Lymphatic Malformations

These are some clinical photographs of children with lymphatic malformations (LM) or lymphangiomas. Sometimes this type of growth is also called a cystic hygroma.  Lymphatic Malformation, is the preferred terminology.

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Some Patients treated with OK-432

This is an example of a macrocystic LM. This child was treated with OK-432. The first photo is before treatment, the second during treatment, and the last after treatment.

         

This is one year after treatment showing complete resolution.

A newborn with a cervical LM.

The same child after a single Ok-432 injection.

This is the result after a second injection.

A neonate with a large cervical LM.

After one OK-432 injection

Another child before and after one ok-432 injection

Before     After

Another patient after Ok-432 treatment

Before     After 

Examples of some surgical patients:

A child with a macrocystic LM in the posterior neck.

         

This child was born with a massive LM.  This was surgically treated, out of necessity.

One year follow-up, demonstrating re-growth of the tumor.

This child has a microcystic/microinvasive LM involving the tongue and cervical region.

 

The same child after surgical tongue reduction.

   

Additional patient examples 

The first photos is of a child born with a LM in the parotid region.  The second photo shows the lesion while infected.  The final photo of this child shows near resolution after the infection was treated. 

This is a typical tongue appearance of LM.

 

A child with diffuse oropharyngeal involvment

An isolated floor of mouth LM.

This child has a previously untreated parotid LM.

The next child has severe bilateral supra and infrahyoid microcystic/microinvasive disease.  The mouth and right eye are also involved with the LM. 

This child has had multiple surgical procedures.  He has continues to have severe mandibular hypertrophy,  problems swallowing, with persistent LM.

  

This is a small macrocystic cervical LM.

A neonate with a parotid LM.

A child in Nepal, with a LM.

An axillary LM, which has typical trans-illumination and MR appearance.

A child with massive cervico-facial and oral disease.

An example of a complex patient requiring multiple management strategies:

A premature neonate with a large cervical LM.

The same child after several infections.

The floor of mouth component of the mass.

Improvement of the floor of mouth after sclerosis with Bleomycin.

Additional improvement with second Bleomycin injection.

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Lymphatic Malformation (LM)

1. Essentials of Diagnosis

Also incorrectly known as cystic hygroma or lymphangioma

• Typically thought of as microcystic or macrocystic, based on the size of the lymphatic spaces within the malformation

• Macrocystic lesions are soft, compressible, and transilluminate (figures 4 and 5)

• Microcystic disease is almost always present at birth, and is associated with distortion of the cervicofacial soft tissue and eventually the maxilofacial bones

• A more practical classification divides these heterogeneous malformations into a “Localized Group” (figure 4), and a “Diffuse Group”

2.  General Considerations

The commonly used term “lymphangioma” implies cellular proliferation, which is incorrect.  Histology of these lesions, like all vascular malformations, demonstrates no proliferative component. In the simplest terms LMs and all vascular malformations are birth defects. 

50-65% of LMs are recognized at birth and 90% by the second year.  80% of all LMs are located in the head and neck.   There is no sex predilection.  A LM tends to be slowly progressive, growing with the child.  In some instances, it is apparent that the LM rapidly increases in size.  In these cases it is likely that the lesion has hemorrhaged into itself or has become infected. There are reports of spontaneous regression, although this is far from typical. With adequate follow up, this regression is usually followed by a “recurrence”.  The incidence of LMs is unclear.

3. Pathogenesis

In 1901, Sabin described the developing lymphatic system as arising from five primitive sacs, which develop from the venous system (paired jugular sacs, a retro peritoneal sac, paired posterior sacs from the sciatic vein)¹.  This implied a venous origin with centrifugal spread.  In 1909, McLure and Sylvester postulated that LM arises from sequestrations of lymphatics and that the neck was a natural location for such malformations because of the amount of lymphatic tissue located there.² Goetsch in 1938 concluded that LM did arise from sequestrations of lymphatics originating from the jugular sacs and these sequestrations had irregular growth potential.³  This lends itself to a theoretical understanding of how a LM arises in the developing fetus.

