Cystic hygroma and lymphangioma are older commonly used terms for a specific type of vascular malformation.
Most often seen in the soft tissue of the neck, axilla, thorax, and lower extremities.
Different prenatal natural history if diagnosed in the first trimester versus the third.
Lymphangiomas presenting in the third trimester usually seen in the anterior or anterolateral neck are not usually associated with other anomalies or hydrops.
Lymphatic vascular malformations consisting of cysts separated by fine septa.
While the mortality of lymphatic vascular malformations prior to 30 weeks’ gestation is high, due to hydrops and karyotype abnormalities, those presenting later have an excellent prognosis.
Cervical lymphangiomas are at risk for airway compromise, and an EXIT procedure should be considered if there is evidence of airway compression or displacement.
Traditionally referred to as lymphangioma or if in the neck cystic hygroma, these are currently considered a form of vascular malformation of the lymphatic system characterized by localized or diffuse malformations of lymphatic channels that can be characterized as microcystic, macrocystic, or both (Christison and Fishman, 2006).
Lymphangioma is a benign type of vascular malformation composed predominantly of dilated cystic lymphatics (Isaacs, 1997). These malformations are often present at birth and are second only to hemangioma as a cause of soft tissue mass in the newborn (Potter and Craig, 1975; Isaacs, 1983, 1991, 1997). Lymphangiomas can occur in almost any location but are most commonly seen in the soft tissue of the neck, axilla, thorax, and lower extremities (Isaacs, 1997). Isaacs reported a series of 97 consecutive lymphangiomas seen at Children’s Hospital of Los Angeles in which 45 occurred in the neck, 22 in the chest wall, 12 in the extremities, and 4 in the abdominal wall. Other less common sites included the omentum, mesentery, larynx, tongue, bowel, retroperitoneum, mediastinum, conjunctiva, and mouth (Isaacs, 1991). These lesions can vary in size from tiny subepidermal skin blebs to large dilated cystic fluid filled– masses that, when presenting in the neck, are commonly referred to as cystic hygromas.
There is a disparity between lymphangiomas that are diagnosed at birth as isolated findings in otherwise healthy infants and those detected prenatally during the first or second trimester (see chapter 31). Prenatal sonographic examination in the first and second trimester identifies a group of fetuses with cystic hygroma in which 60% have associated chromosomal abnormalities and are often associated with other structural anomalies that have an extremely high mortality rate (Romero et al., 1988; Cohen et al., 1989; Welborn and Timm, 1994). In this group of fetuses, cystic hygromas are distinguished by posterior triangle location of the lymphangioma, chromosomal abnormalities, structural anomalies, hydrops fetalis, a high incidence of intrauterine death, and rare postnatal survival. In contrast, isolated cystic hygroma presenting during the third trimester, often with previously normal sonographic studies earlier in gestation, is usually located anteriorly or anterolaterally in the anterior cervical triangle. These two groups of fetuses appear to have lymphangiomas of differing origin, pathophysiology, natural history, and most importantly, prognosis (Lyngbye et al., 1986; Benacerraf and Frigoletto, 1987; Langer et al., 1990).
The lymphatic system develops at the end of the 5th week of gestation with sprouting from the six primary lymph sacs situated in the neck, iliac region, and retroperitoneum. Goetsch (1938) suggested that lymphangiomas are developmental defects secondary to sequestration of lymphatic tissue in early embryonic life. Cystic hygromas are thought to arise because of the failure of the jugular lymph sacs to join the lymphatic system. The hygroma develops fibrillike sprouts from the existing cystic spaces. These endothelial-lined cystic spaces secrete lymphlike fluid, which causes local distention and gradual enlargement of cysts. The walls may become thicker with time, with connective tissue septae separating large cysts (Chervenak et al., 1983; Isaacs, 1997).
