Lymphatic Malformation (Cystic Hygroma)

LMs are thought to arise from the following:

• Sequestration of lymphatic tissue from lymphatic sacs during development
• Failure of these tissues to communicate with the lymphatic or venous system
• Tissue dilation resulting in the cystic morphology ^[5]

These lymphatic rests can penetrate adjacent structures or dissect along fascial planes and eventually become canalized. Because of the lack of an outflow tract, these spaces retain their secretions and develop cystic components. The nature of the surrounding tissue determines whether the lymphangioma is capillary, cavernous, or cystic.

LMs tend to form in loose areolar tissue, whereas capillary and cavernous forms of lymphangiomas tend to form in muscle. Studies using cell proliferation markers have demonstrated that lymphangioma enlargement is associated with engorgement rather than cell proliferation. Molecular studies suggest that vascular endothelial growth factor C (VEGF-C) and its receptors may play an important role in the development of LMs.[6]

LMs can be either congenital or acquired. Acquired LMs can arise from trauma (including surgery), inflammation, or lymphatic drainage pathway obstruction. 

Karyotypic abnormalities are present in 25-70% of children with LMs. LM tends to be more common in patients with Turner syndrome, Klinefelter syndrome, trisomy 21, and trisomy 18 (as well as 13), though these are not considered to be causative.

In addition, several nonchromosomal disorders, including Noonan syndrome, Fryns syndrome, multiple pterygium syndrome, and achondroplasia, are associated with an increased incidence of LM. Intrauterine alcohol exposure has been associated with the development of LM. Another disorder, Gorham-Stout syndrome, consists of dissolution of bone caused by either LMs or hemangiomas.[1, 5]

The incidence of LM is estimated to be 1 per 6000-16,000 live births.

Most LMs (50-65%) are evident at birth, and 80-90% are present by age 2 years. Some authors believe that all LMs are present at birth, even though they may not have fully manifested at that time.[7]  LM can be visualized with abdominal ultrasonography (US) by 10 weeks' gestation, though transvaginal US provides superior detail. Fast-spin magnetic resonance imaging (MRI) can also be used to determine the extent of fetal LM. Elevated alpha-fetoprotein levels in amniocentesis fluid have been reported in pregnancies with LM.

The sex distribution is equal. Most series have reported no racial predominance, though a decreased incidence in African Americans has been described.

In some series, the reported mortality has been as high as 2-6%, usually secondary to pneumonia, bronchiectasis, and airway compromise. Obviously, this figure is pertinent in the larger lesions.

As would be expected, morbidity depends on the anatomic location of the LM. In general, morbidity is related to cosmetic disfigurement and impingement on other critical structures (eg, nerves, vessels, and laryngotracheal complex).

Unlike hemangiomas, LMs do not commonly resolve spontaneously. Recurrence is rare when all gross disease is removed. If residual tissue is left behind, the expected recurrence rate is approximately 15%.

In antenatal cystic hygroma (CH), diagnosis after 30 weeks' gestation is considered a positive prognosticator. A study by Lejeunesse et al involving 69 fetuses with LMs diagnosed in the first trimester suggested that the following were predictors of a poor outcome[8] :

• Nuchal thickness greater than 6.0-6.5 mm
• Presence of hydrops fetalis, abnormalities on US, or both
• Fetal karyotypic abnormalities, evolution of LM on US, or both

A study by Sanhal et al found that fetuses with septated LMs had poor perinatal outcomes.[9]

The presenting signs and symptoms of a lymphatic malformation (LM) vary, depending on the lesion's location.

The microcystic form tends to predominate over macrocystic LM in the oral cavity and oropharynx. Microcystic LMs commonly appear as clusters of clear, black, or red vesicles on the buccal mucosa or tongue. Macrocystic LMs tend to predominate below the mylohyoid muscle and can involve both the anterior and the posterior triangles of the neck. The cysts are typically large and thick-walled and have little involvement of surrounding tissue. The overlying skin can take on a bluish hue or may appear normal.

LMs often present after a sudden increase in size secondary to infection or intralesional bleeding. Spontaneous decompression or shrinkage is uncommon.

