Lymphatic Malformations: Review of Diagnosis and Management for the Interventional Radiologist

Abstract

Lymphatic malformations (LMs) arise from errors in lymphatic vascular development during embryogenesis and encompass an array of conditions that span from common cystic LMs to complex lymphatic anomalies (CLAs). Manifestations of LMs are wide-ranging, from clinically inconsequential to life-threatening. Proper diagnosis and management can be challenging and often benefit from an experienced multidisciplinary team. Cystic LMs are localized entities for which percutaneous sclerotherapy is the mainstay treatment. CLAs, on the other hand, are more diffuse in involvement and typically require multimodal therapy. With advances in the genetic understanding of LMs, targeted systemic therapies have been increasingly utilized with promising results. Thoracic duct interventions, both surgical and percutaneous, have a limited role in CLAs and should be approached cautiously to avoid significant complications. In this review, we discuss the genetic basis, imaging findings, and management options for LMs, with a particular focus on relevant interventional radiology techniques.

Nomenclature is a contentious and ever-changing part of the study of vascular anomalies. For many years, the International Society for the Study of Vascular Anomalies (ISSVA) classification ¹ has been broadly divided into vascular tumors and vascular malformations, despite the accumulating evidence of significant overlap between the two. As genomic technologies continue to advance, it is likely that future nomenclatures will become more mutation and cell-line based. However, for now, society continues to recommend an essentially “plumbing versus tumor” dichotomy. Vascular malformations, which arise from congenital errors of vessel morphogenesis, exhibit normal endothelial turnover. Meanwhile, vascular tumors are characterized by excessive cellular proliferation. Vascular malformations may be composed of capillaries, veins, lymphatics, arteries, or any combination thereof.

Under the ISSVA classification, lymphatic malformations (LMs) are subdivided into common (cystic) LMs and various other conditions that include complex lymphatic anomalies (CLAs). A distinct family of diagnoses sharing the label of primary lymphedema is also considered a lymphatic-type vascular anomaly and is often treated by large vascular anomaly clinics. However, these disorders have little in common with the other lymphatic conditions and will not be covered here in any detail.

Common LMs are localized cystic masses that are further characterized as macrocystic, microcystic, or mixed types. Conglomerations of particularly small microcysts have been referred to as mass-like LM owing to their paucity of fluid content, although this is not ISSVA nomenclature as of the 2018 classification. The vast majority of LMs are focal or geographic macrocysts or microcysts.

CLAs are much less common and typically feature multifocal involvement or abnormalities of the central lymphatic circulation. These diagnoses encompass a group of disorders including Gorham–Stout disease (GSD), generalized lymphatic anomaly (GLA), Kaposiform lymphangiomatosis (KLA), and central conducting lymphatic anomaly (CCLA).

LMs can often be a feature of syndromes that belong to PIK3CA -related overgrowth spectrum (PROS). Somatic activating mutations in the PIK3CA gene lead to a range of disorders characterized by segmental overgrowth of body parts and vascular malformations. Examples include Klippel–Trenaunay syndrome (KTS), CLOVES ( c ongenital l ipomatous o vergrowth, v ascular malformations, e pidermal nevi, s coliosis/skeletal, and spinal anomalies) syndrome, and CLAPO ( c apillary malformation of the lower lip, l ymphatic malformation of the face and neck, a symmetry of face and limbs, p artial/generalized o vergrowth) syndrome.

The major aims of this discussion are to review the genetic basis, imaging findings, and management options of both common LMs and CLAs, with a particular focus on relevant interventional radiology techniques.

Lymphatic Anatomy

The main function of the lymphatic system is to collect excess interstitial fluid from the soft tissues and transport it back to the venous system. The abdominopelvic lymphatic system is made up of soft tissue and splanchnic vessels that coalesce together at the level of the cisterna chyli. They continue beyond the diaphragm as the thoracic duct, to which the pulmonary lymphatics also return their collected fluid. While the term “lymph” refers to the interstitial fluid within most lymphatics, the term “chyle” is reserved for the mixture of lymph with chylomicrons absorbed from the intestine. As such, the volume of chyle within the central lymphatic system is significantly influenced by dietary intake.

