Prenatal Sonographic Findings of Extensive Low-Flow Mixed Lymphatic and Venous Malformations

Prenatal sonographic diagnoses of subcutaneous soft tissue masses include hemangiomas, malformations (capillary, lymphatic, venous, arterial, or mixed), teratomas, and, rarely, sarcomas.1–5 Prenatally depicted malformations may be seen in association with more complex fetal conditions, including Klippel-Trenaunay-Weber (angio-osteohypertrophy) and Proteus syndromes.6–9 We present an unusual case in which extensive multiple soft tissue tumors encompassing the fetal upper chest, back, nuchal area, and bilateral axillae, considered consistent with multiple large lymphatic malformations noted at 23 weeks' gestation, decreased in size throughout the remainder of gestation. At delivery, relatively small subcutaneous masses remained. Tissue histopathologic findings obtained at biopsy and the neonate's clinical course during which the subcutaneous masses underwent a marked spontaneous decrease in size, were consistent with low-flow mixed lymphatic and venous malformations. A 29-year-old patient, gravida 3, para 2, was followed during her third pregnancy at the State University of New York Downstate Medical Center. Her medical and obstetric histories were unremarkable, and her current pregnancy was uneventful. Results of second-trimester serum screening for aneuploidy was negative. Sonography at 23 weeks' gestation depicted a singleton vertex-presenting female fetus with normal-appearing fetal anatomy other than extensive multiple semicystic, semisolid subcutaneous masses located on the entire upper anterior chest wall, both axillae, back, and nuchal areas (Figures 1– 23). Minimal vascularity was depicted on color Doppler imaging. The estimated fetal weight was 700 g (80th percentile for gestational age). Sagittal view of the right anterior chest wall (fetal head is to the right). Note the semicystic, semisolid mass located on the anterior chest wall measuring 5.5 × 4.3 cm (calipers). The subcutaneous soft tissue masses were considered consistent with lymphatic malformations. Given the extensive nature, location (upper chest, back, neck, and bilateral axillae), and potential for marked disfigurement, the patient was counseled and offered termination but elected to continue the pregnancy. Amniocentesis revealed a normal 46,XX karyotype. Because of the concern for potential nonimmune hydrops in association with the extensive lymphatic mal-formations, the patient was followed with additional sonographic examinations at 2-week intervals and later with weekly nonstress fetal heart rate testing.10,11 With advancing gestational age, a gradual decrease in the size of the subcutaneous masses was noted. At 37 weeks' gestation, after documentation of fetal lung maturity, the patient underwent elective cesarean delivery of a female neonate weighing 3185 g with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. Umbilical artery blood gas values were normal (pH, 7.3; PO2, 19 mm Hg; PCO2, 56 mm Hg; and base deficit, 0.1 mEq/L). Axial view of the fetal thorax at the level of the 4-chamber view of the fetal heart. Note cystic and semicystic, semisolid masses in left and right axillae, respectively (arrows). Findings from physical examination of the neonate were normal other than multiple subcutaneous nodules on her upper and mid back, anterior chest, and right axilla measuring between 1 and 10 cm. The nodules were soft, mobile, and flesh colored, although 1 nodule located on the right superior chest was bluish purple and scarred (Figure 4). Inferior to this lesion was a pink, irregularly shaped port wine stain with extension to the right axilla (Figure 5). Areas of redundant skin folds were evident and considered consistent with the in utero regression of the original tumor (Figure 5). The fetal back had large, soft subcutaneous tumors (Figure 6). None of the lesions were pulsatile or emitted bruits, and no dysmorphic features were noted. Complete blood count, serum electrolyte, blood urea nitrogen, and creatinine values were normal. Findings from chest radiography, a skeletal survey, electrocardiography, head computed tomography and sonography, and abdominal sonography were also normal. Chest magnetic resonance imaging with contrast, showing normal visceral structures and multiple subcutaneous masses with a high signal on T2-weighted imaging and a low signal on T1-weighted imaging, was consistent with lymphatic malformations. Histopathologic examination of a biopsy consisting of a 1 × 0.7 × 0.6-cm, tan-red, lobular, cystic structure showed attenuated endothelial cells lining large cystic spaces, which stained positively for the panendothelial marker von Willebrand factor and negatively for D2-40, a specific antibody for lymphatic endothelium. The soft tissue surrounding the cystic spaces revealed lymphatic and venous channels that were abnormal in density and configuration, with positive immunohistochemical staining for D2-40. The neonate was discharged in good health and followed in the outpatient dermatology clinic. An upper respiratory infection was associated with transient enlargement of a number of the lesions in the nuchal region. At 12 months of age, the lesions had a marked spontaneous decrease in size. The multiple subcutaneous masses, histopathologic findings, and subsequent clinical course with a marked spontaneous decrease in size throughout the first year of life were consistent with low-flow mixed lymphatic and venous malformations. Vascular anomalies are divided into 2 major categories: vascular tumors such as hemangiomas, which show a proliferative endothelium, and vascular malformations, which are characterized by a normal nonproliferative