Lymphangiomas diagnosed in utero are commonly seen in association with Turner syndrome, hydrops, oligohydramnios, single-vessel umbilical cord, Noonan syndrome, fetal alcohol syndrome, Fryns syndrome, and trisomies 18 and 21 (Stephens and Shepard, 1980; Chervenak et al., 1983; Pijpers et al., 1988; Golden et al., 1989; Welborn and Timm, 1994). Chromosomal abnormalities are found in more than 60% of fetuses with cystic hygroma. The majority have a 45,X karyotype (Romero et al., 1988; Cohen et al., 1989; Welborn and Timm, 1994), although Trisomies 13, 18, and 21 and Klinefelter syndrome have all been reported (Chervenak et al., 1983; Greenberg et al., 1983; Marchese et al., 1985; Stephens and Shepard, 1980). Conversely, fetuses with a normal karyotype appear to have a much higher incidence of consanguinity or a previous family history of abnormal fetuses (Langer et al., 1990). Cystic hygromas in these patients are more likely to be associated with familial conditions such as Noonan syndrome, multiple pterygium syndrome, polysplenia syndrome, Roberts syndrome, or an isolated autosomal recessive trait (Chen et al., 1982; Cowchock et al., 1982; Graham et al., 1983; Zarabi et al., 1983; Zelante et al., 1984).
Isolated cystic hygromas presenting late in gestation appear to be a completely different entity (Lyngbye et al., 1986; Benacerraf and Frigoletto, 1987; Langer et al., 1990; Fujita et al., 2001; Tanriverdi et al., 2005; Gedikbasi, 2007). These cases had cystic hygromas located in the anterior and lateral location and were not generally associated with other anomalies or hydrops. Langer et al. suggested that in these cases lymphangioma developed much later in gestation. In one of his cases, the fetus had a normal sonographic examination at 17 weeks of gestation (Langer et al., 1990). If this is true, it is unlikely that the mechanism would be similar in the late presenting group of cystic hygromas and the early gestation group. Cystic hygromas may also regress in utero, presumably due to development of collateral lymphatic and venous connections. Webbing of the neck and puffiness of the hands and feet are characteristic features of Turner syndrome, which is thought to be due to fetal cystic hygromas that spontaneously resolve.
Precise estimates of the incidence of cystic hygroma and lymphangioma are difficult to come by and depend on whether prenatal or postnatal data are evaluated. Fonkalsrud estimated the incidence of cystic hygroma to be 1 in 12,000 births, with 50% to 65% of cases presenting at birth, and 80% to 90% presenting by the second year of life (Bill and Sumner, 1965; Fonkalsrud, 1980). A total of 52 confirmed diagnoses of cystic hygroma were reported to the South East Thames Regional Congenital Malformation Registry in a region with an annual birth rate of 52,000, yielding an incidence of 1 in 1000 births. This series included terminations, intrauterine fetal death, stillbirths, and postnatal deaths to give a more accurate account of the incidence of cystic hygroma (Fisher et al., 1996). The incidence of cystic hygroma was as high as 1 in 300 among spontaneous abortuses reported by Byrne et al. (1984).
The sonographic features of cystic hygroma include fluid-filled cystic spaces divided by fine septae commonly observed in the nuchal region and anterior and posterior triangles of the neck (Figure 32-1). They often have a dense midline posterior septum extending from the fetal neck across the full width of the hygroma. This septum is the sonographic equivalent of the nuchal ligament (Chervenak et al., 1985). In order to differentiate cystic hygroma from other diagnoses, it is important to exclude a bony defect in the skull or vertebral column as would be seen with encephalocele. Solid components should be excluded to distinguish cystic hygroma from a cystic teratoma. Cysts separated by septae are helpful in distinguishing nuchal edema from cystic hygroma.
Cystic mass along lateral aspect of fetal head at 31 weeks consistent with cystic hygroma.
Lymphatic malformations may be diagnosed in the chest, abdomen, retroperitoneum or inguinal region. Rasidaki et al. (2005) have reported a chest wall lymphatic malformation in which MRI in addition to ultrasound was used to make the diagnosis. Similarly, there have been several reports of prenatal diagnoses of axillary lymphatic malformations (Song et al., 2002; Zanotti et al., 2001).
