- Email: [email protected]
Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes
Journal of Pediatric Surgery xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes Aliza Olive, Julie S. Moldenhauer, Pablo Laje, Mark P. Johnson, Beverly G. Coleman, Teresa Victoria, Alan W. Flake, N. Scott Adzick ⁎ Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
a r t i c l e
i n f o
Article history: Received 26 December 2014 Received in revised form 18 March 2015 Accepted 21 March 2015 Available online xxxx Key words: axillary lymphatic malformation sclerotherapy prenatal diagnosis
a b s t r a c t Background/Purpose: The purpose of this study is to describe the prenatal findings and postnatal outcomes of fetuses with axillary lymphatic malformations. Methods: Retrospective chart review of fetuses with the prenatal diagnosis of isolated axillary lymphatic malformation detected between 2009 and 2013. Results: There were 8 fetuses diagnosed with isolated axillary lymphatic malformation. Median gestational age at diagnosis was 20.5 (19–28) weeks. All fetuses were evaluated by serial ultrasound and ultrafast fetal MRI. Two pregnancies were electively terminated. All continued pregnancies reached term, and all fetuses were delivered by cesarean section. None of the fetuses developed polyhydramnios or hydrops fetalis. Only one patient had an associated malformation (coarctation of the aorta). All patients were evaluated postnatally by MRI. Treatment included sclerotherapy only (1), sclerotherapy followed by surgical resection (1), surgical resection only (3), and observation (1). The median postnatal hospital stay was 8 (6–15) days. Three cases recurred after the initial treatment, two after surgery and one after sclerotherapy. On a median follow up of 2.1 years, all patients have some degree of visible residual disease. There were no deaths. Conclusions: Prenatal diagnosis of axillary lymphatic malformation is increasing with improved technology. Axillary lymphatic malformations are usually isolated developmental anomalies that do not affect fetal health. Postnatal management options include surgery, sclerotherapy, and observation. Recurrences and residual disease after all types of treatment are frequent. This should be communicated to the parents at the time of prenatal counseling. © 2015 Elsevier Inc. All rights reserved.
Axillary lymphatic malformation may be caused by a failure of lymphatic sacs to communicate with the central venous system. However, the exact pathogenesis is unknown. Lymphatic malformations can occur at any location. The neck and axillae are the most common locations. Lymphatic malformations are rarely familial [1]. Advances in prenatal imaging studies now permit prenatal diagnosis of lymphatic malformations with a great deal of anatomical accuracy. The aim of this study is to describe the prenatal features and postnatal outcome of fetuses with isolated axillary lymphatic malformations. 1. Materials and methods After obtaining institutional review board approval we conducted a retrospective chart review of all fetuses diagnosed with isolated axillary lymphatic malformations at the Center for Fetal Diagnosis and Treatment at The Children’s Hospital of Philadelphia (CHOP) between 2009 and 2013. Counseling, prenatal care, delivery and postnatal care were done at CHOP. Prenatal nondirectional counseling was done by a multidisciplinary team consisting of maternal-fetal-medicine specialists, ⁎ Corresponding author at: Department of Surgery, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA. Tel.: +1 215 590 2727. E-mail address: [email protected] (N.S. Adzick).
pediatric surgeons, neonatologists and fetal therapy coordinators. All potential therapeutic options (surgery, sclerotherapy and observation) were presented to the parents during the prenatal counseling sessions. The interventional radiology team evaluated the baby and met with the parents after birth. Sclerotherapy was done with either direct instillation or catheterdirected instillation of doxycycline according to the protocol published by Molitch [2]. Briefly, a sclerotherapy session consisted of a daily instillation, repeated for a total of 3 days. The doxycycline is vacuum aspirated 6 hours post instillation and is used at a concentration of 10 mg/ml [3]. Other agents for sclerotherapy such as OK 432 and ethanol are available, but none of them was used in the patients included in this study. 2. Results We identified eight fetuses with isolated axillary lymphatic malformations (Table 1). Diagnosis was made in all cases by ultrasound, at a median gestational age of 20 5/7 (19–28) weeks. A midgestation fetal ultrafast MRI was done in all cases at the time of initial evaluation at our center (Fig. 1). Six MRI studies showed macrocystic lesions and two showed mixed macrocystic and microcystic lesions in which microcysts were arbitrarily defined as those with a diameter of less than 2 cm. The median volume of the lymphatic malformations at the
http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066 0022-3468/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Olive A, et al, Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes, J Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066
2
A. Olive et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
Table 1 Fetuses with isolated axillary lymphatic malformation. Cases 7 and 8 underwent termination of pregnancy. GA: gestational age. M: male. N/A: data not available. CoA: coarctation of the aorta. LOS: length of stay.