Rarely, children with LMs display symptoms of newly onset obstructive sleep apnea syndrome (OSAS). This situation may involve children with LM or other space-occupying lesions of the supraglottic or paraglottic region. Suprahyoid lymphangiomas tend to cause more breathing difficulties than infrahyoid lesions.

Potentially life-threatening airway compromise that manifests as noisy breathing (stridor) and cyanosis is a possible symptom of lymphangiomas.

Feeding difficulties, as well as failure to thrive, may alert the clinician to a potential lymphangioma. This is especially true when the lesion affects structures of the upper aerodigestive tract.[10]

Rare locations, such as the middle ear, have been reported.[11]

On physical examination, a typical LM is a soft, painless, compressible (doughy) mass that usually transilluminates.

A comprehensive head and neck examination should be performed to evaluate for any compressive cranial neuropathies related to LM.

In children who present with neck LM, attention must be given to assess for tracheal deviation or other evidence of impending airway obstruction.

Flexible laryngoscopy performed by an otolaryngologist can be a useful adjunct to evaluate vocal fold mobility as well as airway patency.

Complications of LMs include the following:

• Airway obstruction
• Hemorrhage
• Infection
• Deformation of surrounding bony craniofacial structures or dentition (if an LM is left untreated)

Studies have suggested that fluorescent in-situ hybridization (FISH) can be used to evaluate for lymphatic malformation (LM) in antenatal chromosomal analysis (chromosomes 13, 18, 21, X, and Y).[12]

Magnetic resonance imaging (MRI), computed tomography (CT), and ultrasonography (US) are all helpful in delineating the nature of a cystic neck mass. CT and MRI reveal a ringlike margin enhancement with sharp demarcation of cystic areas. The cystic areas tend to appear circumscribed and discrete. A poorly defined isodense mass that obscures muscle and fatty planes is more consistent with a microcystic LM.

Magnetic resonance imaging

MRI is the consensus study of choice. It provides the best soft-tissue detail and can delineate the relation of the lesion to surrounding structures. Contrast can be used to differentiate hemangiomas from lymphangiomas. On MRI, LMs appear hyperintense on T2-weighted images and hypointense on T1-weighted images.

Computed tomography

CT is faster than MRI and may be more readily available; however, it carries the risk of radiation exposure, and detail is lost if the LM is surrounded by tissues of similar attenuation. Contrast helps to enhance cyst-wall visualization and the relation to surrounding blood vessels. On CT, LMs appear isodense to cerebrospinal fluid (CSF). (See the image below.)

Ultrasonography

US is the least invasive study. It is very useful in demonstrating the relationship of LM to the surrounding structures; however, it is of limited value for assessing mediastinal and retropharyngeal structures. US can also be used to detect LM in utero. Echographic visualization of multiple septa in fetal LM has been postulated to be a poor prognostic indicator.[9]

Plain radiography

With any large mass of the head and neck, airway radiography (high-kilovolt anteroposterior and lateral neck radiographs or airway fluoroscopy) can be helpful in delineating possible airway compromise. Plain radiography is a reasonable initial imaging modality in the evaluation of a neck mass with potential airway manifestations.

Lymphoscintigraphy

A case report has also highlighted the ability to visualize LM by means of lymphoscintigraphy.[13]

LMs are composed of large irregular sinuses with a single layer of flattened epithelial lining and fibrous adventitial coats. The thickness of the vessel wall varies, with both striated and smooth muscle components. 

Although most LMs are multicystic, a unilocular cyst is found in approximately 10% of cases. Cysts can range from 1 mm to several centimeters in size and are filled with clear- to straw-colored fluid, which is eosinophilic and protein-rich. Individual cysts may be isolated or may freely communicate. The surrounding stroma is fibrous or fatty and may contain lymphoid aggregates, smooth muscle, or other local tissues.

LMs may contain multiple subtypes (eg, capillary and cavernous) and, in these instances, are categorized according to the predominant subtype. In addition, lesions with a hemangiomatous component are considered hemangiolymphangiomas. Hemorrhage into the cyst is common and can be secondary to trauma or spontaneous bleeding.

Capillary LMs contain capillary-sized lymphatic channels that involve the epidermis. Cavernous LMs infiltrate surrounding structures and are dilated lymphatic channels. Macrocystic LMs are cystic masses lined by a single layer of endothelium with a connective-tissue stroma.