Once cystic hygroma has been detected, a search for other potential associated signs of nonimmune hydrops such as fetal skin edema, ascites, and pleural or pericardial effusions should be sought. In addition, structured anomalies seen in association with cystic hygroma should be sought, including cardiac, facial, vertebral, and genitourinary anomalies and diaphragmatic hernia (Bulas et al., 1992) (Table 32-1).
Table 32-1Associated Structured Anomalies in 19 Fetuses with Cervical Cystic Hygroma ||Download (.pdf) Table 32-1 Associated Structured Anomalies in 19 Fetuses with Cervical Cystic Hygroma
|Cardiac defects ||6 |
|Hydronephrosis ||3 |
|Neural tube defect ||3 |
|Cleft lip and palate ||2 |
|Multiple pterygium syndrome ||2 |
|Skeletal anomalies ||1 |
|Imperforate anus ||1 |
|Ambiguous genitalia ||1 |
The differential diagnosis of cystic neck masses includes nuchal edema, encephalocele or other neural tube defects, cystic teratoma, and twin sac of a blighted ovum. The approach to each of these conditions differs, highlighting the importance of accurate prenatal diagnosis. The presence of skull or vertebral column defects suggests the diagnosis of encephalocele, especially if associated with hydrocephalus. The distinction between cystic hygroma and cervical teratoma can be extremely difficult. Teratomas usually have a more complex sonographic appearance, with solid as well as cystic components. Calcifications within the mass are thought to be diagnostic of teratoma (see Chapter 110). Fetal magnetic resonance imaging (MRI) may be very helpful in distinguishing cystic hygroma from cervical teratoma (Liechty et al., 1997; Hubbard et al., 1998) (Figures 32-2A and 32-2B). Nuchal edema is usually without septae except the midline nuchal ligament and is a few millimeters in thickness (see Chapter 31).
A. Sagittal view of fetus with large right-sided lymphangioma resulting in hyperextension of the neck and compression and distortion of the airway. B. Coronal view of the same fetus with a large lymphangioma.
ANTENATAL NATURAL HISTORY
The natural history of prenatally diagnosed cystic hygroma appears to depend on gestational age at diagnosis, location of the cystic hygroma, and most particularly, whether or not there are associated chromosomal or structural abnormalities (Langer et al., 1990).
The mortality rate for cystic hygromas diagnosed prior to 30 weeks of gestation, with posterior location, is extremely high because of the high incidence of nonimmune hydrops and associated chromosomal defects (see Chapter 128). In the report by Langer et al. of 27 cases diagnosed prior to 30 weeks of gestation, all but 2 fetuses died. Of the 25 that did not survive, nonimmune hydrops developed in 21, 4 spontaneously aborted, and 21 were electively terminated. The only 2 survivors had spontaneous regression and were subsequently diagnosed with Noonan syndrome at birth (Langer et al., 1990). Cystic hygroma associated with nonimmune hydrops is almost uniformly fatal. There are chromosomal abnormalities in approximately 80% of these cases. Fetuses with normal chromosomes have a higher incidence of consanguinity (Langer et al., 1990). These cases of cystic hygroma are also more likely to be associated with familial conditions, such as Noonan syndrome (Zarabi et al., 1983), multiple pterygium syndrome (Chen et al., 1982), polysplenia syndrome, Roberts syndrome (Graham et al., 1983), or an isolated recessive trait (Cowchock et al., 1982). In a review of 100 fetuses with nuchal thickening or cystic hygroma detected sonographically at 10 to 15 weeks of gestation, Nadel et al. (1993) found that a good prognosis could be expected if the karyotype was normal, there were no separations in the mass, and there were no associated hydrops.
In marked contrast to cystic hygromas with associated karyotypic abnormalities, there is a small group of fetuses with an isolated cystic hygroma without chromosomal abnormality, structural anomaly, or familial condition and in which hydrops does not develop. These cystic hygromas usually develop in the third trimester and have an excellent prognosis. The major concern in fetuses with large cystic cervical masses later in gestation is airway compromise at birth. The fetuses often require delivery by EXIT procedure (see below).
