Lymphatic Malformations

Lymphatic malformations (LMs) are slow-flow vascular malformations, composed of dilated lymphatic channels or cysts lined by lymphatic endothelial cells, associated with somatic PIK3CA activating mutations. Depending on the size of the fluid-filled cysts, LM are categorized as microcystic, macrocystic, or mixed. LMs are frequently noted at birth as soft, compressible lesions, with or without overlying skin discoloration; however, a small or deep lesion may not become apparent until it enlarges to produce symptoms or deformity. Superficial LM may produce cutaneous vesicles filled with lymphatic fluid and/or blood called lymphatic blebs. Large LM may also be diagnosed on prenatal imaging. Two-thirds of LMs occur in the head and neck area, some of which extend into the mediastinum, and may impede on the airway, resulting in life-threatening complications such as airway obstruction or tracheal deviation ( Fig. 2 ). ^, Most LM are solitary or regional but can be diffuse or multifocal. LM is also associated with PROS including KTS and CLOVES, all of which are also associated with somatic PIK3CA mutations.

Endoscopy photographs and MRI imaging of a patient with slow-flow vascular malformation involving the airway. ( A ) Endoscopy images of the left laryngeal area and ( B ) piriform fossa. ( C ) Magnetic resonance imaging, axial view, of the same patient demonstrating intense contrast uptake with left vocal cord deviation in the laryngeal area.

Acute enlargement is common and is typically caused by infection, inflammation, trauma, or intralesional bleeding. Intralesional hemorrhage can occur in the absence of injury. LMs have increased risk for cellulitis or soft tissue infection, particularly if the LM involves the oral or nasal mucosa or lymphatic blebs are present. Antibiotics should be used to treat suspected bacterial infections, while non-steroidal anti-inflammatories or corticosteroids can be used to alleviate acute pain and/or substantial enlargement. Chronic issues such as pain, functional limitations, asymmetry, recurrent infection, or hemorrhage should be managed on an individualized basis. Treatment options include sclerotherapy, surgery, and disease-modifying medications such as sirolimus and alpelisib that both target the PIK3-AKT pathway.

Complex Lymphatic Anomalies

Complex lymphatic anomalies (CLAs) are rare, progressive diseases involving multifocal LM that are associated with high morbidity. CLA includes Gorham-Stout disease (GSD), generalized lymphatic anomaly (GLA), and kaposiform lymphangiomatosis (KLA). These diseases typically involve viscera and bone, in addition to the soft tissues and body cavities like isolated LM. Individuals can suffer from numerous complications such as lytic bone lesions, pleural and pericardial effusion, ascites, serious infection, coagulopathy, bleeding, and protein losses. These conditions have phenotypic heterogeneity as well as overlapping symptoms, imaging features, and complications, making diagnosis challenging. However, there are clinical manifestations, radiologic findings, and genetic mutations that can differentiate these conditions. While GSD, GLA, and KLA all have bone involvement, only osteolytic lesions of GSD cause bone cortex destruction and frank loss of bone; GSD has a propensity to affect the calvarium, skull base, vertebrae, and bones of the upper body including the clavicle, sternum, and scapula. KLA is the only CLA associated with coagulopathy, which is characterized by severe thrombocytopenia, hypofibrinogenemia, and bleeding propensity including hemorrhagic effusions. PIK3CA mutations have been discovered in GLA; in contrast, RAS mutations have been found in KLA. Casitas B lineage lymphoma gene mutation has also been found in KLA, which is within the RAS/MAPK pathway. The genetic mutation in GSD has not yet been identified. Given the diffuse nature and significant morbidity of CLA, systemic medical therapeutics play an important role not only in the treatment of clinical manifestations but also in the prevention of progression. Bisphosphonates such as zoledronic acid are also frequently used when lytic bone lesions are present. Correct diagnosis of CLA is critical because use of a targeted drug in the opposing pathway could potentially worsen the disease. Potential molecularly targeted drugs for CLA include sirolimus, alpelisib, and MEK inhibitors.