The thoracic duct is the largest lymphatic channel in the body, draining 80 to 90% of the total lymph volume. ² It terminates at the junction of the left internal jugular and subclavian veins. The rest of the lymph (which comes from the right hemithorax, right head and neck, and right arm) drains via the right lymphatic duct into the junction of the right internal jugular and subclavian veins. Although the right lymphatic terminus is much smaller, both junctions can be resolved by ultrasound and accessed percutaneously. There are significant variations in the thoracic duct anatomy. Typically, the thoracic duct begins at the cisterna chyli, a fusiform dilatation at the level of L1–L2 between the aorta and the inferior vena cava. ³ The size and location are variable, as is the number of cisterns. The thoracic duct ascends from the retroperitoneum into the posterior mediastinum through the aortic hiatus. It often travels to the right of the midline and then crosses the midline at about the level of T5 to ascend the thoracic inlet. ⁴ Distally, it travels a few centimeters above the clavicle and then curves inferiorly to drain into the left jugular–subclavian junction. ⁵

Common LMs are thought to arise from an aberrant bud from a primordial lymph sac that loses communication with the normal lymphatic system. ⁶ The timing in which the abnormality occurs during embryonic development likely determines the distribution and extent of the LM (i.e., the later it occurs, the more peripheral and localized an LM will be). In CLAs, flow abnormalities in the central lymphatic system can lead to leakage into the thoracic or abdominal cavities, manifesting as pleural/pericardial effusions or ascites. The fluid may be clear lymph or chylous depending on the site of leakage. Chylous leaks usually imply leakage from the thoracic duct but can be from other locations if reflux is present. ⁷

Molecular Basis of Lymphatic Disorders

Most LMs are sporadic diseases caused by somatic mutations. While they are nonneoplastic in nature, LMs arise from mutations in genes that are implicated in oncogenic signaling pathways. PI3K is an important signal transduction protein within human cells, responsible for activating by phosphorylation the cellular pathways for cellular growth, vascular development, motility, and proliferation among many others. PIK3CA is the gene that encodes the P110α catalytic subunit of the PI3K protein, representing the upstream element of the PI3K/AKT/mTOR pathway. The majority of common cystic LMs (∼80%) harbor activating PIK3CA mutations. ⁸ These mutations are also found in congenital venous malformations and mosaic overgrowth syndromes, as well as in acquired malignancies. ^{9 10} In patients with PIK3CA -related overgrowth spectrum, such as KTS and CLOVES, the somatic PIK3CA mutations are more widely distributed in the body compared to isolated common LMs, accounting for more diffuse presentation. ¹¹ Knowledge of genetic mutations underlying vascular malformations has led to the use of inhibitors of mTOR (sirolimus) and PI3K (alpelisib) to specifically target PIK3CA -driven disease processes.

CLAs are predominantly linked to activating mutations in various components of the RAS/MAPK pathway. The pathway is a key regulator of cell cycle, growth, and differentiation. Mutations in the RAS/MAPK pathway are also associated with other conditions, such as capillary malformation–arteriovenous malformation syndrome, Noonan syndrome, neurofibromatosis type 1, and tuberous sclerosis. ¹² Examples of somatic mutations associated with CLAs are as follows: KRAS in GSD, NRAS in KLA, and ARAF in CCLA. ⁸ Some patients with GLA harbor somatic mutations in NRAS , while others have mutations in PIK3CA , like those with common LMs. ¹³ This implies that certain mutations in the two different signaling pathways can lead to overlapping disease phenotypes, therefore highlighting the importance of performing genetic testing on individuals to select appropriate targeted therapies. Inhibitors of the RAS/MAPK pathway, including MEK inhibitors (trametinib, selumetinib), have been shown to help in CLAs.

From this point on, the presentation, diagnosis, and management of common LMs will be reviewed first, followed by a discussion on CLAs.

Lymphatic Malformations

Clinical Presentation of Lymphatic Malformations

Common LMs are congenital lesions that affect anywhere from 1 in 6,000 to 16,000 live births internationally. ¹⁴ There is no sex or racial predilection. They are usually noted at birth or within 2 years of age. While LMs can occur in any part of the body, they are typically found in areas rich in lymphatics, especially in the head and neck (up to 75%), as well as the axilla, mediastinum, groin, and abdomen. ¹⁵ The malformations vary widely in size and extent. Large cervicofacial LMs require special attention as they may cause airway obstruction. Endoscopic airway evaluation is warranted if obstructive symptoms or signs are present.

Macrocystic LMs are classically soft and ballotable on physical exam, whereas microcystic LMs tend to be firmer due to the relative paucity of fluid content versus wall. Overlying skin may be normal or may have a bluish tinge. LMs grow proportionally with the child. However, they may suddenly enlarge in the setting of acute inflammation triggered by local trauma or systemic/regional infection (e.g., upper respiratory infection). In fact, previously occult LMs often come to clinical attention after an inflammatory event. On physical exam, they are usually firm and tender, frequently with bruising due to intralesional hemorrhage. The blood products are eventually broken down from weeks 2 to 12, which correlates to a varying degree of firmness of the lesion. Acutely inflamed LMs are often mistaken for an infectious process, which may result in an unnecessary course of antibiotics or even an incision-and-drainage procedure. An actual infection of an LM itself is incredibly rare, however; inflammation of the malformation is due to activation of the immune system, of which the LM is a disordered component.