Classification has been marred by a historical lack of conformity. In 1877, the first system was proposed by Wegener. In 1982, Mulliken and Glowacki presented a cell-based classification of pediatric vascular lesions that is currently used by many authors.[14] Their system stratified lesions into two types: hemangiomas and vascular malformations, with LMs falling into the latter category. The World Health Organization (WHO) has recognized three types of lymphangiomas: capillary, cavernous, and cystic. The former is a synonym for microcystic lymphangioma, and the latter two are macrocystic lymphangiomas. A cystic hygroma is a macrocystic lymphangioma found in the neck.

Giguère et al proposed categorizing lymphangiomas on the basis of the size of the cystic component [15] :

• Macrocystic - Cystic spaces ≥2 cm
• Microcystic - Cystic spaces < 2 cm
• Mixed lesions

De Serres et al proposed the following system for staging of LMs of the head and neck [16] :

• Stage I - Unilateral infrahyoid (17% complication rate)
• Stage II - Unilateral suprahyoid (41% complication rate)
• Stage III - Unilateral and both infrahyoid and suprahyoid (67% complication rate)
• Stage IV - Bilateral suprahyoid (80% complication rate)
• Stage V - Bilateral infrahyoid and suprahyoid (100% complication rate)

Although some authors have reported watchful waiting for lymphatic malformations (LMs), this should be considered only in patients who are asymptomatic. Medical treatment of LMs consists of the administration of sclerosing agents, such as OK-432 (an inactive strain of group A Streptococcus pyogenes), bleomycin, pure ethanol, bleomycin, sodium tetradecyl sulfate, and doxycycline.[17] ​ Guidelines for the use of percutaneous sclerotherapy to treat LMs of the head and neck have been developed by the Society of NeuroInterventional Surgery (SNIS).[4]  Current studies are geared towards understanding the molecular pathology of LMs to allow for more targeted drugs. 

An infected LM should be treated with intravenous (IV) antibiotics, and definitive surgery should be performed once the infection has resolved. Incision and drainage or aspiration results in only temporary shrinkage, and subsequent fibrosis can further complicate the resection. Radiotherapy has not been demonstrated to be effective. Some authors maintain that the preferred treatment of all LMs is surgical resection, positing that only resection can truly offer the potential for cure.

OK-432

OK-432, though not currently approved by the US Food and Drug Administration (FDA), has been reported to be capable of successfully treating LM.[18] The mechanism of action is proposed to be an inflammatory response to the inactive bacteria, leading to fibrosis. OK-432 may be a viable option for large unilocular cysts.

Currently, OK-432 is available in the United States only by protocol. It does not work well for small cysts.[19] Because the procedure for using OK-432 involves aspiration prior to injection of the sclerosant, some have hypothesized that the true effect is from the aspiration.

Bleomycin

Bleomycin, a cytotoxic antibiotic, has been considered a poor choice because of its toxicity (pulmonary fibrosis); LM is a benign disease, and other less toxic treatment options are available. Niramis et al studied 70 patients who underwent sclerotherapy with bleomycin; 83% obtained an excellent or good result, 43% had adverse reactions, and three patients died.[20]

Sainsbury et al studied 75 patients, 83% of whom had a complete or significant response. Five adverse reactions were reported, with no severe morbidity or mortality (including pulmonary fibrosis).[21]

Alcohol

Absolute alcohol as a sclerosing agent has been used with some success in some patients; alcohol works well in vascular malformations. Imperizzilli et al studied computed tomography (CT)-guided ethanol injection and obtained complete resolution in seven of eight patients without complications.[22]

Interferon alfa-2a

This has been used in the treatment of hemangiomas, and its use has been proposed in lymphangiomas. However, its efficacy has never been documented, and it carries a serious side-effect profile.

Fibrin sealant

The use of a fibrin sealant after aspiration of LM has been reported in the literature.