Maternal age (years) GA at diagnosis (weeks) Gender Polyhydramnios Hydrops Associated defects malformations GA at birth (weeks) Birth weight (grams) Neonatal LOS
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
31 28 M No No No 39 3220 6
36 21 M No No No 37 3770 7
26 25 M No No No 38 2920 15
36 24 M No No No 37 2700 7
30 20 M No No CoA 39 4030 9
29 19 M No No No 39 4110 14
26 19 N/A No No No N/A N/A N/A
30 19 N/A No No No N/A N/A N/A
time of diagnosis by fetal MRI was 70 (range 15–438) ml. Five lymphatic malformations were located on the right side and one on the left. Two pregnancies were electively terminated (no associated malformations were detected in either of those two fetuses; no gender data are available). None of the fetuses developed polyhydramnios or hydrops fetalis, and all continued pregnancies reached term. All fetuses were delivered by scheduled cesarean section at a median gestational age of 38 (37–39) weeks. Cesarean section was the preferred mode of delivery owing to concerns of dystocia in all cases. All delivered fetuses were males. Postnatal evaluation was done by MRI and confirmed the prenatal imaging diagnosis of axillary lymphatic malformation in all cases. The median volume of the lymphatic malformations at birth by MRI was 639 (range 128–884) ml. The median neonatal hospital stay was 8 (6–15) days. The treatment strategy was decided by the surgeon in charge of each patient in conjunction with the parents. The size of the lesion did not affect the choice of therapy. Treatment modalities included sclerotherapy only (n = 1), sclerotherapy followed by surgical resection (n = 1), surgical resection only (n = 3) (Fig. 2), and observation only (n = 1) (Table 2). Case 1 was treated exclusively with sclerotherapy. He started treatment at the age of 8 months and underwent three sclerotherapy sessions (8, 10 and 14 months of age). Prior to starting treatment he
had an episode of hematogenous infection of the lymphatic malformation that required a hospital admission and intravenous antibiotics. Currently, at 30 months of follow up he has residual disease. The parents decided to pursue no further treatment at this point and will consider plastic surgery in the future. Case 2 underwent surgery on day of life 3. A near complete resection was achieved with good cosmetic result. Three years later he developed a recurrence, so he underwent another resection and revision of the original scar. He developed a subcutaneous lymphatic collection one month later that required drain placement and resolved in 3 weeks. At 24 months of follow up he has minimal residual disease. Case 3 underwent surgery on day of life 6. A virtually complete resection was achieved. Eight months later he underwent surgery to remove small areas of residual lymphatic malformation in the skin and to obtain a better cosmetic result. Thirty months after the last operation, he has minimal residual disease. Case 4 did not receive treatment, per the parents’ preference. We have followed him closely and currently at the age of 26 months his lymphatic malformation has decreased in size. He has had no episodes of infection. Case 5 underwent surgical resection on day of life 14 (Fig. 3). A near complete resection was achieved. The wound developed an infection that required a surgical wash-out. One year after the resection he has minor residual disease and an area that intermittently opens and drains small amounts of
Fig. 1. Prenatal MRI of a 27-week gestational age fetus with a large macrocystic right axillary lymphatic malformation (star). The airway is not deviated (dashed arrow). The arrow points to the right forearm.
Fig. 2. Surgical resection of a right axillary lymphatic malformation (star). The black arrow shows the brachial plexus and the axillary vascular bundle.
Please cite this article as: Olive A, et al, Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes, J Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066
A. Olive et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
3
Table 2 Treatment modalities and outcomes of fetuses with isolated axillary lymphatic malformation.
Age at initial treatment Initial treatment modality Subsequent treatment modality Recurrent/residual disease Follow up since last treatment Complications of treatment
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
8 months Sclerotherapy None Yes 30 months Resp. distress
3 days Surgery Surgery Yes 24 months Seroma
6 days Surgery Surgery Yes 30 months None
No treatment No treatment No treatment Yes 26 months N/A
14 days Surgery None Yes 12 months Wound abscess
6 months Sclerotherapy Surgery Yes 10 months None
lymphatic fluid. No further treatment is planned at this point. Case 6 underwent initial treatment at 6 months of age with sclerotherapy for a large mixed macro/microcystic lesion (Fig. 4). He developed postsclerotherapy respiratory distress. Sclerotherapy did not achieve any improvement, so he was subsequently treated with staged surgical debulking at 8 and 11 months of age. Currently, 10 months after the last surgery, he still has residual disease for which he will undergo surgical resection in the near future. All patients who underwent surgical resection were confirmed as lymphatic malformations by pathology.
3. Discussion The pathogenesis of lymphatic malformations is largely unknown, but is likely related to a failure of the lymphatic sacs to canalize and communicate properly with the venous system. Lymphatic malformations vary in size from a few millimeters to several centimeters in diameter, and depending on the size of the cysts that form them, they are arbitrarily classified as macrocystic (when all cysts are N 2 cm in diameter), microcystic (when all cysts are b2 cm in diameter), or mixed. Axillary lymphatic malformations are isolated developmental anomalies; the coarctation of the aorta in one of our patients is merely a coincidental finding. Axillary lymphatic malformations are not associated with chromosomal abnormalities (e.g. Turner syndrome, Down syndrome), as opposed to posterior cervical (nuchal) lymphatic malformations (also referred to as cystic hygromas), which often are associated with those chromosomal abnormalities. Therefore,
Fig. 3. Preoperative appearance of a large axillary lymphatic malformation extending into the chest wall and involving the area of the right nipple.