The management of a pregnancy complicated by a fetus with cystic hygroma depends on the presence or absence of nonimmune hydrops, chromosomal abnormalities, or other associated anomalies. Once a cystic hygroma has been detected, a detailed sonographic examination should be performed to search for fetal skin edema, ascites, and pleural or pericardial effusions. In addition, other structural anomalies should be excluded, especially genitourinary and cardiac defects. Genetic amniocentesis is recommended in all cases of cystic hygroma because of the high incidence of associated chromosomal abnormalities. In the presence of nonimmune hydrops the prognosis is grim, and appropriate counseling is indicated. In the presence of severe associated anomalies or a chromosomal abnormality prior to 24 weeks of gestation, elective termination may be offered. Echocardiography should be obtained in cases in which no chromosomal abnormalities are detected to exclude cardiac defects. An isolated cystic hygroma diagnosed in the third trimester has a much more favorable prognosis, and attention should be focused on site and mode of delivery. Because of risks of airway compromise, delivery in a tertiary care center with neonatologists and pediatric surgeons standing by is recommended. Because of the risks of airway compromise, consideration should be given to the EXIT procedure (Liechty et al., 1997; Marwan and Crombleholme, 2006). While a cervical mass of any size can cause airway compromise, masses sufficiently large enough to cause polyhydramnios can obstruct the pharynx or larynx, making intubation exceedingly difficult. Pregnancies with a cystic hygroma should be followed closely for the development of polyhydramnios and secondary uterine irritability. Polyhydramnios in fetuses with large cystic hygromas may be so severe as to require amnioreduction to treat maternal respiratory difficulties and preterm labor.
A few cases of lymphangioma have undergone in utero drainage by ultrasound-guided cyst aspiration. Chen et al. (1996) reported two fetuses that underwent multiple cyst aspirations. In each case karyotype analysis was normal and there were no associated structural anomalies. The rationale for this approach is to prevent polyhydramnios, irreversible facial deformity, and progression to hydrops fetalis. It is unclear, however, that these multiple cyst aspirations had any effect on outcome. While cyst aspiration as an adjunct to securing an airway at birth may be indicated, there are few data to support in utero decompression to prevent progression to nonimmune hydrops or facial deformity. The lack of benefit and risk of repeated aspirations make this fetal intervention difficult to justify. Kaufman et al. (1996) did report successful percutaneous decompression of a large axillary lymphangioma that would have caused skeletal dystocia. Ultrasound-guided aspiration was followed by normal spontaneous vaginal delivery. Figure 32-3 demonstrates an axillary lymphangioma detected antenatally and aspirated prior to birth to allow vaginal delivery.
Fetal MRI demonstrating unilateral cystic mass at lateral aspect of fetal neck consistent with cystic hygroma.
Several groups in Japan have attempted intrauterine sclerotherapy using OK-432 between 27 and 28 weeks’ of gestation (Wattori et al., 1996; Ogita et al., 2001). OK-432 is a lyophilized mixture of a low-virulence strain of Streptococcus pyogenes of human origin incubated with penicillin G. The fetuses had involution of the cystic hygroma, and at birth only a slight skinfold was noted. Cases of lymphatic vascular malformations with normal chromosomes and no associated anomalies with hydrops were considered candidates for in utero sclerotherapy with OK-432 (Ogita et al., 2001). Those lesions with very large lymphangiomas even in the absence of hydrops may also be candidates for OK-432 in Japan. To date there have been no reports of in utero sclerotherapy with OK-432 being used in this country. There are few data on the use of this agent postnatally and none are available on its potential effects in the developing fetus. Currently, the only fetal procedure indicated for large cystic hygromas is EXIT (ex utero intrapartum treatment), which involves placement of an endotracheal tube before the fetus is separated from placental support (Liechty et al., 1997).
Treatment of the fetus with a large cystic hygroma includes an EXIT procedure to secure the airway (Liechty et al., 1997). The EXIT procedure allows up to 1 hour with excellent uteroplacental gas exchange for laryngoscopy, bronchoscopy and, if necessary, tracheostomy with or without partial resection of the mass (Liechty et al., 1997). As fetuses with prenatally diagnosed fetal airway obstruction reach viability, they should be monitored closely for the development or progression of hydrops or cardiac decompensation. If the development or progression of hydrops is noted sonographically, open fetal surgery may be necessary to salvage patients younger than 30 weeks’ gestation. If hydrops is noted later than 30 weeks’ gestation, the fetus should be delivered by using the EXIT strategy.
