28 Venolymphatic Malformations of the Head and Neck

Rulon Hardman and Claire Kaufman

Abstract

Treatment of venolymphatic malformations is primarily based on expert opinion and retrospective small cohort studies. While there are some safety trials and cohort studies published, few randomized, controlled trials comparing various treatment options are available. However, despite the lack of scientific evidence, awareness of these conditions is needed to appropriately diagnose and triage patients. Appropriate diagnosis, characterization, and referral to specialty centers will allow for organized trials to be performed in this disease. Vascular malformations are prevalent in 1 to 4% of the population, but it is still treated as an orphan disease. Practitioners should know the presentation of these lesions, their differential diagnosis, imaging findings, appropriate work-up, and treatment options to develop a multidisciplinary treatment plan.

Key words

venous malformation – lymphatic malformation – sclerotherapy – sotradecol – ethanol

28 Venolymphatic Malformations of the Head and Neck

28.1 Goals

To understand the types of vascular malformations and their clinical presentations.
Review available sclerotherapy agents and any data to support their use in venolymphatic malformations.
Understand emerging medical therapies of medical management for venolymphatic malformations.
Review available literature regarding the treatment and follow-up of venolymphatic malformations.

28.2 Case Examples

28.2.1 Case Example 1 History of Present Illness

A 29-year-old Pacific Islander male with increasing facial swelling over the past few years presents for evaluation. The swelling is in the left face from the temple to the submandibular region. His swelling is associated with dull pain. He reports his pain can range from 2/10 at baseline up to 8/10 when he has upper respiratory infections.

Past medical history: No other medical conditions.

Family history: Noncontributory.

Social history: Married with two children. Works in construction. Denies smoking and alcohol or illicit drug use.

Physical examination: Left facial swelling over the mandible and extending up the lateral left face. No discoloration to the skin, no palpable pulse.

Imaging studies: See Fig. 28.1.

Treatment Plan

The imaging and presentation of this patient is that of a venolymphatic malformation. Treatment plan is focused on the resolution of pain in this patient, with a hope of additional cosmetic improvement. Treatment often requires three to four treatment sessions, which needs to be explained to the patient and an expected treatment plan written out for the treatment course. Treatment involved percutaneous sclerotherapy over three treatments (Fig. 28.2). Mixed agent sclerotherapy using bleomycin (Blenoxane) and sodium tetradecyl sulfate foam (STS, Sotradecol, Angiodynamics) was employed.

Follow-up

The patient’s pain resolved after the second treatment. Cosmetic swelling improved over the treatments, and the patient felt comfortable with his appearance after three treatments. He did develop a minor complication of chemical cellulitis after the second treatment, which was treated with oral cephalexin with a good result. Patients are followed up in the clinic as there is a high level of recurrence with these lesions after 8 to 10 years.

28.2.2 Case Example 2

History of Present Illness

A 26-year-old Ph.D. student from Iran presented with a forehead/scalp lesion. Patient has had this soft lesion as long as he can remember. The lesion is not painful. He had a magnetic resonance imaging (MRI) 8 years ago of the lesion, but the physicians he encountered did not believe there was any possible treatment of the lesion.

Past medical history: No other medical conditions.

Family history: Noncontributory.

Social history: Currently in graduate school. Nonsmoker. Occasional alcohol use.

Physical examnation: 4-cm round, soft mass at the left forehead/scalp extending into the hairline. Mass is not mobile on the calvarium and is nonpulsatile but has a bluish discoloration.

Imaging studies: See Fig. 28.3.

Treatment Plan

The imaging appearance of internal flow voids and contrast enhancement on gadolinium MRI confirm this to be a venous malformation. Typically, therapy is reserved for painful masses. Other indications for treatment include disfigurement, consumption coagulopathy, respiratory compromise, and bleeding. Treatment plan includes percutaneous sclerotherapy and possible surgical resection. Considering the surrounding structures is important for any malformation treatment, but especially of scalp and oropharynx lesions. Venous drainage pathways may be difficult to control, and treatment may cause thrombosis of cerebral venous structures. Oropharynx lesions may cause enough swelling to obstruct the airway. Percutaneous sclerotherapy with bleomycin was used in this lesion (Fig. 28.4). There is a plan for surgical resection after venous sclerotherapy. Possible other treatments for venous malformations include radiofrequency or cryoablation. ¹²

**Fig. 28.1**Case 1: A 29-year-old male with left facial swelling and pain. The lesion is submandibular and extends along the mandibular angle. **(a)** B-mode ultrasound. An anechoic lesion is seen below the mandible *(yellow arrow).* There was no flow seen within the mass. (b,c) Axial computed tomography (CT) contrast-enhanced images showing the patient’s submandibular mass *(green arrows).* CT is usually not the imaging modality of choice but was performed by the referring provider. There is no internal enhancement of the lesion that crosses compartments of the neck. Peripheral enhancement of the lesion is present.

