REVIEW URRENT C OPINION
Lymphatic malformations Scott C. Manning and Jonathan Perkins
Purpose of review To update current knowledge of basic science and clinical care of lymphatic malformations. Recent findings Advances in gene sequencing methods have allowed further elucidation of the genetic pathways involved in vascular development. New cell culture techniques are promising the development of practical models to test novel therapeutic interventions. Clinical treatment trends are continuing to shift more away from early surgery and toward sclerotherapy in appropriate cases. New emphasis has been placed upon quality of life analysis of treatment outcomes. Summary Basic science is increasing the understanding of vascular anomalies in general and may lead us soon toward more effective nonsurgical therapies. Focus on quality of life measures will help to elucidate the most effective therapeutic interventions. Keywords lymphatic malformation, quality of life, sclerotherapy
INTRODUCTION Vascular malformations are defined by disorganized vascular development without new cell growth. The International Society for the Study of Vascular Anomalies Classification is given below: (1) Vascular tumors (a) Hemangioma at infancy (b) Congenital hemangioma (i) Rapidly involuting congenital hemangioma (ii) Noninvoluting congenital hemangioma (c) Tufted angioma (d) Kaposiform hemangioendothelioma (2) Vascular malformations (a) Slow flow: (i) Capillary (ii) Port-wine (venular) (iii) Venous malformation (iv) Lymphatic malformation (v) Complex combined: Klippel–Trenaunay syndrome Proteus syndrome (b) Fast flow (i) Arterial malformation (ii) Arteriovenous fistula (iii) Arteriovenous malformation
The cause of lymphatic malformations is not known, but presumably involves failure of embryonic lymphatic systems to adequately separate from or connect to the venous system. Approximately half are diagnosed at birth or prenatally and a majority involve the head and neck, with axilla and abdominal wall comprising the next most common sites. Several staging systems have been proposed in order to better predict outcomes and guide therapeutic decisions. One summary of staging in general for the head and neck might be that low and lateral (excluding mediastinum) has a better prognosis than high and medial [1,2]. The best prognosis is for infrahyoid unilateral lesions, which tend to be macrocystic (greater than 2 cm diameter cysts) with usually good response to either surgery or sclerotherapy. The worst prognosis is for
Division Pediatric Otolaryngology-Seattle Children’s Hospital, Seattle, Washington, USA Correspondence to Scott C. Manning, Division Pediatric OtolaryngologySeattle Children’s Hospital, Department Otolaryngology-University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, USA. Tel: +1 206 987 5075; e-mail: [email protected] Curr Opin Otolaryngol Head Neck Surg 2013, 21:571–575 DOI:10.1097/MOO.0000000000000007
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KEY POINTS Advances in biology will lead to better understanding and hopefully better medical management of lymphatic malformations. Treatment paradigms are moving away from early surgical excision toward more conservative management. Sclerotherapy is the usual primary treatment for persistent macrocystic disease. Quality of life measures will help to guide treatment pathways.
suprahyoid bilateral (‘beard’) disease which tends to be more microcystic and woven into normal tissue. Mucosal involvement predicts worse response to therapy and more disease burden by quality of life measures [3 ]. &&
EPIDEMIOLOGY Lymphatic malformations are relatively rare, and isolated malformations account for about 12% of vascular anomalies in pediatric referral center databases (with hemangiomas comprising about 65%). Another 10% or so of referral center cases can be classified as mixed low flow lymphatic venous malformations [4]. The estimated frequency of lymphatic malformation in live births is approximately one in 500. The sex ratio is even for lymphatic malformations, and many cases present after birth with new onset swelling related to infection or local trauma. Lymphatic malformations (and/ or nuchal translucency) are seen frequently on prenatal ultrasound, but a large percentage appear to involute spontaneously before birth. Lymphatic or mixed lymphatic venous malformations can be associated with syndromes such as Noonan’s and Klippel–Trenaunay [5,6].
HISTOLOGY/CELL MARKERS Within the spectrum of vascular tissue, lymphatic malformation vessels have thin walls with little smooth muscle surrounded by fibroblasts, adipose cells, and leukocytes. Lymphatic tissue appears to undergo active remodeling in response to growth and inflammation, and the surrounding stromal cells undoubtedly play a role. One interesting finding is the prevalence of tertiary lymphoid organs in high-stage lymphatic malformations with mucosal involvement [7 ]. Lymphatic endothelial hyaluronan receptor-1 can be used as an &
572
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immunohistochemical marker on histology to differentiate lymphatic endothelial cells. Interestingly, there is little histologic difference between micro and macrocystic malformations other than the size of the cysts [8].