Venous Malformations

Venous malformations (VMs) are slow-flow vascular malformations composed of ectatic, dysmorphic venous vessels that may be solitary/isolated, regional, multifocal (separate malformations involving multiple body areas), or extensive (involving multiple body regions or entire extremities). Like LM, VMs are also associated with PROS, KTS, and CLOVES. Superficial VMs appear as abnormal veins or blue-purple skin discoloration, while deeper VMs may only be palpable as a soft tissue swelling or may not be detectable on examination if within muscle or bone. VM typically increases in volume with increased venous pressure (eg, Valsalva maneuver or straining), when the affected body area is dependent, or with exercise. VM may also occur in the aerodigestive tract, potentially causing airway compromise, dysphagia, and gastrointestinal (GI) bleeding. Although VM can occur anywhere in the body, 40% occur in the head and neck, most commonly in the muscles of mastication, the lip, and the tongue.

Due to the abnormally decreased or stagnant blood flow through the distorted vessels, affected individuals are at increased risk for thrombophlebitis and thrombosis of the VM. Individuals are also predisposed to phleboliths, which are organized thrombi that have calcified. Risk for deep vein thrombosis and venous thromboembolism is highly dependent on an individual’s malformation and connections to the normal deep venous system. During periods of systemic inflammation, local injury, or hormone fluctuations, VM can develop thrombophlebitis and become more painful and swollen. In pubertal females, progestin-only hormonal control or oral contraceptives are recommended given the known increased risk of thrombosis with estrogen-containing medications in addition to the high likelihood of clinical worsening of the VM. Anticoagulation with low molecular weight heparin or direct-acting oral anticoagulants, such as rivaroxaban or apixaban, should be considered for patients with recurrent thrombophlebitis at prophylactic or treatment dosing. Aspirin and clopidogrel have been reportedly used, albeit with less success, and caution should be used as these drugs also should be stopped 5 to 7 days prior to a procedure to avoid bleeding complications.

Affected individuals, particularly those with extensive or multifocal venous involvement, frequently have an elevated D-dimer, suggesting an increased generation of thrombin, accompanied by fibrinolysis, presumably due to recurrent thrombophlebitis and/or chronic formation of microthrombi. Elevated D-dimer and concurrent moderate to severe hypofibrinogenemia occur in approximately 6% to 10% of patients. Despite hypofibrinogenemia and/or thrombocytopenia, individuals do not appear to have increased bleeding without an additional inciting factor. Both venous thromboembolism and worsening coagulopathy have occurred, speculatively due to manipulation or trauma of the malformation with surgery, sclerotherapy, embolization, or injury. Sirolimus has been reported to improve thrombophlebitis, phlebolith formation, and laboratory hematologic abnormalities in patients with VMs or combined VMs. If hematologic abnormalities are present and surgical intervention is planned, pre-operative hematology/oncology consultation is highly advised.

Venous malformations are caused by both inherited and somatic mutations. Germline VMs include glomuvenous malformation, inherited by a loss-of-function GLMN mutation, and multiple cutaneous and mucosal VM syndromes, inherited by autosomal dominant activating mutations in TEK/TIE2 . Lacking family history, blue rubber bleb syndrome is another multifocal VM that is associated with somatic TEK/TIE2 mutations but has a propensity to involve the aerodigestive tract and cause GI bleeding. Sporadically occurring VMs are associated with either somatic PIK3CA or TEK/TIE2 mutations. While the phase 2 clinical trial of sirolimus treatment did not include isolated VM, the results suggested improvements in complicated malformations with a venous component. Additional studies and case series have provided additional support for the benefits of sirolimus treatment in VM. ^, Prospective clinical trials for use of molecularly targeted drugs in simple/isolated VM are lacking. In clinical practice, sirolimus may alleviate symptoms and provide clinical benefits for VM. The PIK3CA inhibitor, alpelisib, may also be beneficial in VM with a PIK3CA mutation.

Arteriovenous Malformations

Arteriovenous malformations (AVMs) are high-flow or fast-flow malformations caused by aberrant development of vasculature that abnormally connects arteries and veins, disrupting blood flow and oxygen circulation. Since these 2 types of vessels are normally connected by high-resistance capillary beds, venous vessel walls are not intended to handle the high-pressure blood flow occurring in AVM. As a result, the venous component of the AVM becomes permanently altered and weak, making these vessels vulnerable to bleeding and rupture. AVM can occur anywhere in the body and typically progress over time. The arterial to venous shunting leads to ischemia with destruction of surrounding tissue, pain, ulceration, bleeding, and potentially cardiac overload. AVMs have traditionally been thought to be congenital, arising from dysfunction of developmental pathways implicated in vasculogenesis and/or vascular maturation. However, de novo AVM formation has been described in the brain and extra-cranially.