**Fig. 28.2** Case 1: Treatment of the left facial lymphatic malformation. (a,b) The lesion is a lobulated macrocystic lymphatic malformation *(yellow arrow).* The patient underwent sclerotherapy of the lesion over three separate sessions. The first treatment session involved injecting 180 mg of STS (Sotradecol) percutane-ously through a 21-gauge needle. A second needle was placed to vent the lesion. The second treatment involved similar protocol of accessing the malformation using a 21-gauge needle under ultrasound guidance. A mixture of 8 Units of bleomycin and contrast was injected and left to dwell for 30 minutes, then drained from the malformation. During the third treatment, a small drain was placed and sclerotherapy was performed using Sotradecol followed by bleomycin.

**Fig. 28.3** Case 2: A 26-year-old male with a soft mass on the forehead. The mass is not painful but is cosmetically deforming, **(a)** B-mode ultrasound images of the malformation demonstrate a few large spaces within the mass *(green arrow),* **(b)** Ultrasound image demonstrates internal low velocity flow voids. Diagnosis of venous malformation is made based on the ultrasound. Magnetic resonance imaging (MRI) is performed to determine the depth of the lesion, bone involvement, and plan locations for needle placement during treatment. MRI images of this venous malformation are typical for venous malformations *(yellow arrows).* **(c)** T1-weighted (T1W) images show the mass is isointense to muscle. Internal enhancement is present on post-gadolinium T1 W images in venous malformations (d). Both venous malformations and lymphatic malformations are hyperintense on T2W images (e).

Follow-up

Even after surgical resection, patients should be followed annually due to the high probability of recurrence. Additional treatment should be based on the same considerations as the first treatment, namely, controlling pain and improving deformity.

28.3 Case Summary

What imaging is indicated to evaluate vascular malformations?

Plain films play a little role in diagnosing and evaluating vascular malformations. ³ In some cases, plain film can demonstrate bone loss associated with malformations, such as in Gorham disease (lymphatic malformation that is associated with bone resorption). Ultrasound is the first-line imaging modality to evaluate venolymphatic malformations. ³ Ultrasound can exclude high-flow malformations such as arterial venous malformations. Ultrasound can often distinguish between venous and lymphatic malformations. Initial evaluation should be with b-mode (2D gray-scale imaging). Phle-boliths can often be seen, which are pathognomonic for a vascular malformation. Phleboliths are most often seen in venous malformations, although they can be seen in lymphatic malformations with prior internal hemorrhage. Duplex ultrasound may show flow within vascular malformations. However, at least 15% of venous malformations will have no internal flow by ultrasound. ³ ^, ⁴ Computed tomography (CT) has a little role in evaluating venolymphatic malformations. The malformations tend to be of the same soft tissue density as surrounding tissues, making full evaluation of the extent of the malformation difficult. MRI has become the mainstay for evaluating the extent, depth, and character of venolymphatic malformations. ⁵ ^, ⁶ MRI protocols include Tl, T2, and contrast-enhanced images in at least two orthogonal planes. Contrast-enhanced MRI has a 100% sensitivity and 95% specificity of distinguishing vascular malformations from other lesions. ⁷ Venous malformations tend to have internal enhancement on contrast-enhanced images, but no flow voids on T2 images. Lymphatic malformations tend to have no internal enhancement but have an enhancing rim. MRI is also helpful to plan needle placement for therapy ⁸ and follow-up treatment response.
Which vascular lesions require or respond to treatment?

Treatment of arteriovenous malformations (AVMs) differs from that of venolymphatic malformations. When approaching an AVM of the head and neck, the goal of therapy can be to aid with pain and deformity. Patients can present with heart failure with high-flow lesions, and airway compromise when they involve the airway. Often, therapy involves a team of otolaryngologists, plastic surgeons, vascular surgeons, and interventional radiologists in addition to the neurosurgeon. ³ ^, ⁸ Percutaneous sclerotherapy prior to resection may be needed to minimize bleeding during surgery. Treatment strategy for AVM is beyond the scope of this chapter but involves treating the nidus of the malformation with sclerosants such as ethanol or liquid embolics, such as n-bu-tyl-cyanoacrylate glue (Histoacryl Blau, B Braun Medical, Sempach, Schweiz).

Venous and lymphatic malformations do not resolve spontaneously, and if symptomatic, will require treatment. Common indications for treatment include pain, deformity, bone loss, airway compromise, consumptive coagulopathy, or for lymphatic malformations, recurrent infections. Venous malformations can activate the coagulation cascade, perhaps by slow flow through the lesion. The activated coagulation leads to an elevated D-dimer and consumption of platelets. This condition is seen in 42% of patients with venous malformations. ⁹ Lymphatic and venous malformations do tend to respond to percutaneous sclerotherapy, with reported rates ranging from 50 to 100% overall response. ¹⁰ Macrocystic lymphatic malformations tend to have the best response. Mi-crocystic lymphatic malformations tend not to respond as well to percutaneous sclerotherapy.
What medical therapies are available to treat venolymphatic malformations?

Several medical therapies have been pursued for venolymphatic malformations, but the mammalian target of rapamy-cin (mTOR) inhibitor, Sirolimus, has the most promise at this time. Several randomized trials are in process to confirm the outcomes of Sirolimus treatment.