GENES AND PATHWAYS Lymphatics probably derive from prospero homeobox protein-1 positive endothelial cells after induction with SRY-related homeobox-related transcription factor-18 expression. Clinical disorders of lymphogenesis such as lymphaniectasia lymphedema (Noonan syndrome patients) can involve defects in the RAS/RAF pathway (protein kinases involved in cell signaling pathways). Other ‘RAS opathies’ involving abnormal lymphogenesis include Parkes–Weber syndrome with recently identified mutations in RASA1 [9 ]. Lymphangiogenesis involves expression of vascular endothelial growth factor receptor-2 and 3 and activation of kinase pathways [10]. Mutations in VEGR3 as well as in TIE2/TEK genes (tyrosine kinase receptors) have been implicated in lymphatic malformations as well as in other vascular tumors [11,12]. Recent advances with lymphatic cell culture techniques will hopefully jump start new research into lymphatic malformation biology and treatment modalities [13 ]. &&
&
INFLAMMATION Infection is a common clinical problem in young patients with lymphatic malformations especially those with high-stage lesions. Previous studies have showed lymphocytopenia in young patients with high-stage malformations [14], and stasis of flow through lymphatic malformations may be another contributing factor to infection. Inflammation can stimulate new lymphatic vessel growth [15] and can also perhaps create auto-sclerosis with subsequent shrinking of macrocystic malformations. Anecdotally, glucocorticoid therapy can be of great clinical benefit during flare-ups of lymphatic malformation infection, and studies using the mouse corneal suture model of lymphangiogenesis have shown lymphatic suppression with glucocorticoids [16 ]. &
DIAGNOSIS The head and neck is the most common site of clinically relevant lymphatic malformations. MRI is arguably the best overall imaging modality for characterizing lymphatic malformations although general anesthesia may be required in young children [17,18]. Macrocystic lesions are usually Volume 21 Number 6 December 2013
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lymphatic malformations Manning and Perkins
multilocular with high T 2 signal and often have a medial apex at the deep level of the jugular vein. Macrocystic unilateral neck lesions may be difficult to distinguish from sialoceles or type 2 branchial cleft cysts. Beard distribution lesions are usually characterized by macrocystic spaces laterally in the parotid and submandibular areas and microcystic disease in floor of mouth and tongue. Ultrasound is utilized for following response to therapy and often as a guide for sclerotherapy. Increasingly, lymphatic malformations are being diagnosed prenatally [19]. Large lymphatic malformations of the head and neck can be an indication for ex-utero intrapartum treatment procedures involving head and neck specialists for initial airway control [20].
TREATMENT: CONSERVATIVE Lymphatic malformation patients with extensive disease who are treated with surgery have a high potential for significant complications including cranial neuropathies (Fig. 1). Conservation approaches might include managing infection flare-ups with antibiotics and steroids, managing airway obstruction with tonsillectomy, conservative tongue reduction or tracheotomy, and waiting for maturation of systemic immunity. A recent report from Cincinnati documents eight children with mostly macrocystic malformations who showed significant reduction of mass size over a mean period of 34 months with conservative management alone [21]. Low and lateral disease appears to have the best prognosis regardless of the initial size of the macrocystic lesion [22]. In a recent case report, a patient treated with sildenafil for pulmonary hypertension was noted to have some spontaneous regression of a lymphatic malformation [23], but other centers to date have been unable to find a therapeutic effect.
TREATMENT: SCLEROTHERAPY Sclerotherapy has been utilized as a treatment for lymphatic malformations in one form or another for the last several decades. Study interpretation is often hampered by lack of standardized classification of initial disease and by lack of standardized clinical or imaging outcome measures. However, a general consensus exists that macrocystic head and neck lymphatic malformations have a good chance of having a clinically relevant response to most sclerotherapy techniques with a reasonable risk profile. OK-432 (Pacibanil) was first proposed as a sclerotherapy agent for lymphatic malformations
FIGURE 1. Nine-month-old boy, original MRI showing extensive mostly macrocystic cervical lymphatic malformation. The patient was treated at an outside institution with initial bleomycin sclerotherapy then two surgeries with resultant Horner’s syndrome, vocal cord paralysis, and cranial nerve 9 and 11 deficits.
