious
thread potentially arises from local compression
phenomena.6 Lymphatic malformations of the fetal neck
with lymphangiomas constitute the most prevalent fetal neck
mass.1,2,4,8 In the last two decades there were a
number of attempts to classify these lesions according to their
etiological origin8,10, morphological
appearance5,10, histological
features5,7 or postnatal course.10All these different classifications can coexist and their
characteristics occur side by side. A common and generally accepted
classification of lymphatic malformations is merely based on
histological criteria. There are four distinct histological types of
lymphangiomas consisting of capillary or cavernous lymphangioma, cystic
hygroma and vasculolymphatic malformation.7 However,
Eivazi et al. stressed that this traditional histological classification
is obsolete as with increasing frequency, it has been shown, that
anterolateral lymphangiomas receive their growth stimuli by activating
missense mutations characterizing regional-located tumors in
PROS.10–12 Axt-Fliedner et al. mentioned, that
theories of origin of lymphatic malformations include the failure in
connection between the lymphatic and the venous system and that they
could be suitable to explain the origin of lymphangiomas
embryologically.5,8 However, they also emphasized,
that in cases with late presenting, regional-located, anterolateral
lymphangiomas, this theory has to be questioned.8 It
therefore might be that late-presenting lymphangiomas beyond 30 weeks of
pregnancy rather arise as a result of direct alteration in DNA from a
post-zygotic PIK3CA mutation.
Depending on time of post-zygotic cell division in embryogenesis, either
somatic or, even rarer, constitutional mutations are the
result.6,9,15 As one of the most frequent hot-spot
missense mutations, c.1633G>A;p.Glu545Lys was identified in
the helical domain of PIK3CA.6,16 Hot spot mutations,
activating, gain-of-function variants, show significantly elevated
biological and biochemical activities.14,16 These are
often associated with higher numbers of transformed cell foci suggesting
more rapid cell proliferation.17
In 2015, diagnostic criteria have been defined by Keppler-Noreuil et al.
to standardize entities, that originate from PIK3CA mutations, and to
simplify the diagnostic work-up.14 Accordingly, in the
present case, the regional-located and sporadic overgrowth of
predominantly lymphatic tissue of the fetal neck, already detected
prenatally and classified as a lymphangioma, combined with the molecular
biological detection of the somatic mutation in the PIK3CA gene with
low‐level mosaics, clearly point to the definitive diagnosis of a
disorder within the spectrum of PROS.
Due to their inexorable growth throughout all tissue layers, diagnosis
and treatment of lymphangiomas within PROS disorders is often
difficult.3,4,8 However, prenatal ultrasound remains
the primary diagnostic method of choice in the detection of congenital
tumors. Additional volume ultrasound, combined with color Doppler
interrogation, may act as an adjunct in establishing the most likely
diagnosis as it potentially provides valuable information regarding the
spatial relationship to surrounding cervical structures and general
extent of PROS disorders.19 The value of an additional
fetal MRI to accomplish the diagnostic work-up and to give further
essential information, particularly in unfavorable maternal conditions
(high Body-Mass-Index) and in complex fetal tumors with multiloculated
masses in a variety of affected anatomical regions has been highlighted
by a number of publications.8,19,20 Combined with
information from 3D volume ultrasound, it can increase the accuracy of
prenatal diagnosis including location, architecture of tissue, volume or
intracranial or thoracic spread.18,19
Histopathologically, in the present case, the cyst wall-coating cells
presented themselves without expression of D2-40, a lymphatic
endothelial marker, but showed clear CD31 expression, characterizing
blood vascular endothelial cells, so that the finding was classified
most likely as a cavernous hemangioma due to the complex histologic
pattern (Fig. 3). But considering the clinical aspects, a lymphangioma
should be assumed. The D2-40 negativity does not exclude a lymphangioma.
A distinct histological or immunohistochemical differentiation between a
lymphangioma and a hemangioma was not possible. Due to the histological
expression pattern (CD31+/D2-40−),
it is most likely, that endothelial cells harbor the PIK3CA
mutation.13,21
All case reports published so far highlight the complexity of prenatal
diagnosis of somatic mosaic mutations.9,18 In 2014,
Keppler-Noreuil et al. also defined testing eligibility criteria for
somatic PIK3CA mutations.17 Adequate tissue sampling
is already a challenge postnatally – and, above all, as a highly
invasive procedure, prenatally.17,18 Maybe cultured
amniocytes obtained by amniocentesis for prenatal diagnosis might be
promising and are less invasive.9,17,18
Using NGS, the sensitivity of genetic testing has improved significantly
and molecular diagnosis of somatic overgrowth has become
feasible.15–17 By now, mosaic levels can be detected
with a variant allele frequency (VAF) down to 1 %.16In the tissue received in this case from multiple biopsies, the
activating missense mutation-hotspot c.1633G>A;p.Glu545Lys
with low-grade somatic mosaic and a VAF of 6.5 % was detected. This is
one of the most frequent mutation hotspots in the PIK3CA gene, causing
somatic overgrowth in PROS. Only with the change from the pure
morphologic description of lymphangiomas to the recognition of their
molecular causes, they can be categorized into the spectrum of PROS
diseases.
The identification of a component of the PI3K-AKT-mTOR signaling pathway
can partly explain the effect of the mTOR-inhibitor Sirolimus, which
resulted temporarily in a minimal size reduction. The targeted
application of a PIK3-inhibitor could be more promising, even as a
serious alternative treatment to surgical debulking. Finally, obtaining
tissue for histopathological and molecular genetic examination to
confirm the definitive diagnosis is mandatory.18
From a therapeutic perspective, debulking procedures were the most
promising approaches yet.3–6,8,13 However, in the
future, a shift from surgical debulking to personalized, targeted
pharmacological intervention has been proposed.15,18Pharmacological therapy approaches are sclerosing therapy of fetal neck
lymphangiomas with Bleomycin or Picibanil (OK-432), maybe prenatal. In
addition, various molecule inhibitors, targeting different components of
the PI3K-AKT-mTOR signaling pathway, are under clinical investigation:
mTOR-inhibitors like Sirolimus (SRL or Rapamycin) or Everolimus
(RAD-001) and recently, PIK3-inhibitors like Alpelisib (BYL719). Due to
the increasing understanding of molecular biology of PROS disorders,
targeted therapies are highly promising and less invasive. Moreover, it
can improve quality of life of affected
patients.2,4–6,10,13,22
Despite all efforts, there is a high risk of
recurrence.4,10 Fetal prognosis of congenital tumors
of the neck depends largely on the nature of lesion, on their location
and size, the affected surrounding structures as well as the presence of
other anomalies.7,20