Treatment of AVM has been mostly surgical and is challenging with embolization or resection frequently resulting in subsequent recurrence or expansion of collateral vessels in up to 80% of cases. Additionally, incomplete resection and embolization can cause aggressive growth of the remaining nidus (where feeding arteries link directly to draining veins), and the risk of progression is up to 50% during the first 5 years, with recurrences possible 10 years later. Embolization materials (coils, ethanol, cyanoacrylate, polyvinyl alcohol known as Onyx, fibrin glue, etc.) have varying rates of successful AVM regression and differing complications.

Extracranial AVM most commonly affect the head and neck area (47.4%), with an estimated 50% of head and neck AVM affecting the oral and maxillofacial region. Bleeding complications are common for individuals with angiodysplasias or AVM involving mucosal surfaces, particularly in the nasopharyngeal and GI tracts, and cause significant morbidity. Supportive care with blood product transfusion and intravenous iron replacement is critical but is only supportive and disruptive to affected patients’ lives. Surgical interventions can be beneficial but may be limited or insufficient due to the diffuse nature of these vascular diseases. As a result, there is an increased interest in using angiogenesis inhibitors, many of which are now employed in cancer treatment regimens, to treat these problematic vascular lesions complicated by bleeding. In sporadically occurring extracranial AVM, activating mutations in MAP2K1 , KRAS , NRAS , and BRAF have been identified. El Sissy and colleagues reported that KRAS mutations were associated with severe extended facial AVM, for which relapse after surgical resection is frequently observed, while MAP2K1 variants were associated with less severe AVM located on the lips. All identified mutations in sporadically occurring AVM are within the RAS/MAPK pathway, suggesting that MEK inhibitors may be potential therapeutic agents for individuals with extracranial AVM. In 2 case reports, children with problematic AVM were treated off-label with oral trametinib and reported decreased blood flow through the AVM as well as reduced vessel caliber after 6 months of therapy. ^,

Intracranial AVM can lead to significant neurologic disability or death, usually because of intracranial hemorrhage (ICH). ^, Over half of brain AVM detected will first present with hemorrhage, and previous hemorrhage is the most important indicator for subsequent bleeding. ^, In the absence of ICH, persistent headache is the most common symptom. Intracerebral AVM are high-flow lesions and distinctly different from cavernous malformations of the brain, which are low flow. Approximately 95% of brain AVMs are sporadic while the remainder are associated with hereditary conditions of which hereditary hemorrhagic telangiectasia (HHT) is the most common. In sporadic brain AVM, KRAS mutations have been recently identified in most patients, and more rarely BRAF mutations. EPHB4 mutations have also been found in sporadic vein of Galen aneurysmal malformations, which are a subtype of cerebral AVM. Pathogenesis of sporadic intracranial AVM is not understood, but well-known associated factors such as angiogenic factors and inflammatory cytokines likely influence the development of brain AVM. Inhibiting the RAS/MAPK cascade with MEK inhibition may be a promising approach to treating non-hereditary brain AVM.

Capillary malformation-AVM (CM-AVM) syndrome is an inherited autosomal dominant disorder with high penetrance characterized by multiple cutaneous CM and risk of having 1 or more AVM and/or arteriovenous fistulas. CM-AVM is subdivided by its causative mutations,RAS P21 protein activator 1 ( RASA1) and ephrin-type B receptor 4 ( EPHB4) , into CM-AVM1 and CM-AVM2, respectively. CM-AVM1 is caused by a heterozygous loss-of-function mutation in the RASA1 , which encodes RASp21, a protein that acts as a suppressor of RAS function. CM-AVM2 is caused by a loss-of-function mutation in EPHB4, which, along with its ligand Ephrin B2, plays a significant role in arteriovenous differentiation. Of note, Parkes-Weber syndrome is a phenotype that is characterized by CM-AVM and hypertrophy of the underlying bone and tissue, resulting in limb overgrowth. Since Parkes-Weber syndrome is a phenotype, the associated RASA1 mutation may be germline or somatic. Molecularly targeted medications have not been widely used to treat CM-AVM patients yet, but case reports and small series are emerging.