Over time, these lesions may undergo either complete or partial spontaneous involution, a process referred to as autosclerosis. While the mechanism of autosclerosis is not clear, it is speculated that the acute inflammatory process may be similar to that produced purposefully by sclerotherapy, the mainstay treatment for LMs. In a significant minority of patients (12–13%), autosclerosis leads to total spontaneous resolution without requiring any treatment. ^{16 17} Even for those wherein autosclerosis does not lead to complete resolution of the LM, it often reduces the size and conspicuity of the malformation to a significant degree, potentially obviating the need for intervention.

Imaging of Lymphatic Malformations

Ultrasound is the imaging modality of choice for common LMs. If the lesion is large, deep, or atypical, MRI is helpful to evaluate its extent and identify potential complications such as airway obstruction in cases of large cervicofacial LMs. A downside of MRI is its requirement for sedation in young children.

Prenatal imaging can play a crucial role in planning safe delivery by detecting large LMs early ( Fig. 1 ). Ex utero intrapartum treatment is a technique in which the fetus is partially delivered via hysterotomy while maintaining placental support, allowing for interventions like endotracheal intubation or tracheostomy. ¹⁸ This can be lifesaving in cases of airway obstruction due to large cervicofacial LMs.

Fig. 1.

A large lymphatic malformation at the lateral neck seen in a third-trimester fetus. ( a ) An exophytic multicystic lesion is seen on fetal ultrasound (arrow). ( b ) There is minimal color Doppler flow within the septae. ( c ) Coronal T2-weighted fetal MRI better demonstrates the lesion's anatomic extent into the neck and thoracic inlet. Prenatal identification of large cervicofacial LMs is crucial for delivery planning.

Macrocystic LMs

These are cysts generally defined as >1 cm in size with thin septations, often multiple and transspatial, crossing more than one tissue plane. On ultrasound, the cysts may appear anechoic ( Fig. 2a ) or demonstrate internal echoes due to proteinaceous content. There should be no internal color Doppler flow, but a mild flow may be present within the thin septations. Fluid–fluid levels indicating layering blood products can be seen in the initial acute inflammatory phase of autosclerosis ( Fig. 3 ). This complex appearance on ultrasound can be often confused for pus, although true infection of an LM is very rare as mentioned earlier. On MRI, macrocystic LMs appear as multiseptated hyperintense lesions on T2-weighted imaging ( Fig. 2b ). Proteinaceous content or blood products appear as hyperintensities within the cyst on T1-weighted imaging. Postcontrast imaging demonstrates enhancement limited to the septa.

Fig. 2.

A 12-year-old female with a right supraclavicular macrocystic lymphatic malformation. ( a ) Ultrasound demonstrates a multicystic anechoic lesion. ( b ) Axial T2-hyperintense fat-saturated MR imaging shows a subcutaneous hyperintense mass with multiple thin septations at the base of the right neck laterally (arrow). ( c ) Ultrasound-guided insertion of a 25-gauge needle (arrow) into the LM with subsequent aspiration of 30 mL of serous fluid. ( d ) A mixture of doxycycline and contrast was injected under fluoroscopic guidance, demonstrating contrast conforming within the space of the LM without extravasation.

Fig. 3.

A 16-day-old male with a large cervicofacial lymphatic malformation with delivery-associated intralesional hemorrhage, resulting in a significant mass effect. ( a ) Ultrasound of the neck demonstrates multicystic, predominantly macrocystic LM with fluid–fluid levels, indicating dependently layering blood products (H). ( b ) Similar findings are seen on an axial T2-weighted MR image. Septae of LMs have fragile vasculature that can bleed in the setting of trauma or local inflammation. The presence of blood products within an LM can limit the effectiveness of percutaneous sclerotherapy; results are often better after waiting 6 to 8 weeks for the process to resolve.

The differential diagnosis of macrocystic LMs includes congenital cystic lesions (e.g., branchial cleft cyst, enteric duplication cysts), abscesses, and cystic malignancies ( Fig. 4 ). ¹⁹ Malignancies such as rhabdomyosarcoma or synovial sarcoma may simulate cysts on T2-weighted imaging but are more likely to show solid or nodular enhancement or low diffusivity indicating high cellularity. ²⁰ For large multicystic macrocystic LMs of the abdominal cavity, cystic teratoma should always be on the differential and any areas suspicious for solid mass lesion warrant biopsy.