amniocentesis for karyotype assessment is not routinely required in fetuses with isolated axillary lymphatic malformations. The prenatal imaging diagnosis of axillary lymphatic malformations and lymphatic malformations at any other location has been available for three decades, but the current availability of high-definition fetal MRI allows characterization of these lesions with an unprecedented degree of detail [4–6]. In the case of axillary lymphatic malformations, the MRI can precisely determine if there is extension of the mass along the chest wall, any extension toward the mediastinum, the degree of proximity to the brachial plexus, and most importantly, the presence of deep cervical extensions that can potentially compromise the airway at birth. Prenatal MRI is a costly study but we believe it is fully justified by the need to rule out airway compromise, which is difficult to diagnose by ultrasound alone. The median gestational age at diagnosis and delivery were 20 5/7 and 38 weeks, respectively. The 50th percentile for fetal weight at 20 and 38 weeks of gestation is roughly 330 and 3000 g, respectively, which represents a nine-fold increase. We observed, on average, the same rate of volume growth for the lymphatic malformations: 70 ml at diagnosis and 638 ml at delivery. Isolated axillary lymphatic malformations do not affect fetal growth or general fetal health. The main effect that an isolated axillary lymphatic malformations can have on the pregnancy is the potential for birth dystocia. Fetuses with small lymphatic malformations that do not cause abduction of the ipsilateral arm may be delivered vaginally, but fetuses with larger lymphatic malformations that produce abduction of the arm should be delivered by cesarean section. The volume of the lymphatic malformation at the time of delivery in 2 of our patients was 128 and 190 ml, respectively. Both patients had some degree of arm abduction, but is likely that they could have been delivered vaginally without complications. We elected to err on the safe side. In the other 4 patients the volumes were 483, 796, 838 and 884 ml, which carried a risk of dystocia despite the pliable nature of the lesions. Kaufman reported a case of prenatal percutaneous decompression of the lymphatic malformation to reduce the risk of dystocia, but the risks of such procedure do not appear to outweigh the risks of a routine cesarean section [7]. If left untreated after birth, axillary lymphatic malformations can lead to a number of complications. Spontaneous or trauma-related internal bleeding is not uncommon and results in pain and a sudden enlargement of the mass. Infection of the poorly vascularized lymphatic malformation is infrequent but possible, and hospital admission for intravenous antibiotics is often required in such circumstances. It is also quite common to see significant swelling of the lymphatic mass when the patient experiences any intercurrent infections (e.g. upper respiratory viral infection). Equally important is the fact that untreated axillary lymphatic malformations may interfere with the normal motor development of the ipsilateral arm and shoulder. Because of all these potential complications it is our preference to offer surgical therapy during the newborn period. Postnatally, lymphatic malformations are best evaluated by MRI, as is the case for other soft tissue masses. The high content of fluid provides a sharp contrast between the lymphatic mass and the normal anatomical structures on T2-weighted sequences. Sclerotherapy is a well-established treatment modality for lymphatic malformations in general, and the axillary location is not an
Please cite this article as: Olive A, et al, Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes, J Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066
4
A. Olive et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
Fig. 4. Postnatal MRI of a large mixed macrocystic and microcystic axillary lymphatic malformation (white stars). A: the arrows point to the lung apices. B: three-dimensional MRI rendering of the lymphatic malformation, which extends along the right chest wall.
exception. Macrocystic lesions tend to respond to sclerotherapy better than microcystic or mixed lesions, and that is also true for surgical therapy. Sclerotherapy has a number of disadvantages compared to surgery: it requires multiple rounds of treatment for which patients need a hospital admission, residual disease is always present, and the patients are exposed to doxycycline toxicity, which includes metabolic acidosis, hypoglycemia, hemolytic anemia and nerve damage. In addition, the use of percutaneous catheters puts the lymphatic mass at a higher risk of infection during the treatment sessions. Recurrences after sclerotherapy are common. Despite all the potential disadvantages, sclerotherapy is the only option in some cases, particularly in highly infiltrative deep lymphatic malformations for which surgery is deemed not suitable, and possibly in cases that have recurred after surgical resection. Surgical resection can be perceived by the parents as the obvious one-stop treatment. While some degree of success can be achieved in all cases and many cases require only one operation, it is important to inform the parents that recurrences are frequent, even after a neartotal resection. Surgery for axillary lymphatic malformations is not free of risks, including damage to the brachial plexus which can be embedded within the lymphatic mass. To minimize the risk of nerve damage we use intraoperative nerve monitoring (NIM-Neuro 3.0, Medtronic Inc., Minneapolis, MN). The electrodes of the monitoring system are placed sterilely and percutaneously in the muscles innervated by the branches of the nerves that need to be protected. In the event of any electrical or thermal stimulation of the nerves involved, the system triggers an audible and visual signal. From a technical standpoint, it is