by Fugita in 1987. Long-term follow-up studies show a 67% marked long-term improvement for macrocystic lesions [24 ]. The exact mechanism of therapeutic effect for sclerotherapy is unknown, but presumably involves local and even potentially system upregulation of inflammation [25]. One institution has even reported two cases of successful intrauterine OK-432 injection for large prenatally diagnosed cervical lymphatic malformations [26]. OK-432 is not approved for use in the United States, and results with microcystic disease have been less promising. Doxycycline with or without detergent is perhaps the most commonly used sclerosing agent for lymphatic malformations currently in the United States. As with OK-432, published series report good results with low complication rates for macrocystic disease [27]. Ethyl alcohol by itself or combined with other agents such as doxycycline is another common sclerotherapy agent. Reported results with ethyl alcohol are similar to those in the literature for other agents for macrocystic disease [28,29]. Complications are not infrequent with sclerotherapy and can include airway obstruction
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&&
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573
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Pediatric otolaryngology
from edema [30], necrosis of overlying skin, marginal mandibular nerve weakness, and cranial neuropathies. Fortunately, most complications are self-resolving. The risk of complication goes up considerably when the injection or infusion gets outside of a macrocystic space into the interstitial planes (higher when treating areas of microcystic disease).
TREATMENT: SURGERY Surgery has been the most common traditional therapy for symptomatic lymphatic malformations, and interpretation of results is limited by lack of standardization of classification of initial diagnosis and treatment outcomes. Not much new has been reported recently in operative treatment techniques other than the interesting concept of intraoperative endoscopy inside lymphatic spaces in order to better define the extent of macrocystic disease [31,32]. Surgery has excellent results with a low complication rate in reports from experienced tertiary care centers for cervical macrocystic disease [33]. Those are also the patients with the highest likelihood of spontaneous resolution and the best response rates to sclerotherapy. Some centers still report a high rate of cranial nerve injury with surgery [34], and surgery is probably a better option in centers with experience in head and neck cancer including the concept of identifying and isolating cranial nerves first in the dissection [35]. Most centers seem to be evolving toward a stepped protocol with early conservation management followed by sclerotherapy for symptomatic macrocystic disease without evidence of spontaneous resolution followed by surgery at a later age for patients with persistent (often microcystic) disease or airway compromise [36].
TREATMENT: ABLATION The biggest challenge in the treatment of lymphatic malformations remains those patients with highstage often beard distribution disease with mucosal involvement. A high percentage of these patients have airway involvement at the level of supraglottic larynx to tongue [37] and will require tracheotomy or some type of disease ablation procedure for airway maintenance. Controlled studies are lacking, but authors report good results for multiple modalities of transoral or laryngoscopic ablation with radiofrequency, laser, or traditional cautery [38–40].
FIGURE 2. Fifteen-year-old girl with a large beard distribution macro and microcystic lymphatic malformation treated with right and left parotidectomy and neck dissections at ages 4 and 6, respectively. She now desires better mandibular symmetry, but she has good occlusion. The plan is to do soft tissue debulking on her chin from a submandibular incision before considering any mandibular surgery.
area or the oral cavity. A recent case–control study confirms an increase in gonial angle and anterior open bite deformity in patients with beard distribution malformations contributing to oral cavity functional deficits [41]. These patients usually also suffer from chronic dental caries probably related to loss of local immunity as a consequence of mucosal lymphatic malformation involvement. Management of these difficult patients is a team effort with dental medicine and oral surgery. Mandibular surgery for improved cosmesis and function is a great challenge with little in the literature to guide decision making (Fig. 2).
TREATMENT: ORBIT Extensive lymphatic malformations of the orbit represent exceptional challenges requiring a team approach involving interventional radiology, ophthalmology, and head and neck surgery. Small lesions may be observed or managed with focused excision, whereas large lesions may require combinations of sclerotherapy and craniofacial surgical approaches [42,43].