Symptomatic control has been attempted with heparin in venous malformations. ¹¹ Thrombus that occurs in venous malformations is unlikely to result in symptomatic pulmonary emboli in patients due to the superficial nature of these lesions, but recurrent thromboses are bothersome to some patients. Prophylactic heparin or low-molecular-weight heparin can be used to reduce these thrombosis events. Lymphatic malformations are prone to infection, and sometimes require antibiotic treatment for cellulitis, usually cephalexin. Propranolol is helpful in hemangiomas but has little benefit for venolymphatic malformations. Sildenafil has had mixed results in cohort studies but may have some symptom relief by its effect on smooth muscle. ¹²

Sirolimus is a tyrosine kinase inhibitor of the mTOR pathway, which is involved in the angiogenesis and the PI3K-AKT pathway. ¹³ Sirolimus was first reported to have effect in a case series of six patients, five with microcystic lymphatic malformations. ¹³ All patients had response to the treatment. Adams et al have subsequently performed a prospective analysis of 57 patients treated with Sirolimus for various vascular malformations. ¹⁴ Partial response was noted in 83% after 6 treatments and 85% after 12 treatments. Currently, there are phase II (NCT00975819, NCT02509468) and phase III (NCT02638389) trials testing Sirolimus in venolymphatic malformations. See Fig. 28.5.
What sclerotherapy agent should be used in venous and lymphatic malformations?

The type of sclerosant and method of application of the sclerotherapy varies throughout the literature. Unfortunately, most reports are small population retrospective studies and have mixed location of sclerosant administration, few in the head and neck. Common agents that are used for sclerotherapy include ethanol, bleomycin, STS (or Sotradecol), doxycy-cline, OK-432, polidocanol, and ethanolamine. Ethanol is the first and the most commonly reported sclerosant in all malformations. Ethanol denatures proteins, which destroys the vascular wall endothelium. Ethanol also causes thrombosis. In their systematic review of studies on head and neck malformations, Horbach et al found 6 studies that met criteria in 327 patients. ¹⁰ The overall response was between 84 and 100%. However, it is important to note that ethanol has the highest reported complication rate, with studies showing up to 61% of patients having complications. ¹⁵

Sotradecol is the next most used agent in vascular malformations in all sites. Sotradecol is a strong detergent, which breaks down the cellular lipid bilayer. Sotradecol is often applied as a foam, as described by Tessari. ¹⁶ Hor-bach et al could only find two studies that met criteria for STS in head and neck. The reports showed overall response rates of 100% and no complications, but few patients are included (n = 12). ¹⁰ Bleomycin is a chemotherapy agent that was found to have sclerosing properties on the endothelium. Several groups prefer to use bleomycin, believing it to be less caustic in sensitive areas such as the head and neck. Hor-bach et al found five studies on bleomycin, with 70 to 100% overall response rate. ¹⁰ Bleomycin had higher recurrence rates in a study when compared to ethanol. ¹⁵ A subtype of bleomycin, pingyangmycin, has mostly been studied in China. Pingyangmycin reports are the largest in the literature in head and neck sclerotherapy, with 8 studies in 693 patients. The overall response rate is > 95% with complete response rates of 48 to 100% described. Quality of the reports has been questioned as the groups only report a 2% adverse event rate. OK-432 (Picibanil) is a lyophilized group A streptococcus pyogenes with low virulence which is incubated with benzyl-penicillin. High-volume groups report good response to therapy in lymphatic malformations, ¹¹ ^, ¹⁷ but the agent was not approved by the FDA and therefore is not available in the United States. Overall response rate in nine studies was 50 to 95%. ¹⁰ Complications were reported in 0 to 30% of patients. ¹⁰ Polidocanol is also a detergent agent. Two studies are evaluated by Horbach et al in 39 patients. ¹⁸ The overall response rate was 100%, but in small studies. Doxycycline also has been reported in 2 studies involving 22 patients. ¹⁸ The overall response rate was 67 to 100%.

Doxycycline was reported to cause zero complications in the reports but was used predominantly in lymphatic malformations. ¹⁹
When is surgery indicated for venolymphatic malformations?

A systemic review by Van der Vleuten reported only a single study with at least 10 patients. ²⁰ Zhong et al reported retrospective outcomes of 10 patients with head and neck malformations, ²¹ with a 90% clinical success in their series. Surgical management in isolation is difficult in these lesions. ⁸ ^, ²² ^, ²³ ^, ²⁴ ^, ²⁵ Malformations are prone to bleeding, which can limit evaluation of the surgical field, leave residual malformation, and lead to injury of critical structures. A combined approach usually involving percutaneous sclerotherapy of the venous malformation or macrocystic components of lymphatic malformations prior to resection is now advocated. Surgical resection goals then involve debulking, with the knowledge that additional therapy by sclerotherapy can be pursued in the future if needed. Lee et al have described their surgical approach using a multidisciplinary team, which involves 15 different specialties. Of their patient cohort, about 10% of the patients had surgical management of their vascular malformations, with 72% receiving concurrent sclerotherapy. ²⁶ This study reported nine minor complications in the surgical group. ²⁶