Recently, new research has begun on the possible cellular growth factors, which may someday help explain the progression of abnormal lymphatic development.  Some of this research pertains to vascular endothelial cell growth factor-C (VEGF-C) and its receptor, vascular endothelial c growth factor-receptor-3 (flt-4).   Flt-4 has been shown to specifically stain lymphatics. VEGF-C, when over expressed in mice, causes lymphatic hyperplasia.  Additionally, in the developing embryo flt-4 has been found to be expressed in high concentrations in the areas first described by Sabin as the one of the main origins of the lymphatic system.⁴

4. Clinical Findings

An MRI scan is the typical and best means for evaluating patients with a presumed LM.  An LM is hyper-intense on a T2 image and has only a slight increase in intensity on T1.  A LM does not enhance on gadolinium contrast images.  Based on the radiographic appearance of the size of the lymphatic spaces located within the lesion, the LMs are then broadly categorized as either macrocystic or microcystic.  Further categorization may then be done based on the location of the lesion, as was originally proposed by deSerres.⁵  This type of staging system does offer some important prognostic information. Generally, as the stage increases the prognosis for cure decreases.  It is also generally true that facial and oropharyngeal involvement are associated with a worse prognosis. 

While the deSerres classification system is helpful prognostically, the staging system does not simplify the clinical complexities of dealing with the children.   A more practical classification designates these malformations as either “Localized” and macrocystic, or “Diffuse” and interdigitating.   Therapeutic goals and appropriate treatments for the two groups are dramatically different.

The increased use of prenatal ultrasound has led the diagnosis of patients with LM in utero.  This has led to some treatment dilemmas at very early stages of life.  It should be made clear that not all fetal ultrasound diagnosis of  “cystic hygroma” equates with the post-natal condition of Lymphatic Malformation.  Posterior nuchal swellings are often referred to as “cystic hygroma” on ultrasonography.  This finding is associated with chromosomal abnormalities and increased fetal death rates.  These posterior nuchal swellings, identified at fetal ultrasound, are not necessarily associated with LM.  Anterior and lateral neck swellings identified on fetal ultrasound, which remain persistent on repeat ultrasound, do likely represent congenital LMs, and are sometimes massive (figure 5).^6,7,8  This distinction is well known to the experienced radiologist; however, the terminology can lead to confusion. Children with massive congenital LMs are usually born by “an exit procedure”, in which the airway is stabilized by intubation, bronchoscopy, or tracheostomy.  These neonates should not necessarily undergo massive neonatal dissection unless symptoms dictate.  These procedures are more likely to result in surgical complications and, at least, require a dedicated surgical team to do as complete a job as possible.  This is often a long and meticulous procedure.

5.    Differential Diagnosis

When these lesions become infected or hemorrhage into themselves, the rapid enlargement can be misdiagnosed as an infected branchial cyst, or acute lymphadenitis.

6.    Complications

Diffuse microcystic cervicofacial disease often results in mandibulomaxillary hypertrophy.  This is due to direct invasion of the bone and growth of the LM within the bone⁹.  After the child has matured, this can be managed with mandibular osteotomy, and if necessary Le Fort osteotomies.

A secure airway is essential in patients with diffuse microcystic cervicofacial disease.  It is often necessary to perform a tracheostomy to avoid acute respiratory problems.  

LMs often swell with the onset of general viral infection or remote bacterial infection.  This typically resolves with the resolution of the infection.  Occasionally the LM itself will become infected.  This sort of infection generally requires IV antibiotics.

7.    Treatment

There have been multiple treatments employed for the management of the lesions, which is a sure sign that none has been completely effective.  It is helpful to consider treatment of the localized and diffuse groups separately. 

Treatment of the “Localized” group relies essentially on sclerosis or surgery, except in some specialized locations, which will be addressed separately.  Both surgery and sclerosis are very effective for this type of lesion, and choosing between these two modalities depends on the surgeons experience and the specifics of the patient’s situation.  There have been numerous agents used in an effort to sclerose these lesions including: boiling water; tetracycline; cyclophosphamide; sodium tetradecyl sulfate; bleomycin¹⁰; alcohol¹¹; and OK-432.¹²   Alcohol is effective but has frequent complications including skin necrosis, and some have been hesitant to inject it near the carotid sheath.  It is available in a thickened form in Europe and Canada known as Ethibloc.  Ok-432 is a medication developed in Japan with extensive worldwide experience.  In the United States the medication is under FDA investigation.  The medication, a streptococcus culture treated and killed with penicillin incites an immune response in the location of the LM.  Typically, the lesion swells and subsequently resolves.  It may be necessary to inject several times for large lesions.  Sclerosant therapy is especially indicated in the instances where the localized lesion has an extension into the retropharyngeal location, as it is unlikely that this can be completely removed surgically.  There are other localized lesions that require special mention because of their location within the tongue or the glottis. 