important to stay on the surface of the lymphatic mass during the dissection, and if at all possible preserve the integrity of the cysts during the resection to enhance the possibility of maximal resection (Fig. 5). Lymphatic malformations that invade the dermis can result in lymphatic vesicles at the scar site, which can also be resected at a later point to improve the cosmetic result (Fig. 6). In addition to sclerotherapy and surgery, there are other forms of therapy for lymphatic malformation that, while still not widely used, provide some hope for the future. Among those is the systemic use of rapamycin. There is extensive experimental evidence that rapamycin is a potent inhibitor of the vascular endothelial growth factor (VEGF)C, exerting a strong antilymphangiogenic activity in live animal models. There are several case reports in the literature on the use of rapamycin for lymphatic malformations in humans [8,9]. The beta-blocker propranolol is widely used in the management of different forms of hemangiomas. However, its efficacy in the management of lymphangiomas is not encouraging, according to most reports [10,11]. There are anecdotal reports in the literature on the use of the cGMP-specific phosphodiesterase type 5 inhibitor sildenafil, but its efficacy has not been proven [12]. We have no experience with any of these forms of therapy. There are no prospective randomized trials comparing sclerotherapy versus surgery and no treatment algorithms, so the treatment modality for each patient remains a matter of treating team’s and parent’s preference [13]. In our experience we have favored surgical resection for macrocystic, noninvasive lymphatic malformations, and favored sclerotherapy for infiltrative microcystic ones. Although the efficacy of
Fig. 5. Resection of a left axillary lymphatic malformation. The mass was kept intact during the dissection, which allowed for a near-total resection. Black arrow: left nipple. Black dotted arrow: brachial plexus. White arrow: intact lymphatic mass.
Please cite this article as: Olive A, et al, Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes, J Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066
A. Olive et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
5
In summary, we have observed that isolated axillary lymphatic malformations do not affect fetal health, can be treated with surgery, sclerotherapy or a combination of both, and that the incidence of residual disease and recurrence is significant after either treatment modality. This fact should be communicated to the parents at the time of prenatal counseling. References
Fig. 6. Lymphatic vesicles are seen along the scar 6 months after the resection (black arrows). Dotted arrow: right nipple.
sclerotherapy on microcystic lymphatic malformations is variable, success rates of up to 80% have been reported [14]. We recommend early neonatal treatment for those cases deemed good surgical candidates, because we believe that there are several risks associated with postponing therapy. On the other hand, for patients who are chosen to be treated with sclerotherapy the interventional radiology team prefers to wait a few months before initiating treatment due to the potential complications of sclerotherapy, which are better tolerated beyond the newborn period.
[1] Brouillard P, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet 2007;16:R140–9. [2] Molitch HI, Unger EC, Witte CL, et al. Percutaneous sclerotherapy of lymphangiomas. Radiology 1995;194:343–7. [3] Cahill AM, Nijs E, Ballah D, et al. Percutaneous sclerotherapy in neonatal and infant head and neck lymphatic malformations: a single center experience. J Pediatr Surg 2011;46:2083–95. [4] Hoffman-Tretin J, Koenigsberg M, Ziprkowski M, et al. Antenatal demonstration of axillary cystic hygroma. J Ultrasound Med 1988;7:233–5. [5] McCoy MC, Kuller JA, Chescheir NC, et al. Prenatal diagnosis and management of massive bilateral axillary cystic lymphangioma. Obstet Gynecol 1995;85:853–6. [6] Koelblinger C, Herold C, Nemec S, et al. Fetal magnetic resonance imaging of lymphangiomas. J Perinat Med 2013;41:437–43. [7] Kaufman GE, D'Alton ME, Crombleholme TM. Decompression of fetal axillary lymphangioma to prevent dystocia. Fetal Diagn Ther 1996;11:218–20. [8] Akyüz C, Ataş E, Varan A. Treatment of a tongue lymphangioma with sirolimus after failure of surgical resection and propranolol. Pediatr Blood Cancer 2014;61:931–2. [9] Reinglas J, Ramphal R, Bromwich M. The successful management of diffuse lymphangiomatosis using sirolimus: a case report. Laryngoscope 2011;121:1851–4. [10] Maruani A, Brown S, Lorette G, et al. Lack of effect of propranolol in the treatment of lymphangioma in two children. Pediatr Dermatol 2013;30:383–5. [11] Ozeki M, Kanda K, Kawamoto N, et al. Propranolol as an alternative treatment option for pediatric lymphatic malformation. Tohoku J Exp Med 2013;229:61–6. [12] Swetman GL, Berk DR, Vasanawala SS, et al. Sildenafil for severe lymphatic malformations. N Engl J Med 2012;366:384–6. [13] Elluru RG, Balakrishnan K, Padua HM. Lymphatic malformations: diagnosis and management. Semin Pediatr Surg 2014;23:178–85. [14] Alomari AI, Karian VE, Lord DJ, et al. Percutaneous sclerotherapy for lymphatic malformations: a retrospective analysis of patient-evaluated improvement. J Vasc Interv Radiol 2006;17:1639–48.
