Introduction
Congenital fetal neck tumors constitute exceedingly rare antenatal conditions. Prenatal diagnosis is usually straightforward by detailed sonographic examination. According to current literature these lesions are categorized into different types.1–3 The most frequently described subtypes of neck tumors comprise lymphangiomas, followed by teratomas and hemangiomas.1 However, the exact incidence of lymphangiomas remains unclear. It considerably varies whether pre- or postnatal cohorts are analyzed. Prenatal data suggest an estimated incidence of up to 1 in 1,000 live births.2,4,5
Although lymphangiomas are non-malignant vascular malformations of the lymphatic system and histologically mostly benign, extensive and heterogeneous tumor masses may compress vital cervical structures, so the final prognosis has been reported to be poor.1,2,6,7
The clinical course of lymphangiomas is related to the type of lymphatic malformation and varies from a mild symptomatic that tends to regress spontaneously to an aggressively invasive growth into surrounding vital structures.5 Spontaneous regression in the latter cases is unlikely, but possible.4,8 By compressing phenomena, polyhydramnios or airway obstruction can occur, a potentially life-threatening event.5,6,8,9
Lymphatic malformations like lymphangiomas usually arise from the defective embryological development of primordial lymphatic structures.3,8,10 Recent data revealed that lymphangiomas receive their growth stimuli by activating missense mutations characterizing regional-located tumors in PIK3CA-Related Overgrowth Spectrum (PROS).9,11–13
PROS encompasses a group of disorders that are predominantly characterized by benign segmental overgrowth of several tissues with vascular and lymphatic malformations. Caused by heterozygous, mostly somatic mosaic-like pathogenic variants in the PIK3CA gene that arise post-zygotically, affected patients may present with regional-located or multiple-located findings.6,9,14,15 The clinical picture strongly depends on the embryonic stage in which the causative mutation occurred, as well as the tissue type affected by this mutation.15 Specific somatic activating mutations in the phosphatidylinositol-3-kinase/AKT/mTOR (PI3K-AKT-mTOR) pathway lead to heterogeneous segmental overgrowth phenotypes.14The PIK3CA gene encodes the 110 kD catalytic alpha subunit (p110α) of the PI3K protein complex, a lipid kinase of the PI3K-AKT-mTOR pathway, a signaling pathway, which is crucially involved in the regulation of cell proliferation, metabolism and survival as well as in angiogenesis. Hence, PI3K plays a key role in cell growth and division, cell migration and survival.6,9,16 An altered activity of PI3K leads to uncontrolled cell division and as somatic mosaics, these mutations may trigger the development of overgrowth syndromes with segmental growth of several tissues with venous as well as lymphatic malformations to varying degrees.6,9,13,16
Over the past years, cancer associated PIK3CA mutations have been also reported to be responsible for a wide range of clinical benign overgrowth disorders.6,17 Recent insights emphasize the topicality of PROS disorders.9,13,18
Lymphangiomas, developed regionally located in the context of PROS, are scarcely mentioned in the literature and informative case reports are almost completely missing. While the acronym PROS is an umbrella term for various clinical entities, even those entities itself, like lymphangiomas, can morphologically resemble as a chameleon.14
In the present report the prenatal and postnatal course of a fetus suffering from a huge cervical lymphangioma within the PROS will be delineated. We discuss the clinical picture to what is known from current literature and focus on the targeted multidisciplinary approach to establish the final confirmation of an activating missense mutation-hotspot c.1633G>A;p.Glu545Lys identified by next generation sequencing.