Fig. 4.

A 2-month-old female initially diagnosed with a venolymphatic malformation based on imaging. Axial T2-weighted fat-saturated MR image of the head demonstrates a hyperintense multicystic lesion in the left temporal region (arrow). Laterally, there is a heterogeneously hypointense component. This was surgically resected and was found to be a mature teratoma on pathological examination.

Microcystic LMs

These consist of numerous small (<1 cm) cysts, which may be separate or interconnected. Ultrasound may show multiple tiny cystic spaces ( Fig. 5a ), but often the cysts cannot be individually discerned and appear as nonspecific soft tissue thickening or edema. On MRI, they are infiltrative and hyperintense on T2-weighted imaging ( Fig. 5b ). If the cysts are very minuscule and their septa tightly packed, these may resemble solid tissue and may enhance mildly. These are referred to as mass-like LMs; their cystic spaces are too small to resolve by imaging, appearing as a mat of innumerable septations ( Fig. 6a, b ). When seen on ultrasound, mass-like LM is hyperechoic, and may have isolated foci of resolvable microcysts.

Fig. 5.

A 4-year-old male patient with a microcystic lymphatic malformation in the left gluteal and perineal region. ( a ) Ultrasound demonstrates numerous small cysts within the subcutaneous tissue, as well as areas of skin thickening/lymphedema-like appearance. ( b ) Axial T2-weighted fat-saturated MR image shows expansion of the left gluteal subcutaneous soft tissues with infiltrative hyperintense multicystic lesions that extend into the left perineum. (For reference, the marrow signal in the right femur is circled and can be seen similarly on the left.) ( c ) One of the larger cysts is targeted with a 25-gauge needle (arrow) under ultrasound guidance in order to make percutaneous sclerotherapy possible. ( d–f ) Serial fluoroscopic images demonstrate the fluid continuity of the microcysts and their progressive distension with the injection of bleomycin in contrast. Because of its direct effect on endothelial cells and lack of secondary edema, bleomycin allows for an extravasation-tolerant approach to treating these lesions that would likely lead to severe wound complications with other agents.

Fig. 6.

A 10-month-old female with a left submandibular mass-like lymphatic malformation. ( a ) Axial T2-weighted fat-saturated MR image demonstrates a hyperintense mass with peripheral macro- and microcysts. ( b ) Postcontrast MR image shows mild central enhancement which resembles a solid soft tissue mass. ( c ) A peripheral macrocyst was targeted with a 25-gauge needle and was injected with bleomycin, demonstrating some fluid continuity with neighboring cysts. ( d ) Additional macrocysts were targeted, demonstrating sclerosant infiltrating more centrally into the mass-like LM. ( e ) MRI at 27 months after two sessions of sclerotherapy demonstrates a smaller but persistent mass-like LM. ( f ) Postcontrast MRI at 6 years of age after surgical resection demonstrates no residual lesion. As demonstrated in this case, sclerotherapy can debulk mass-like LM but is often limited in overall effect.

Traditionally, the differential diagnosis of microcystic LMs has included cellulitis or lymphedema. ¹⁹ Yet, as these conditions are clinically associated with subcutaneous microcysts there has likely been some misattribution in the literature. Subcutaneous microcysts may bring a lymphedematous appearance to the overlying skin and surrounding tissues. Likewise, the skin loses its inherent barrier function when microcysts penetrate to the surface, and consequently cellulitis is a common complication of severe microcystic skin disease.

Mixed LMs

These lesions are made up of both macrocystic and microcystic components. In the perinatal period, the differential diagnosis includes congenital teratoma, which typically contains more solid components with greater mass effect and characteristically contains fat and/or calcifications.

Management of Lymphatic Malformations

A multidisciplinary team approach is key to managing lymphatic disorders. Having a dedicated vascular anomalies clinic in which a team of physicians trained in a wide range of specialties including pediatric surgery, plastic surgery, otolaryngology, interventional radiology, dermatology, oncology, and clinical genomics allows for simultaneous evaluation and joint clinical decision making. ²¹ Because many treatment options exist for lymphatic disorders, such a robust interdisciplinary clinic is integral to facilitating combined or staged interventions.