Please cite this article as: Olive A, et al, Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes, J Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes Aliza Olive, Julie S. Moldenhauer, Pablo Laje, Mark P. Johnson, Beverly G. Coleman, Teresa Victoria, Alan W. Flake, N. Scott Adzick ⁎ Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
a r t i c l e
i n f o
Article history: Received 26 December 2014 Received in revised form 18 March 2015 Accepted 21 March 2015 Available online xxxx Key words: axillary lymphatic malformation sclerotherapy prenatal diagnosis
a b s t r a c t Background/Purpose: The purpose of this study is to describe the prenatal findings and postnatal outcomes of fetuses with axillary lymphatic malformations. Methods: Retrospective chart review of fetuses with the prenatal diagnosis of isolated axillary lymphatic malformation detected between 2009 and 2013. Results: There were 8 fetuses diagnosed with isolated axillary lymphatic malformation. Median gestational age at diagnosis was 20.5 (19–28) weeks. All fetuses were evaluated by serial ultrasound and ultrafast fetal MRI. Two pregnancies were electively terminated. All continued pregnancies reached term, and all fetuses were delivered by cesarean section. None of the fetuses developed polyhydramnios or hydrops fetalis. Only one patient had an associated malformation (coarctation of the aorta). All patients were evaluated postnatally by MRI. Treatment included sclerotherapy only (1), sclerotherapy followed by surgical resection (1), surgical resection only (3), and observation (1). The median postnatal hospital stay was 8 (6–15) days. Three cases recurred after the initial treatment, two after surgery and one after sclerotherapy. On a median follow up of 2.1 years, all patients have some degree of visible residual disease. There were no deaths. Conclusions: Prenatal diagnosis of axillary lymphatic malformation is increasing with improved technology. Axillary lymphatic malformations are usually isolated developmental anomalies that do not affect fetal health. Postnatal management options include surgery, sclerotherapy, and observation. Recurrences and residual disease after all types of treatment are frequent. This should be communicated to the parents at the time of prenatal counseling. © 2015 Elsevier Inc. All rights reserved.
Axillary lymphatic malformation may be caused by a failure of lymphatic sacs to communicate with the central venous system. However, the exact pathogenesis is unknown. Lymphatic malformations can occur at any location. The neck and axillae are the most common locations. Lymphatic malformations are rarely familial [1]. Advances in prenatal imaging studies now permit prenatal diagnosis of lymphatic malformations with a great deal of anatomical accuracy. The aim of this study is to describe the prenatal features and postnatal outcome of fetuses with isolated axillary lymphatic malformations. 1. Materials and methods After obtaining institutional review board approval we conducted a retrospective chart review of all fetuses diagnosed with isolated axillary lymphatic malformations at the Center for Fetal Diagnosis and Treatment at The Children’s Hospital of Philadelphia (CHOP) between 2009 and 2013. Counseling, prenatal care, delivery and postnatal care were done at CHOP. Prenatal nondirectional counseling was done by a multidisciplinary team consisting of maternal-fetal-medicine specialists, ⁎ Corresponding author at: Department of Surgery, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA. Tel.: +1 215 590 2727. E-mail address: [email protected] (N.S. Adzick).
pediatric surgeons, neonatologists and fetal therapy coordinators. All potential therapeutic options (surgery, sclerotherapy and observation) were presented to the parents during the prenatal counseling sessions. The interventional radiology team evaluated the baby and met with the parents after birth. Sclerotherapy was done with either direct instillation or catheterdirected instillation of doxycycline according to the protocol published by Molitch [2]. Briefly, a sclerotherapy session consisted of a daily instillation, repeated for a total of 3 days. The doxycycline is vacuum aspirated 6 hours post instillation and is used at a concentration of 10 mg/ml [3]. Other agents for sclerotherapy such as OK 432 and ethanol are available, but none of them was used in the patients included in this study. 2. Results We identified eight fetuses with isolated axillary lymphatic malformations (Table 1). Diagnosis was made in all cases by ultrasound, at a median gestational age of 20 5/7 (19–28) weeks. A midgestation fetal ultrafast MRI was done in all cases at the time of initial evaluation at our center (Fig. 1). Six MRI studies showed macrocystic lesions and two showed mixed macrocystic and microcystic lesions in which microcysts were arbitrarily defined as those with a diameter of less than 2 cm. The median volume of the lymphatic malformations at the
http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066 0022-3468/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Olive A, et al, Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes, J Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066
2
A. Olive et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
Table 1 Fetuses with isolated axillary lymphatic malformation. Cases 7 and 8 underwent termination of pregnancy. GA: gestational age. M: male. N/A: data not available. CoA: coarctation of the aorta. LOS: length of stay.