TREATMENT: BONE Boney hypertrophy with esthetic and functional consequences is a frequent and frustrating problem with high-stage lymphatic malformations in the 574
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CONCLUSION Advances in knowledge of vascular biology and genetics will hopefully lead to better medical Volume 21 Number 6 December 2013
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lymphatic malformations Manning and Perkins
treatment modalities for lymphatic malformations. Current trends in clinical care include more conservative initial management while waiting for possible spontaneous resolution and maturation of systemic immunity. Sclerotherapy is often the first modality chosen for noninvoluting macrocystic disease. Surgery has a role for refractory lesions, but results are better for macrocystic disease. Focusing on quality of life will help to define better treatment pathways. Acknowledgements None. Conflicts of interest The authors have no conflicts of interest or grant support relevant to the views expressed in this article.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. de Serres LM, Sie KC, Richardson MA. Lymphatic malformations of the head and neck. A proposal for staging. Arch Otolaryngol Head Neck Surg 1995; 121:577–582. 2. Hamoir M, Plouin-Gaudon I, Rombaux P, et al. Lymphatic malformations of the head and neck: a retrospective review and a support for staging. Head Neck 2001; 23:326–337. 3. Balakrishnan K, Edwards TC, Perkins JA. Functional and symptom impacts of && pediatric head and neck lymphatic malformations: developing a patientderived instrument. Otolaryngol Head Neck Surg 2012; 147:925–931. This is the first article to examine quality of life factors associated with lymphatic malformations. 4. Fraulin FO, Flannigan RK, Sharma VK, et al. The epidemiological profile of the vascular birthmark clinic at the Alberta Children’s Hospital. Can J Plast Surg 2012; 20:67–70. 5. Oduber CE, van Beers EJ, Bresser P, et al. Venous thromboembolism and prothrombic parameters in Klippel-Trenaunay syndrome. Neth J Med 2013; 71:246–252. 6. Croonen EA, Nillesen WM, Stuurman KE, et al. Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings. Eur J Hum Genet 2013; 21:936–942. 7. Kirsh AL, Cushing SL, Chen EY, et al. Tertiary lymphoid organs in lymphatic & malformations. Lymphat Res Biol 2011; 9:85–92. Inflammation influences vascular development. 8. Perkins JA, Manning SC, Tempero RM, et al. Lymphatic malformations: current cellular and clinical investigations. Otolaryngol Head Neck Surg 2010; 142:789–794. 9. Burrows PE, Gonzalex-Garay ML, Rasmussen JC, et al. Lymphatic && abnormalities are associated with RASA1 gene mutations in mouse and man. Proc Natl Acad Sci 2013; 110:8621–8626. Advances in vascular biology and genetics will help elucidate future treatments. 10. Yong D, Atri D, Eichmann A, Simons M. Endothelial ERK signaling controls lymphatic fate specification. J Clin Invest 2013; 123:1202– 1215. 11. Frigerio A, Stevenson DA, Grimmer JF. The genetics of vascular anomalies. Curr Opin Otolaryngol Head Neck Surg 2012; 20:527–532. 12. Ye C, Pan L, Huang Y, et al. Somatic mutations in exon 17 of the TEK gene in vascular tumors and vascular malformations. J Vasc Surg 2011; 54:1760– 1768. 13. Lokmic Z, Mitchell GM, Koh Wee Chong N, et al. Isolation of human & lymphatic malformation endothelial cells, their in vitro characterization and in vivo survival in a mouse xenograft model. Angiogenesis 2013; PMID 23884796 [Epub ahead of print]. Successful cell culturing could lead to new treatments. 14. Tempero RM, Hannibal M, Finn LS, et al. Lymphocytopenia in children with lymphatic malformation. Arch Otolaryngol Head Neck Surg 2006; 132: 93–97.
15. Kelley PM, Connor AL, Tempero RM. Lymphatic vessel memory stimulated by recurrent inflammation. Am J Pathol 2013; 182:2418–2428. 16. Steele MM, Kelley PM, Schieler AM, Tempero RM. Glucocorticoids suppress & corneal lymphangiogenesis. Cornea 2011; 30:1422–1427. Inflammation influences lymphatic growth. 17. Wilmanska D, Antosik-Biernacka A, Przewratil P, et al. The role of MRI in diagnostic algorithm of cervicofacial vascular anomalies in children. Pol J Radiol 2013; 78:7–14. 18. Flors L, Leiva-Salinas C, Maged IM, et al. MR imaging of soft-tissue vascular malformations: diagnosis, classification, and therapy follow-up. Radiographics 2011; 31:1321–1340. 19. Croonen EA, Nillesen WM, Stuurman KE, et al. Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings. Eur J Hum Genet 2013; doi: 10. 1038/ejhg. 2012. 285 PMID 23321623 [Epub ahead of print] 20. Stefini S, Bazzana T, Smussi C, et al. EXIT (Ex utero Intrapartum Treatment) in lymphatic malformations of the head and neck: discussion of three cases and proposal of an EXIT-TTP (Team Time Procedure) list. Int J Pediatr Otorhinolaryngol 2012; 76:20–27. 21. Dasqupta R, Adams D, Elluru R, et al. Noninterventional treatment of selected head and neck lymphatic malformations. J Pediatr Surg 2008; 43:869–873. 22. Perkins JA, Maniglia C, Magit A, et al. Clinical and radiographic findings in children with spontaneous lymphatic malformation regression. Otolaryngol Head Neck Surg 2008; 138:772–777. 23. Swetman GL, Berk DR, Vasanawala SS, Bruckner AL. Sildenafil for severe lymphatic malformations. N Engl J Med 2012; 366:384–386. 24. Weitz-Tuoretmaa A, Rautio R, Valkila J, et al. Efficacy of OK-432 sclerotherapy && in treatment of lymphatic malformations: long-term follow-up results. Eur Arch Otorhinolaryngol 2013; PMID 23649509 [Epub ahead of print]. Sclerotherapy has become the treatment of choice for macrocystic disease. 25. Narkio-Makela M, Makela T, Saarinen P, et al. Treatment of lymphatic malformations of head and neck with OK-432 sclerotherapy induce systemic inflammatory response. Eur Arch Otorhinolaryngol 2011; 268:123–129. 26. Mikovic A, Simic R, Egic A, et al. Intrauterine treatment of large fetal neck lymphangioma with OK-432. Fetal Diagn Ther 2009; 26:102–106. 27. Shergill A, John P, Amaral JG. Doxycycline sclerotherapy in children with lymphatic malformations: outcomes, complications and clinical efficacy. Pediatr Radiol 2012; 42:1080–1088. 28. 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; 46:2083–2095. 29. Impellizzeri P, Romero C, Borruto FA, et al. Sclerotherapy for cervical cystic lymphatic malformations in children. Our experience with computed tomography-guided 98% sterile ethanol insertion and a review of the literature. J Pediatr Surg 2010; 45:2473–2478. 30. Churchill P, Otal D, Pemberton J, et al. Sclerotherapy for lymphatic malformations in children: a scoping review. J Pediatr Surg 2011; 46:912–922. 31. Eivazi B, Werner JA. Management of vascular malformations and hemangiomas of the head and neck-an update. Curr Opin Otolaryngol Head Neck Surg 2013; 21:157–163. 32. Eivazi B, Teymoortash A, Wiegand S, et al. Intralesional endoscopy of advanced lymphatic malformations of the head and neck: a new diagnostic approach and a potential therapeutic tool. Arch Otolaryngol Head Neck Surg 2010; 136:790–795. 33. Bajaj Y, Hewitt R, Ifeacho S, Hartley BE. Surgical excision as primary treatment modality for extensive cervicofacial lymphatic malformations in children. Int J Pediatr Otorhinolaryngol 2012; 35:60–67. 34. Benazzou S, Boulaadas M, Essakalli L. Giant pediatric cervicofacial lymphatic malformations. J Craniofac Surg 2013; 24:1307–1309. 35. Lee GS, Perkins JA, Oliaei S, Manning SC. Facial nerve anatomy, dissection and preservation in lymphatic malformation treatment. Int J Pediatr Otorhinolaryngol 2008; 72:759–766. 36. Gilony D, Schwartz M, Shpitzer T, et al. Treatment of lymphatic malformations: a more conservative approach. J Pediatr Surg 2012; 47:1837–1842. 37. TM O, Rickert SM, Diallo AM, et al. Lymphatic malformations of the airway. Otolaryngolo Head Neck Surg 2013; 149:156–160. 38. Thottam PJ, Al-Barazi R, Madgy DN, Rozzelle A. Submucosal resection of a microcystic oropharyngeal lymphatic malformation using radiofrequency ablatioin. Int J Pediatr Otorhinolaryngol 2013; 77:1589–1592. 39. Kim SW, Kavanagh K, Orbach DB, et al. Long-term outcome of radiofrequency ablation for intraoral microcystic lymphatic malformation. Arch Otolaryngol Head Neck Surg 2011; 137:1247–1250. 40. Goswamy J, Penney SE, Bruce IA, Rothera MP. Radiofrequency ablation in the treatment of paediatric microcystic lymphatic malformations. J Laryngol Otol 2013; 127:279–284. 41. TM O, Kwak R, Portnof JE, et al. Analysis of skeletal mandibular abnormalities associated with cervicofacial lymphatic malformations. Laryngoscope 2011; 121:91–101. 42. Wiegand S, Eivazi B, Bloch LM, et al. Lymphatic malformations of the orbit. Clin Exp Otorhinolaryngol 2013; 6:30–35. 43. Greene AK, Burrows PE, Smith L, Mulliken JB. Periorbital lymphatic malformation: clinical course and management in 42 patients. Plast Reconstruc Surg 2005; 115:22–30.