Doxycycline

Doxycycline has been reported as a potential sclerotherapy agent, with both safety and efficacy. Like most other sclerosant agents, it has shown the highest efficacy in macrocystic lesions and the lowest efficacy in microcystic ones.[23]

Sildenafil

A limited case series has been reported using sildenafil for severe lymphatic malformations. A prospective trial has been performed, which did not demonstrate a significant effect on LM.[24]

Sirolimus

Sirolimus (rapamycin) is a mammalian target of rapamycin (mTOR) inhibitor that may be helpful in treating LMs. It works through deregulation of the mTOR pathway, which is suspected of playing a role in the pathogenesis of vascular anomalies. Sirolimus causes a decrease in vascular endothelial growth factor (VEGF), which is a known regulator in lymphangiogenesis.[25]

Sirolimus has been studied in several small series, but the optimal dose and duration have not been identified.[26, 27, 28, 29] In a systematic review, treatment results from 105 patients with LM were reported, with more than 91% of patients showing at least a partial response to treatment.[25] Although complete response was seldom seen, many patients did benefit from the partial response and pain-relieving action. In complex cases where surgical therapy or sclerotherapy is difficult, sirolimus may be a useful option.[30]  A multicenter clinical trial is under way to assess the safety and efficacy of sirolimus in treating LMs; the hope is that sirolimus may become the new first-line therapy.[31]  

The mainstay of treatment of LMs is surgical excision.[32] Although surgery is the standard treatment, LM is a benign lesion. If acute infection occurs prior to resection, surgery should be delayed at least 3 months.

The surgical team should attempt to remove the LM completely or, failing that, to remove as much as possible, sparing all vital neurovascular structures. Complete excision has been estimated to be possible in roughly 40% of cases.

LMs are ideally removed in a single procedure; secondary excisions are complicated by fibrosis and distorted anatomic landmarks.

Microcystic lesions are much more difficult to remove, given their intimate association with nearby tissues. Laser therapy may be used for microcystic lesions as well.

The exceptions to excision at the time of diagnosis are few and include premature infants who are small and those with involvement of crucial neurovascular structures that are small and difficult to identify (eg, facial nerve). If no airway obstruction is present, surgery can be delayed until the child is aged 2 years or older, especially when the operation is around the facial nerve.

Signs of airway obstruction necessitate surgical evaluation at the time of diagnosis. In emergency situations, aspiration with an 18- or 20-gauge needle may obviate the need for an emergency tracheostomy.

Although traditional wisdom has dictated that LMs should not be aspirated, a study by Burezq et al documented success with serial aspiration of LM.[33] In this series, 14 patients were treated with aspiration alone (three needed multiple aspirations), with a mean follow-up of 5.75 years. No failures were reported. This technique may hold promise for the future management of LM. Other authors contend that aspiration has no role and believe that aspiration is often followed by recurrence, hemorrhage, or infection.

Radiofrequency ablation (RFA) has been advocated for use with intraoral LMs, especially microcystic lesions. Kim et al reported high long-term success rates with RFA (median follow-up, 47 mo), with 81% of patients not requiring further treatment.[34]

Magnetic resonance–controlled laser-induced interstitial thermotherapy is a newer therapy that has been proposed for the treatment of LM.

LM can present on routine antenatal ultrasonography (US) as a large obstructing airway mass, as can other pathologic conditions (eg, teratoma or rhabdomyosarcoma). If such a mass is visible on US, magnetic resonance imaging (MRI) should be performed to delineate the mass further. In these cases, a multispecialty team, including a high-risk obstetrician, a pediatric otolaryngologist, a pediatric surgeon, and a neonatologist, should be present at the ex-utero intrapartum treatment (EXIT) procedure.

A planned cesarean delivery is performed, and intubation or tracheostomy is used to establish an airway. Extracorporal membrane oxygenation (ECMO) should also be available. Excision of the LM is delayed until the child is stable. Intrauterine cyst aspiration to facilitate vaginal delivery has  also been reported in the literature.

Complications from surgical excision of an LM are myriad and are related to the location and structures adjacent to the mass; these include the following:

• Damage to neurovascular structures (including cranial nerves)
• Chyle leak and chylothorax
• Hemorrhage
• Infection
• Recurrence - Most recurrences develop within the first year, but some have arisen as long as 10 years following excision

Patients with LM should be directed to avoid direct trauma to the area; intralesional bleeding or infection can be precipitated by localized injury.

Depending on the anatomic location of the lesion, referral to a surgeon or surgical specialist is appropriate. In patients with LM of the head and neck, referral to an otolaryngologist as well as an interventional neurosurgeon/radiologist is appropriate.