Maternal age (years) GA at diagnosis (weeks) Gender Polyhydramnios Hydrops Associated defects malformations GA at birth (weeks) Birth weight (grams) Neonatal LOS
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
31 28 M No No No 39 3220 6
36 21 M No No No 37 3770 7
26 25 M No No No 38 2920 15
36 24 M No No No 37 2700 7
30 20 M No No CoA 39 4030 9
29 19 M No No No 39 4110 14
26 19 N/A No No No N/A N/A N/A
30 19 N/A No No No N/A N/A N/A
time of diagnosis by fetal MRI was 70 (range 15–438) ml. Five lymphatic malformations were located on the right side and one on the left. Two pregnancies were electively terminated (no associated malformations were detected in either of those two fetuses; no gender data are available). None of the fetuses developed polyhydramnios or hydrops fetalis, and all continued pregnancies reached term. All fetuses were delivered by scheduled cesarean section at a median gestational age of 38 (37–39) weeks. Cesarean section was the preferred mode of delivery owing to concerns of dystocia in all cases. All delivered fetuses were males. Postnatal evaluation was done by MRI and confirmed the prenatal imaging diagnosis of axillary lymphatic malformation in all cases. The median volume of the lymphatic malformations at birth by MRI was 639 (range 128–884) ml. The median neonatal hospital stay was 8 (6–15) days. The treatment strategy was decided by the surgeon in charge of each patient in conjunction with the parents. The size of the lesion did not affect the choice of therapy. Treatment modalities included sclerotherapy only (n = 1), sclerotherapy followed by surgical resection (n = 1), surgical resection only (n = 3) (Fig. 2), and observation only (n = 1) (Table 2). Case 1 was treated exclusively with sclerotherapy. He started treatment at the age of 8 months and underwent three sclerotherapy sessions (8, 10 and 14 months of age). Prior to starting treatment he
had an episode of hematogenous infection of the lymphatic malformation that required a hospital admission and intravenous antibiotics. Currently, at 30 months of follow up he has residual disease. The parents decided to pursue no further treatment at this point and will consider plastic surgery in the future. Case 2 underwent surgery on day of life 3. A near complete resection was achieved with good cosmetic result. Three years later he developed a recurrence, so he underwent another resection and revision of the original scar. He developed a subcutaneous lymphatic collection one month later that required drain placement and resolved in 3 weeks. At 24 months of follow up he has minimal residual disease. Case 3 underwent surgery on day of life 6. A virtually complete resection was achieved. Eight months later he underwent surgery to remove small areas of residual lymphatic malformation in the skin and to obtain a better cosmetic result. Thirty months after the last operation, he has minimal residual disease. Case 4 did not receive treatment, per the parents’ preference. We have followed him closely and currently at the age of 26 months his lymphatic malformation has decreased in size. He has had no episodes of infection. Case 5 underwent surgical resection on day of life 14 (Fig. 3). A near complete resection was achieved. The wound developed an infection that required a surgical wash-out. One year after the resection he has minor residual disease and an area that intermittently opens and drains small amounts of
Fig. 1. Prenatal MRI of a 27-week gestational age fetus with a large macrocystic right axillary lymphatic malformation (star). The airway is not deviated (dashed arrow). The arrow points to the right forearm.
Fig. 2. Surgical resection of a right axillary lymphatic malformation (star). The black arrow shows the brachial plexus and the axillary vascular bundle.
Please cite this article as: Olive A, et al, Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes, J Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066
A. Olive et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
3
Table 2 Treatment modalities and outcomes of fetuses with isolated axillary lymphatic malformation.
Age at initial treatment Initial treatment modality Subsequent treatment modality Recurrent/residual disease Follow up since last treatment Complications of treatment
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
8 months Sclerotherapy None Yes 30 months Resp. distress
3 days Surgery Surgery Yes 24 months Seroma
6 days Surgery Surgery Yes 30 months None
No treatment No treatment No treatment Yes 26 months N/A
14 days Surgery None Yes 12 months Wound abscess
6 months Sclerotherapy Surgery Yes 10 months None
lymphatic fluid. No further treatment is planned at this point. Case 6 underwent initial treatment at 6 months of age with sclerotherapy for a large mixed macro/microcystic lesion (Fig. 4). He developed postsclerotherapy respiratory distress. Sclerotherapy did not achieve any improvement, so he was subsequently treated with staged surgical debulking at 8 and 11 months of age. Currently, 10 months after the last surgery, he still has residual disease for which he will undergo surgical resection in the near future. All patients who underwent surgical resection were confirmed as lymphatic malformations by pathology.
3. Discussion The pathogenesis of lymphatic malformations is largely unknown, but is likely related to a failure of the lymphatic sacs to canalize and communicate properly with the venous system. Lymphatic malformations vary in size from a few millimeters to several centimeters in diameter, and depending on the size of the cysts that form them, they are arbitrarily classified as macrocystic (when all cysts are N 2 cm in diameter), microcystic (when all cysts are b2 cm in diameter), or mixed. Axillary lymphatic malformations are isolated developmental anomalies; the coarctation of the aorta in one of our patients is merely a coincidental finding. Axillary lymphatic malformations are not associated with chromosomal abnormalities (e.g. Turner syndrome, Down syndrome), as opposed to posterior cervical (nuchal) lymphatic malformations (also referred to as cystic hygromas), which often are associated with those chromosomal abnormalities. Therefore,
Fig. 3. Preoperative appearance of a large axillary lymphatic malformation extending into the chest wall and involving the area of the right nipple.