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Lymphatic malformations Scott C. Manning and Jonathan Perkins
Purpose of review To update current knowledge of basic science and clinical care of lymphatic malformations. Recent findings Advances in gene sequencing methods have allowed further elucidation of the genetic pathways involved in vascular development. New cell culture techniques are promising the development of practical models to test novel therapeutic interventions. Clinical treatment trends are continuing to shift more away from early surgery and toward sclerotherapy in appropriate cases. New emphasis has been placed upon quality of life analysis of treatment outcomes. Summary Basic science is increasing the understanding of vascular anomalies in general and may lead us soon toward more effective nonsurgical therapies. Focus on quality of life measures will help to elucidate the most effective therapeutic interventions. Keywords lymphatic malformation, quality of life, sclerotherapy
INTRODUCTION Vascular malformations are defined by disorganized vascular development without new cell growth. The International Society for the Study of Vascular Anomalies Classification is given below: (1) Vascular tumors (a) Hemangioma at infancy (b) Congenital hemangioma (i) Rapidly involuting congenital hemangioma (ii) Noninvoluting congenital hemangioma (c) Tufted angioma (d) Kaposiform hemangioendothelioma (2) Vascular malformations (a) Slow flow: (i) Capillary (ii) Port-wine (venular) (iii) Venous malformation (iv) Lymphatic malformation (v) Complex combined: Klippel–Trenaunay syndrome Proteus syndrome (b) Fast flow (i) Arterial malformation (ii) Arteriovenous fistula (iii) Arteriovenous malformation
The cause of lymphatic malformations is not known, but presumably involves failure of embryonic lymphatic systems to adequately separate from or connect to the venous system. Approximately half are diagnosed at birth or prenatally and a majority involve the head and neck, with axilla and abdominal wall comprising the next most common sites. Several staging systems have been proposed in order to better predict outcomes and guide therapeutic decisions. One summary of staging in general for the head and neck might be that low and lateral (excluding mediastinum) has a better prognosis than high and medial [1,2]. The best prognosis is for infrahyoid unilateral lesions, which tend to be macrocystic (greater than 2 cm diameter cysts) with usually good response to either surgery or sclerotherapy. The worst prognosis is for
Division Pediatric Otolaryngology-Seattle Children’s Hospital, Seattle, Washington, USA Correspondence to Scott C. Manning, Division Pediatric OtolaryngologySeattle Children’s Hospital, Department Otolaryngology-University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, USA. Tel: +1 206 987 5075; e-mail: [email protected] Curr Opin Otolaryngol Head Neck Surg 2013, 21:571–575 DOI:10.1097/MOO.0000000000000007
1068-9508 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-otolaryngology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pediatric otolaryngology
KEY POINTS Advances in biology will lead to better understanding and hopefully better medical management of lymphatic malformations. Treatment paradigms are moving away from early surgical excision toward more conservative management. Sclerotherapy is the usual primary treatment for persistent macrocystic disease. Quality of life measures will help to guide treatment pathways.
suprahyoid bilateral (‘beard’) disease which tends to be more microcystic and woven into normal tissue. Mucosal involvement predicts worse response to therapy and more disease burden by quality of life measures [3 ]. &&
EPIDEMIOLOGY Lymphatic malformations are relatively rare, and isolated malformations account for about 12% of vascular anomalies in pediatric referral center databases (with hemangiomas comprising about 65%). Another 10% or so of referral center cases can be classified as mixed low flow lymphatic venous malformations [4]. The estimated frequency of lymphatic malformation in live births is approximately one in 500. The sex ratio is even for lymphatic malformations, and many cases present after birth with new onset swelling related to infection or local trauma. Lymphatic malformations (and/ or nuchal translucency) are seen frequently on prenatal ultrasound, but a large percentage appear to involute spontaneously before birth. Lymphatic or mixed lymphatic venous malformations can be associated with syndromes such as Noonan’s and Klippel–Trenaunay [5,6].
HISTOLOGY/CELL MARKERS Within the spectrum of vascular tissue, lymphatic malformation vessels have thin walls with little smooth muscle surrounded by fibroblasts, adipose cells, and leukocytes. Lymphatic tissue appears to undergo active remodeling in response to growth and inflammation, and the surrounding stromal cells undoubtedly play a role. One interesting finding is the prevalence of tertiary lymphoid organs in high-stage lymphatic malformations with mucosal involvement [7 ]. Lymphatic endothelial hyaluronan receptor-1 can be used as an &
572
www.co-otolaryngology.com
immunohistochemical marker on histology to differentiate lymphatic endothelial cells. Interestingly, there is little histologic difference between micro and macrocystic malformations other than the size of the cysts [8].