The tongue may be involved with small blebs, that bleed and become infected.  An old term used to describe this type of lesion is “lymphangioma circumscriptum”.  This can also be a component of diffuse cases, and can be managed with laser resurfacing.  The tongue can also be massively enlarged because of lymphatic malformation (figure 6).  These children cannot be managed with laser and generally require tongue reduction surgery.  There has been anecdotal experience using radio frequency ablation for this type of lesion.   This may prove to be efficacious, with further study. 

Glottic involvement is best managed with the CO₂ laser, opening lesions and debulking airway obstruction.  A tracheostomy tube should always be in place for this type of airway surgery.

The management of diffuse cases is much more complex, and it should be understood that management may be a lifelong endeavor.  This is precisely the reason that initial management decisions should not increase the morbidity of the disease by causing cranial nerve injury.  The first goals of management of “Diffuse” cervicofacial disease are to allow for an adequate airway and feeding.  This will often require a tracheostomy and possibly a gastrostomy.  The next task is to break the problem down into to anatomic zones and then attempt to manage those zones as individual problems until that zone is free of disease.  A typical boundary used to divide these massive problems into several more manageable problems is the mylohyoid.  It is also advisable to approach the divided components of the total malformation from the “top-down”, if possible.  For instance, attempt to deal with the tongue before the floor of mouth, and then approach the neck; this will avoid proximal swelling of the untreated zone.  An effort should be made to remove the malformation completely from each zone.  If gross disease remains, recurrence is more likely.  Additionally, children with diffuse cervicofacial disease will also frequently require maxillomandibular reconstruction because of overgrowth of the facial bones.

Also advisable in the global care of children with diffuse disease is to involve a child psychiatrist.  It is likely that these children will have long-term morbidity and a means for dealing with the psychosocial implications is essential.

References

1.Sabin FR et al: On the origin of the lymphatic system from the veins and the development of the lymph heart and the thoracic  duct in the pig. Am J Anat;1. (A description of the hypothetical origins of the lymph system.)

2.  Mcclure CFW et al:  A comparative study of the lymphatico-venous communication in adult mammals.  Anat Rec; 3.  (original work and theories of the origins of LM)

3.  Goetsch E.  Hygroma Colli cysticum and Hygroma axillae. Arch Surg: 36.(original work and theories of the origins and growth potential of LM)

4. Breugem CC et al: Progress Toward Understanding Vascular Malformations.  Plastic and Reconstructive Surgery; 107:6. [PMID: 11335828] (A detailed review of the current understanding of the pathogenesis of these birth defects.)

5.  deSerres LM et al.  Lymphatic malformation of the head and neck. Arch Otolaryngol Head Neck Surg;121. [PMID:  7727093] (An outline of a novel staging system)

6.  Marler JJ et al.  Prenatal diagnosis of vascular anomalies.  J Pediatr Surg 2002 Mar;37:3.  [PMID: 11877641] ( A discussion of prenatal diagnosis and its implications)

7. Wong GB, Mulliken JB, Benacerraf BR.  Prenatal sonographic diagnosis of major craniofacial anomalies. Plast Reconstr Surg 2001;108. [PMID: 11604640] ( A discussion of prenatal diagnosis and its implications)

8.  Fisher R, Partington A, Dykes E.  Cystic hygroma:  comparison between prenatal and postnatal diagnosis.  J Pediatr Surg;31. [PMID: 8801294] ( A discussion of prenatal diagnosis and its implications)

9.  Padwa BL et al. Cervicofacial lymphatic malformation:  clinical course, surgical intervention, and pathogenesis of skeletal hypertrophy. Plast Reconstr Surg; 95. [PMID:  7732142] (A convincing explanation for skeletal hypertrophy in patients with diffuse LM of the cervicofacial area)

10.  Oxford J et al.  Bleomycin therapy for cystic hygroma.  J Pediatr Surg; 30. [PMID: 8523225  ] (A description of experience with a novel treatment)

11.  Berenguer B et al: Sclerotherapy of Crainiofacial Venous Malformations: Complications and Results. Plastic and Reconstructive Surgery; 104:1. [PMID: 10597669] (A review of a large experience with detailed description of techniques.)

12. Greinwald JH et al.  Treatment of lymphangiomas in children:  an update of Picibanil (OK-432) sclerotherapy.  Otolaryngol Head Neck Surg;121. [PMID: 10504592] (An update on the American drug trial)