amniocentesis for karyotype assessment is not routinely required in fetuses with isolated axillary lymphatic malformations. The prenatal imaging diagnosis of axillary lymphatic malformations and lymphatic malformations at any other location has been available for three decades, but the current availability of high-definition fetal MRI allows characterization of these lesions with an unprecedented degree of detail [4–6]. In the case of axillary lymphatic malformations, the MRI can precisely determine if there is extension of the mass along the chest wall, any extension toward the mediastinum, the degree of proximity to the brachial plexus, and most importantly, the presence of deep cervical extensions that can potentially compromise the airway at birth. Prenatal MRI is a costly study but we believe it is fully justified by the need to rule out airway compromise, which is difficult to diagnose by ultrasound alone. The median gestational age at diagnosis and delivery were 20 5/7 and 38 weeks, respectively. The 50th percentile for fetal weight at 20 and 38 weeks of gestation is roughly 330 and 3000 g, respectively, which represents a nine-fold increase. We observed, on average, the same rate of volume growth for the lymphatic malformations: 70 ml at diagnosis and 638 ml at delivery. Isolated axillary lymphatic malformations do not affect fetal growth or general fetal health. The main effect that an isolated axillary lymphatic malformations can have on the pregnancy is the potential for birth dystocia. Fetuses with small lymphatic malformations that do not cause abduction of the ipsilateral arm may be delivered vaginally, but fetuses with larger lymphatic malformations that produce abduction of the arm should be delivered by cesarean section. The volume of the lymphatic malformation at the time of delivery in 2 of our patients was 128 and 190 ml, respectively. Both patients had some degree of arm abduction, but is likely that they could have been delivered vaginally without complications. We elected to err on the safe side. In the other 4 patients the volumes were 483, 796, 838 and 884 ml, which carried a risk of dystocia despite the pliable nature of the lesions. Kaufman reported a case of prenatal percutaneous decompression of the lymphatic malformation to reduce the risk of dystocia, but the risks of such procedure do not appear to outweigh the risks of a routine cesarean section [7]. If left untreated after birth, axillary lymphatic malformations can lead to a number of complications. Spontaneous or trauma-related internal bleeding is not uncommon and results in pain and a sudden enlargement of the mass. Infection of the poorly vascularized lymphatic malformation is infrequent but possible, and hospital admission for intravenous antibiotics is often required in such circumstances. It is also quite common to see significant swelling of the lymphatic mass when the patient experiences any intercurrent infections (e.g. upper respiratory viral infection). Equally important is the fact that untreated axillary lymphatic malformations may interfere with the normal motor development of the ipsilateral arm and shoulder. Because of all these potential complications it is our preference to offer surgical therapy during the newborn period. Postnatally, lymphatic malformations are best evaluated by MRI, as is the case for other soft tissue masses. The high content of fluid provides a sharp contrast between the lymphatic mass and the normal anatomical structures on T2-weighted sequences. Sclerotherapy is a well-established treatment modality for lymphatic malformations in general, and the axillary location is not an
Please cite this article as: Olive A, et al, Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes, J Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066
4
A. Olive et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
Fig. 4. Postnatal MRI of a large mixed macrocystic and microcystic axillary lymphatic malformation (white stars). A: the arrows point to the lung apices. B: three-dimensional MRI rendering of the lymphatic malformation, which extends along the right chest wall.
exception. Macrocystic lesions tend to respond to sclerotherapy better than microcystic or mixed lesions, and that is also true for surgical therapy. Sclerotherapy has a number of disadvantages compared to surgery: it requires multiple rounds of treatment for which patients need a hospital admission, residual disease is always present, and the patients are exposed to doxycycline toxicity, which includes metabolic acidosis, hypoglycemia, hemolytic anemia and nerve damage. In addition, the use of percutaneous catheters puts the lymphatic mass at a higher risk of infection during the treatment sessions. Recurrences after sclerotherapy are common. Despite all the potential disadvantages, sclerotherapy is the only option in some cases, particularly in highly infiltrative deep lymphatic malformations for which surgery is deemed not suitable, and possibly in cases that have recurred after surgical resection. Surgical resection can be perceived by the parents as the obvious one-stop treatment. While some degree of success can be achieved in all cases and many cases require only one operation, it is important to inform the parents that recurrences are frequent, even after a neartotal resection. Surgery for axillary lymphatic malformations is not free of risks, including damage to the brachial plexus which can be embedded within the lymphatic mass. To minimize the risk of nerve damage we use intraoperative nerve monitoring (NIM-Neuro 3.0, Medtronic Inc., Minneapolis, MN). The electrodes of the monitoring system are placed sterilely and percutaneously in the muscles innervated by the branches of the nerves that need to be protected. In the event of any electrical or thermal stimulation of the nerves involved, the system triggers an audible and visual signal. From a technical standpoint, it is