endothelium and are caused by developmental errors, leading to the formation of anomalous vascular channels.12,13 Vascular malformations are further defined by their type of anomalous channel (capillary, venous, lymphatic, or arterial) and flow characteristics. All fast-flow malformations have an arterial component, whereas slow-flow malformations are of capillary, lymphatic, or venous composition. Malformations may be pure, composed of only 1 type of anomalous channel, or complex with 2 or more anomalous channels depicted. The overall incidence of congenital vascular malformations ranges between 1.2% and 1.5%.14–17 Approximately two thirds of congenital vascular malformations are predominately venous, and one fourth of these lesions are completely or partially of lymphatic origin and called low- or slow-flow malformations.14 The lesions range in size from small to extensive.14 Lymphatic malformations consist of fluid-filled lymphatic spaces that are either microcystic or macrocystic. Macrocystic lesions appear as large, soft, translucent masses under normal or bluish skin. Microcystic lesions are small vesicles also referred to as lymphangioma circumscriptum. Both types of lesions may occur in a single individual. In 70% to 80% of cases, they are located in the head-neck region. Less common locations include the axillae, thorax, and extremities. Axial view of the semicystic, semisolid mass in the right axilla measuring 3.5 × 2.5 cm (calipers). Lymphatic malformations may frequently include a venous component.18 This is best explained by the close relationship between the lymphatic and venous systems during embryologic development. Recent studies favor the theory that superficial lymphatic vessels, derived from mesenchymal lymphocytes, develop independently from the deep lymphatic vessels, which are thought to sprout from veins.19,20 Rarely, lymphatic malformations, especially those with a venous component, have been found to show spontaneous resolution, estimated at a rate of 3%.19,21,22 It is thought that this resolution may be due to the establishment of venous lymphatic shunts or may represent collapse of engorged cystic spaces and vessels as opposed to a true involution (characterized by cell apoptosis and death), as is seen with hemangiomas. This is supported by the observation in our patient that clinically many of the lesions of the neck, chest, axillae, and upper back appeared to have resolved by 1 year of age. Interestingly, after an upper respiratory infection, a number of the lesions, especially in the nuchal region, showed transient enlargement. This observation is consistent with numerous reports of acute enlargement of lymphatic malformations in association with systemic viral or bacterial illness.18,21 Anterior view of the neonatal chest on day 2 of life. Note the subcutaneous bluish purple vascular lesion protruding from the right anterior chest superior and immediately lateral to the right nipple. Note the vertical fibrous tissue strands separating the vascular areas. Lateral view of the anterior chest wall mass and right axilla on day 2 of life. Note the abundant redundant skin folds in the right axilla, lateral to the vascular mass. Also note the port wine stain lesion. Posterior view of the neonatal back on day 2 of life. Complex lymphatic vascular malformations pose a diagnostic challenge both clinically and histologically. D2-40, a monoclonal antibody specific for lymphatic endothelium, was used to define the composition of our patient's malformations. The biopsy specimen showed abnormally dilated D2-40-positive lymphatic spaces in the soft tissue surrounding the centrally dilated space; however, the latter was D2-40-negative. Grossly dilated lymphatic spaces such as those seen in our patient often show only a focal or negative immunoreaction. Despite its high specificity, the sensitivity of D2-40 has been found to be decreased in large cystic dilated lymphatic spaces.23 Routine application of prenatal sonography has resulted in increased diagnosis of congenital vascular anomalies. Notwithstanding, prenatal diagnosis of lymphatic malformations has been complicated by confusing and outdated terminology. Historically, lymphatic malformations have been referred to as lymphangiomas, yet this term is inadequate because these lesions are not true neoplasms and do not show endothelial hyperplasia.15,19,21 These lesions do contain a population of nonproliferative, flattened endothelial cells.14,23 Low-flow complex lymphatic venous malformations may be found as part of several syndromes, including Proteus syndrome and, uncommonly, as part of blue rubber bleb nevus syndrome and Maffucci syndrome.9,14,24 The latter two syndromes are primarily venous malformation syndromes. Klippel-Trenauney syndrome presents with capillary malformations but is associated with pure lymphatic malformations with or without lymphedema.6,7,14 The extensive distribution of the subcutaneous malformations in our patient raised the possibility of Proteus syndrome, following that lymphatic venous malformations are the most common types of vascular lesions in this condition.9 In addition, port wine stains as seen in our patient have also been reported. However, Proteus syndrome is characteristically progressive and not regressive, as was the clinical course of our case.9 A systematic English language literature search (PubMed and MEDLINE) of articles published between 1966 and 2006 using the search terms “vascular,” “malformation,” “soft tissue tumor,” “low-flow,” “mixed venous and lymphatic,” and “ultrasound” indicated that the prenatal sonographic findings of low-flow mixed venous and lymphatic malformations have not been reported previously.