HHT is an inherited autosomal dominant disease, with an estimated prevalence of 1 in 5000, which is characterized by AVM that can occur in the brain, lungs, liver, and spine and mucocutaneous telangiectasias. Diagnosis is based on the Curacao criteria, published by Shovlin and colleagues in 2000 and revised in 2020. ^, Clinical symptoms vary not only among HHT patients but even within families carrying the same disease-causing mutation. The most common symptom is recurrent, spontaneous epistaxis because of telangiectatic lesions in the nasal mucosa, affecting 95% of HHT patients, followed by GI bleeding occurring in 13% to 30% of affected individuals. Severity of epistaxis and GI bleeding can range from occasional and brief to life-threatening and lead to red blood cell transfusion and intravenous iron infusion-dependence. With age, the amount of telangiectasias increases, and epistaxis and/or GI bleeds typically worsen, leading to iron deficiency anemia, poorer quality of life, and increased healthcare resource utilization, including the need for frequent transfusions and hospitalizations. Treatment of epistaxis can range from topical intranasal medications to laser, nasal packing, and nasal closure in the very severe. Telangiectatic lesions in the GI tract are addressed with thermal probes or local laser treatment.

AVM can form in the brain in up to 10% of HHT patients, the lungs in 15% to 45%, and the liver in 75% of patients. Chronic bleeding or acute rupture of these AVM can result in severe or potentially fatal complications, including internal hemorrhage, embolic or hemorrhagic stroke, seizures, migraines, brain abscesses, high-output cardiac failure, and pulmonary hypertension. ^,

In 97% of patients with a definite clinical diagnosis of HHT, a causative loss-of-function mutation is identified in 1 of 3 genes: endoglin (ENG), activin receptor-like kinase-1, and mothers against decapentaplegic homolog 4 (SMAD4). Recently, Balachandar and colleagues proposed that a heterozygous GDF2/BMP9 variant is also a cause of HHT associated with pulmonary AVM. Researchers are beginning to make strides in correlating genotype-phenotype, with the ENG mutation more frequently associated with the presence of pulmonary AVM and brain vascular malformations whereas GI bleeding was more often associated with SMAD4 genotype. Each of these 3 genes encodes proteins involved in the TGF/BMP superfamily signaling pathways and plays an important role in angiogenic balance, making vascular endothelial growth factor an appealing target for molecular-based drug therapy. Use of anti-angiogenic drugs for problematic HHT-associated bleeding is addressed later in this article.

Capillary Malformations

Capillary malformations (CM), previously referred to as “port wine stains” or PWS, consist of abnormally dilated capillaries within the skin and mucosa, appearing as pink to red macules that blanch with pressure. When involving the face, CM may thicken and darken over time and develop inflammatory nodules or overlying pyogenic granulomas. In CM that has high blood flow, soft tissue and/or bony overgrowth may also occur. Identified gene mutations in CM include GNAQ and GNA11. Due to phenotypic heterogeneity and variable penetrance, some individuals with a family history of HHT or CM-AVM may present with CM only. If a patient has CM only but tests positive for germline mutation consistent with HHT or CM-AVM, then the individual needs referral to a specialty vascular center for further comprehensive evaluation including family history/assessment.

The indications and effectiveness of molecularly targeted medications remain unclear for CM. Unsurprisingly, given the different causal mechanisms of these conditions, systemic and topical sirolimus have not demonstrated any benefits for CM or the capillary components of combined malformations. ^{, ,} In fact, combined use of topical sirolimus and pulsed dye laser for treatment of CM may result in increased complications such as delayed ulceration and increased systemic absorption. Topical MEK inhibition could potentially be a therapeutic option in the future for inflammatory issues related to CM. Sturge-Weber syndrome, arising from a somatic GNAQ mutation, is a congenital neurologic disorder that is associated with a CM on the face, with high-risk areas including the upper eyelid area, forehead, and scalp. One small prospective study investigated use of sirolimus in children with Sturge-Weber syndrome and suggested that sirolimus may be beneficial for cognitive impairments, such as in those with impaired processing speed or a history of stroke-like episodes.

Continued as Part 3 of 3 parts in the following article.