A number of important considerations must be taken into account when applying the EXIT procedure in the setting of giant fetal neck masses. The most pressing issue is the successful securing of the fetal airway. Although fetal neck masses can cause polyhydramnios and preterm labor, the most significant aspect of their management is treating a compromised airway at the time of delivery. The timing of the EXIT is often dictated by severity of polyhydramnios and preterm labor. The mean gestational age of fetuses with neck masses undergoing EXIT procedure is 34 weeks. Airway compromise is a function of the location of the mass and distortion of the airway, not necessarily the absolute size of the neck mass. As mentioned previously, the surgeon must be prepared for every possible airway contingency. All the available modalities to secure the fetal airway are detailed under the description of the EXIT procedure and are outlined in the algorithm in Figure 32-4. Other important issues to consider when performing an EXIT procedure for giant neck masses include: (1) the possibility of wedging of the lungs in the apex of the chest as a result of the neck hyperextension (despite the fact that a successful EXIT strategy can be applied in these cases, significant morbidity and mortality should be anticipated because of the associated lung hypoplasia); (2) the chance of the trachea being pulled up into the neck may lead to the underestimation of the site of tracheostomy, leading to an inappropriately low tracheostomy site; (3) the occurrence of polyhydramnios as a result of esophageal compression (this may lead to underestimation of the proximity of the placental edge to the site of hysterotomy with increased risk of bleeding); and (4) some fetal neck masses are caused by a cystic mass lesion. In such cases, decompression of the mass before the hysterotomy under US guidance will help in fashioning the hysterotomy and in delivering the fetal head and neck. Based on our cumulative experience in the application of the EXIT procedure in different clinical situations, we have summarized pitfalls and lessons learned to provide guidance when applying the EXIT approach (See Chapter 5, Table 5-6). If the fetus is premature and at increased risk for respiratory distress syndrome, surfactant replacement therapy can be administered while on placental support. In addition, in a three-vessel cord, and umbilical artery catheter, and even an umbilical venous catheter can be placed while on placental support to facilitate newborn resuscitation.
Algorithm for EXIT-to-Airway intraoperative decision-making.
Once an airway has been established, the care of the newborn should focus on any underlying lung disease and exclusion of any associated anomalies and chromosomal abnormalities, if this has not already been done. Once the newborn is able to be transported to a tertiary care facility, a computed tomographic (CT) scan and MRI scan with magnetic resonance angiography should be obtained of the infant’s head and neck to confirm the diagnosis of lymphangioma and to determine the extent of the hygroma (Figures 32-5A and 32-5B). Of particular concern is to define whether there is extension into the mediastinum or the floor of the mouth and tongue.
A and B. Postnatal MRI images demonstrating large submental cystic mass resting on the anterior surface of the fetal chest.
The infant with a large cystic hygroma has an intrinsically unstable airway, and resection should proceed as soon as the diagnostic evaluation is completed. Cystic hygromas of a modest size can be dealt with on a more elective basis if they do not pose a risk for airway compromise. The nature of the lymphangioma often precludes a complete resection. The surgical approach is focused on resection of as much of the mass as possible without sacrificing vital structures. Some surgeons have recommended a conservative approach in asymptomatic lymphangiomas because of occasional spontaneous regression. More commonly, these lesions grow proportionately with the growth of the infant. There may also be acute increases in the size of the cyst due to hemorrhage or infection. Because of difficulty in achieving a complete resection, alternative treatments have been tried with variable results.