GENES AND PATHWAYS Lymphatics probably derive from prospero homeobox protein-1 positive endothelial cells after induction with SRY-related homeobox-related transcription factor-18 expression. Clinical disorders of lymphogenesis such as lymphaniectasia lymphedema (Noonan syndrome patients) can involve defects in the RAS/RAF pathway (protein kinases involved in cell signaling pathways). Other ‘RAS opathies’ involving abnormal lymphogenesis include Parkes–Weber syndrome with recently identified mutations in RASA1 [9 ]. Lymphangiogenesis involves expression of vascular endothelial growth factor receptor-2 and 3 and activation of kinase pathways [10]. Mutations in VEGR3 as well as in TIE2/TEK genes (tyrosine kinase receptors) have been implicated in lymphatic malformations as well as in other vascular tumors [11,12]. Recent advances with lymphatic cell culture techniques will hopefully jump start new research into lymphatic malformation biology and treatment modalities [13 ]. &&
&
INFLAMMATION Infection is a common clinical problem in young patients with lymphatic malformations especially those with high-stage lesions. Previous studies have showed lymphocytopenia in young patients with high-stage malformations [14], and stasis of flow through lymphatic malformations may be another contributing factor to infection. Inflammation can stimulate new lymphatic vessel growth [15] and can also perhaps create auto-sclerosis with subsequent shrinking of macrocystic malformations. Anecdotally, glucocorticoid therapy can be of great clinical benefit during flare-ups of lymphatic malformation infection, and studies using the mouse corneal suture model of lymphangiogenesis have shown lymphatic suppression with glucocorticoids [16 ]. &
DIAGNOSIS The head and neck is the most common site of clinically relevant lymphatic malformations. MRI is arguably the best overall imaging modality for characterizing lymphatic malformations although general anesthesia may be required in young children [17,18]. Macrocystic lesions are usually Volume 21 Number 6 December 2013
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lymphatic malformations Manning and Perkins
multilocular with high T 2 signal and often have a medial apex at the deep level of the jugular vein. Macrocystic unilateral neck lesions may be difficult to distinguish from sialoceles or type 2 branchial cleft cysts. Beard distribution lesions are usually characterized by macrocystic spaces laterally in the parotid and submandibular areas and microcystic disease in floor of mouth and tongue. Ultrasound is utilized for following response to therapy and often as a guide for sclerotherapy. Increasingly, lymphatic malformations are being diagnosed prenatally [19]. Large lymphatic malformations of the head and neck can be an indication for ex-utero intrapartum treatment procedures involving head and neck specialists for initial airway control [20].
TREATMENT: CONSERVATIVE Lymphatic malformation patients with extensive disease who are treated with surgery have a high potential for significant complications including cranial neuropathies (Fig. 1). Conservation approaches might include managing infection flare-ups with antibiotics and steroids, managing airway obstruction with tonsillectomy, conservative tongue reduction or tracheotomy, and waiting for maturation of systemic immunity. A recent report from Cincinnati documents eight children with mostly macrocystic malformations who showed significant reduction of mass size over a mean period of 34 months with conservative management alone [21]. Low and lateral disease appears to have the best prognosis regardless of the initial size of the macrocystic lesion [22]. In a recent case report, a patient treated with sildenafil for pulmonary hypertension was noted to have some spontaneous regression of a lymphatic malformation [23], but other centers to date have been unable to find a therapeutic effect.
TREATMENT: SCLEROTHERAPY Sclerotherapy has been utilized as a treatment for lymphatic malformations in one form or another for the last several decades. Study interpretation is often hampered by lack of standardized classification of initial disease and by lack of standardized clinical or imaging outcome measures. However, a general consensus exists that macrocystic head and neck lymphatic malformations have a good chance of having a clinically relevant response to most sclerotherapy techniques with a reasonable risk profile. OK-432 (Pacibanil) was first proposed as a sclerotherapy agent for lymphatic malformations
FIGURE 1. Nine-month-old boy, original MRI showing extensive mostly macrocystic cervical lymphatic malformation. The patient was treated at an outside institution with initial bleomycin sclerotherapy then two surgeries with resultant Horner’s syndrome, vocal cord paralysis, and cranial nerve 9 and 11 deficits.