important to stay on the surface of the lymphatic mass during the dissection, and if at all possible preserve the integrity of the cysts during the resection to enhance the possibility of maximal resection (Fig. 5). Lymphatic malformations that invade the dermis can result in lymphatic vesicles at the scar site, which can also be resected at a later point to improve the cosmetic result (Fig. 6). In addition to sclerotherapy and surgery, there are other forms of therapy for lymphatic malformation that, while still not widely used, provide some hope for the future. Among those is the systemic use of rapamycin. There is extensive experimental evidence that rapamycin is a potent inhibitor of the vascular endothelial growth factor (VEGF)C, exerting a strong antilymphangiogenic activity in live animal models. There are several case reports in the literature on the use of rapamycin for lymphatic malformations in humans [8,9]. The beta-blocker propranolol is widely used in the management of different forms of hemangiomas. However, its efficacy in the management of lymphangiomas is not encouraging, according to most reports [10,11]. There are anecdotal reports in the literature on the use of the cGMP-specific phosphodiesterase type 5 inhibitor sildenafil, but its efficacy has not been proven [12]. We have no experience with any of these forms of therapy. There are no prospective randomized trials comparing sclerotherapy versus surgery and no treatment algorithms, so the treatment modality for each patient remains a matter of treating team’s and parent’s preference [13]. In our experience we have favored surgical resection for macrocystic, noninvasive lymphatic malformations, and favored sclerotherapy for infiltrative microcystic ones. Although the efficacy of
Fig. 5. Resection of a left axillary lymphatic malformation. The mass was kept intact during the dissection, which allowed for a near-total resection. Black arrow: left nipple. Black dotted arrow: brachial plexus. White arrow: intact lymphatic mass.
Please cite this article as: Olive A, et al, Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes, J Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066
A. Olive et al. / Journal of Pediatric Surgery xxx (2015) xxx–xxx
5
In summary, we have observed that isolated axillary lymphatic malformations do not affect fetal health, can be treated with surgery, sclerotherapy or a combination of both, and that the incidence of residual disease and recurrence is significant after either treatment modality. This fact should be communicated to the parents at the time of prenatal counseling. References
Fig. 6. Lymphatic vesicles are seen along the scar 6 months after the resection (black arrows). Dotted arrow: right nipple.
sclerotherapy on microcystic lymphatic malformations is variable, success rates of up to 80% have been reported [14]. We recommend early neonatal treatment for those cases deemed good surgical candidates, because we believe that there are several risks associated with postponing therapy. On the other hand, for patients who are chosen to be treated with sclerotherapy the interventional radiology team prefers to wait a few months before initiating treatment due to the potential complications of sclerotherapy, which are better tolerated beyond the newborn period.
[1] Brouillard P, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet 2007;16:R140–9. [2] Molitch HI, Unger EC, Witte CL, et al. Percutaneous sclerotherapy of lymphangiomas. Radiology 1995;194:343–7. [3] Cahill AM, Nijs E, Ballah D, et al. Percutaneous sclerotherapy in neonatal and infant head and neck lymphatic malformations: a single center experience. J Pediatr Surg 2011;46:2083–95. [4] Hoffman-Tretin J, Koenigsberg M, Ziprkowski M, et al. Antenatal demonstration of axillary cystic hygroma. J Ultrasound Med 1988;7:233–5. [5] McCoy MC, Kuller JA, Chescheir NC, et al. Prenatal diagnosis and management of massive bilateral axillary cystic lymphangioma. Obstet Gynecol 1995;85:853–6. [6] Koelblinger C, Herold C, Nemec S, et al. Fetal magnetic resonance imaging of lymphangiomas. J Perinat Med 2013;41:437–43. [7] Kaufman GE, D'Alton ME, Crombleholme TM. Decompression of fetal axillary lymphangioma to prevent dystocia. Fetal Diagn Ther 1996;11:218–20. [8] Akyüz C, Ataş E, Varan A. Treatment of a tongue lymphangioma with sirolimus after failure of surgical resection and propranolol. Pediatr Blood Cancer 2014;61:931–2. [9] Reinglas J, Ramphal R, Bromwich M. The successful management of diffuse lymphangiomatosis using sirolimus: a case report. Laryngoscope 2011;121:1851–4. [10] Maruani A, Brown S, Lorette G, et al. Lack of effect of propranolol in the treatment of lymphangioma in two children. Pediatr Dermatol 2013;30:383–5. [11] Ozeki M, Kanda K, Kawamoto N, et al. Propranolol as an alternative treatment option for pediatric lymphatic malformation. Tohoku J Exp Med 2013;229:61–6. [12] Swetman GL, Berk DR, Vasanawala SS, et al. Sildenafil for severe lymphatic malformations. N Engl J Med 2012;366:384–6. [13] Elluru RG, Balakrishnan K, Padua HM. Lymphatic malformations: diagnosis and management. Semin Pediatr Surg 2014;23:178–85. [14] Alomari AI, Karian VE, Lord DJ, et al. Percutaneous sclerotherapy for lymphatic malformations: a retrospective analysis of patient-evaluated improvement. J Vasc Interv Radiol 2006;17:1639–48.
Please cite this article as: Olive A, et al, Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes, J Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.066