Cystic aspiration is of little benefit except in the rare instance of a large dominant cyst as a means of emergency decompression. However, the cysts rapidly reaccumulate. Sclerosing agents have been used as an alternative to resection, using boiling water or sodium morrhuate, with disappointing results. Bleomycin has been used as microspheres in oil bleomycin fat emulsions (BLM), and seems more effective than other preparations (Tanigawa et al., 1987; Tanaka et al., 1990). After cyst aspiration, injection into the lymphangioma via fine needle of 0.3 to 0.6 mg of BML per kilogram of body weight is recommended. This treatment requires admission to the hospital for observation and is contraindicated in infants younger than 6 months or in the presence of airway compromise or mediastinal involvement due to significant tissue edema that results. Side effects of bleomycin include fever, diarrhea, vomiting, infection, and bleeding. In addition, the incidence of long-term complications such as pulmonary fibrosis is unknown.
The sclerosing agent OK-432 is the product of incubating S. pyogenes of human origin with penicillin G (Ogita et al., 1996). Intracystic injection of 0.1 mg of OK-432 in 10 mL of saline solution following cyst aspiration is recommended. If necessary, the treatment can be repeated 3 to 4 weeks later. No prospective trials confirming the efficiency of this treatment have been reported. Laser treatment of lymphangioma has also been reported, but again with mixed results (Ogita et al., 1996).
The mortality of cystic hygroma diagnosed prior to 30 weeks of gestation and associated with nonimmune hydrops is virtually 100%. There is also a high incidence of associated chromosomal abnormalities that may, as in trisomy 18 and 13, be lethal. The outcome for isolated cystic hygroma presenting in the third trimester, however, is quite different. The overall mortality in this group is very low. However, complete resection is possible in only 75% of cases (Hancock et al., 1982). Despite complete resection, recurrence can occur in as many as 10% to 27% of cases. In cases in which only a partial resection can be achieved, recurrence is observed in 50% to 100% of patients. Significant complications can occur in up to 30% of patients. Significant neurologic problems can result from injury to cranial nerves, especially the facial nerve (VII). However, injuries to the 9th, 10th, 11th, and 12th cranial nerves have also been reported. In addition, Horner syndrome due to injury to the sympathetic chain and diaphragmatic paralysis from phrenic nerve injury has occurred during resection of the cystic hygroma. Extensive involvement of the larynx, trachea, or extensive involvement of the floor of the mouth may necessitate tracheostomy tube placement. Often multiple operations are required to bring lymphangiomas under control. The long-term outcome depends on the ability to achieve a complete resection. This becomes unlikely in the face of extensive involvement of the floor of the mouth, tongue, larynx, or trachea.
GENETICS AND RECURRENCE RISK
Prenatally diagnosed cystic hygroma has a 50% to 60% incidence of abnormal karyotype. The most common associated chromosomal abnormalities are listed in Tables 32-1 and 32-2. Because some fetuses with cystic hygroma may have chromosomal mosaicism, it may be necessary to study several tissues to make a diagnosis. There are two reports of familial cystic hygroma occurring in eight patients in three families (Tricoire et al., 1993; Teague et al., 2000). In the first family, two fetuses with normal karyotypes and cystic hygromas had camptomelic dysplasia (see Chapter 91). Only one other fetus had anomalies—meningomyelocele and cleft palate. In all cases parental consanguinity was found, suggesting an autosomal recessive mode of inheritance. In another report, a 19-year-old gravida 3 para 0 was diagnosed with a large cystic hygroma at 11 weeks’ gestation. The fetal subsequently developed increasing sign of a septated nuchal mass and ascites. A 46XX fetal karyotype had been noted on two prior pregnancies, both of which had also been complicated by cystic hygroma and hydrops. Cystic hygroma associated with a normal karyotype can be inherited as an autosomal recessive (Teague et al., 2000).
Table 32-2Chromosomal and Nonchromosomal Abnormalities Associated with Cystic Hygroma ||Download (.pdf) Table 32-2 Chromosomal and Nonchromosomal Abnormalities Associated with Cystic Hygroma
|Trisomy 18 |
|Trisomy 13 |
|Trisomy 21 |
|13q deletion |
|18p deletion |
|Partial 11q:22q trisomy |
|Trisomy 22 mosaicism |
|Noonan syndrome |
|Fetal alcohol syndrome |
|Distichiasis-lymphedema syndrome |
|Congenital diaphragmatic hernia |
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