by Fugita in 1987. Long-term follow-up studies show a 67% marked long-term improvement for macrocystic lesions [24 ]. The exact mechanism of therapeutic effect for sclerotherapy is unknown, but presumably involves local and even potentially system upregulation of inflammation [25]. One institution has even reported two cases of successful intrauterine OK-432 injection for large prenatally diagnosed cervical lymphatic malformations [26]. OK-432 is not approved for use in the United States, and results with microcystic disease have been less promising. Doxycycline with or without detergent is perhaps the most commonly used sclerosing agent for lymphatic malformations currently in the United States. As with OK-432, published series report good results with low complication rates for macrocystic disease [27]. Ethyl alcohol by itself or combined with other agents such as doxycycline is another common sclerotherapy agent. Reported results with ethyl alcohol are similar to those in the literature for other agents for macrocystic disease [28,29]. Complications are not infrequent with sclerotherapy and can include airway obstruction
1068-9508 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
www.co-otolaryngology.com
573
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Pediatric otolaryngology
from edema [30], necrosis of overlying skin, marginal mandibular nerve weakness, and cranial neuropathies. Fortunately, most complications are self-resolving. The risk of complication goes up considerably when the injection or infusion gets outside of a macrocystic space into the interstitial planes (higher when treating areas of microcystic disease).
TREATMENT: SURGERY Surgery has been the most common traditional therapy for symptomatic lymphatic malformations, and interpretation of results is limited by lack of standardization of classification of initial diagnosis and treatment outcomes. Not much new has been reported recently in operative treatment techniques other than the interesting concept of intraoperative endoscopy inside lymphatic spaces in order to better define the extent of macrocystic disease [31,32]. Surgery has excellent results with a low complication rate in reports from experienced tertiary care centers for cervical macrocystic disease [33]. Those are also the patients with the highest likelihood of spontaneous resolution and the best response rates to sclerotherapy. Some centers still report a high rate of cranial nerve injury with surgery [34], and surgery is probably a better option in centers with experience in head and neck cancer including the concept of identifying and isolating cranial nerves first in the dissection [35]. Most centers seem to be evolving toward a stepped protocol with early conservation management followed by sclerotherapy for symptomatic macrocystic disease without evidence of spontaneous resolution followed by surgery at a later age for patients with persistent (often microcystic) disease or airway compromise [36].
TREATMENT: ABLATION The biggest challenge in the treatment of lymphatic malformations remains those patients with highstage often beard distribution disease with mucosal involvement. A high percentage of these patients have airway involvement at the level of supraglottic larynx to tongue [37] and will require tracheotomy or some type of disease ablation procedure for airway maintenance. Controlled studies are lacking, but authors report good results for multiple modalities of transoral or laryngoscopic ablation with radiofrequency, laser, or traditional cautery [38–40].
FIGURE 2. Fifteen-year-old girl with a large beard distribution macro and microcystic lymphatic malformation treated with right and left parotidectomy and neck dissections at ages 4 and 6, respectively. She now desires better mandibular symmetry, but she has good occlusion. The plan is to do soft tissue debulking on her chin from a submandibular incision before considering any mandibular surgery.
area or the oral cavity. A recent case–control study confirms an increase in gonial angle and anterior open bite deformity in patients with beard distribution malformations contributing to oral cavity functional deficits [41]. These patients usually also suffer from chronic dental caries probably related to loss of local immunity as a consequence of mucosal lymphatic malformation involvement. Management of these difficult patients is a team effort with dental medicine and oral surgery. Mandibular surgery for improved cosmesis and function is a great challenge with little in the literature to guide decision making (Fig. 2).
TREATMENT: ORBIT Extensive lymphatic malformations of the orbit represent exceptional challenges requiring a team approach involving interventional radiology, ophthalmology, and head and neck surgery. Small lesions may be observed or managed with focused excision, whereas large lesions may require combinations of sclerotherapy and craniofacial surgical approaches [42,43].
TREATMENT: BONE Boney hypertrophy with esthetic and functional consequences is a frequent and frustrating problem with high-stage lymphatic malformations in the 574
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CONCLUSION Advances in knowledge of vascular biology and genetics will hopefully lead to better medical Volume 21 Number 6 December 2013
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Lymphatic malformations Manning and Perkins
treatment modalities for lymphatic malformations. Current trends in clinical care include more conservative initial management while waiting for possible spontaneous resolution and maturation of systemic immunity. Sclerotherapy is often the first modality chosen for noninvoluting macrocystic disease. Surgery has a role for refractory lesions, but results are better for macrocystic disease. Focusing on quality of life will help to define better treatment pathways. Acknowledgements None. Conflicts of interest The authors have no conflicts of interest or grant support relevant to the views expressed in this article.
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