Indications for treatment include recurrent swelling, pain, deformity, and interference with physical activity. Treating children at an early age can be beneficial for several reasons. Because skin grows and expands when put under tension from underlying structures, treating a large malformation early in life typically prevents the need for reconstructive surgery later in life, as the patient will grow into excess tissue once the underlying malformation is no longer a factor. Even lesions with minimal associated deformity should be treated early, as they can become a point of psychological distress and social stigma for children older than 5 years. That said, we will typically defer initial treatment to 6 months of age unless there is concern for airway compromise, given the increased risks associated with anesthesia in neonates.

In general, sclerotherapy is the first-line treatment for common LMs, although the location and subtype can determine the likelihood of treatment success. Macrocystic LMs respond best to sclerotherapy, while mass-like LMs often respond minimally if at all and require surgical resection ( Fig. 6c–f ). Extensive microcystic LMs are often treated with systemic therapies such as sirolimus or alpelisib. A complete cure may not be achievable, but the goal is to improve function and cosmesis.

Small asymptomatic LMs can be observed and may never require intervention. Procedures should be delayed for LMs that are acutely inflamed since they will likely autosclerose on their own ( Fig. 7 ), and sclerotherapy is less effective in the midst of an autoinflammatory cascade already in progress. Supportive therapy in the form of nonsteroidal anti-inflammatory drugs is typically sufficient for the 1 to 2 weeks it takes for the acute inflammatory cascade to run its course, after which point the LM will likely undergo at least some degree of autosclerosis and involution. Follow-up imaging in 3 to 6 months after the full resolution of inflammation is recommended. If there is a significant residual lesion, sclerotherapy may then be performed.

Fig. 7.

A 2-year-old male with a right cervicofacial lymphatic malformation with primarily microcystic and mass-like components. ( a ) At baseline, the lesion involves the parotid and extends into the parapharyngeal space with minimal mass effect, as shown on the axial T2-weighted fat-saturated MR image. ( b ) Follow-up MRI performed in the setting of rapid lesional expansion and erythema after upper respiratory infection. The image demonstrates the fluid–fluid levels (arrow) and signal voids characteristic of intralesional hemorrhage. ( c ) Follow-up MRI 6 months after inflammatory event demonstrates near-total autosclerosis of the previously noted lymphatic tissue without interval medical intervention.

Sclerotherapy

Sclerotherapy is a minimally invasive, image-guided procedure whereby a chemical agent is injected into a vascular malformation, resulting in endothelial damage. Inflammation ensues, followed by fibrosis and eventual obliteration of the malformation lumen. Historically, a wide variety of chemical agents, or sclerosants, have been used for LMs, including ethanol, doxycycline, bleomycin, and sodium tetradecyl sulfate. Doxycycline and bleomycin are currently the most commonly used for LM due to their efficacy and favorable safety profile. ²²

Macrocystic LMs respond particularly well to sclerotherapy. Greater than 80% can be destroyed fully. ²³ Macrocysts, in practical terms, are cysts large enough to aspirate and inject into (generally >1 cm). Therefore, they are first drained of their fluid content and then injected with sclerosant to maximize its dose to the endothelial lining and minimize the risk of extravasation ( Fig. 2c d ). Doxycycline is the sclerosant of choice for macrocystic LMs. Doxycycline is a broad-spectrum antibiotic from the tetracycline class. It has been shown to induce an inflammatory reaction resulting in fibrin and collagen deposition in pleurodesis animal models. ²⁴ Additionally, its inhibition of matrix metalloproteinases and vascular endothelial growth factors may help suppress lymphangiogenesis. ¹⁵

A patient population that warrants special attention are neonates with massive cervicofacial LMs. They may benefit from upfront surgical debulking followed by sclerotherapy. Performing sclerotherapy first in this population is challenging due to weight-based dosage limitations of doxycycline (20 mg/kg), ²⁵ the need for multiple drains, and risk of significant inflammatory response. ²¹ Sclerotherapy after surgical debulking allows for lower sclerosant dosing. In addition, neonates can develop severe hypoglycemia following sclerotherapy with doxycycline and must be monitored closely postprocedurally. ²⁶ If there is no urgent need for sclerotherapy, such as airway compromise, it is recommended to delay treatment until the patient is older than 6 months to decrease potential anesthesia risks. When there are airway concerns—most commonly due to the presence of LM within the parapharyngeal and/or retropharyngeal spaces—sclerotherapy should focus specifically on these airway-adjacent lesions and not attempt to percutaneously debulk the process at large.

Microcystic LMs respond less well to sclerotherapy, often requiring repeated treatments or combining with other treatment modalities. Microcysts refer to cysts that are too small to be aspirated, but which can be resolved by ultrasound and often targeted for needle puncture. These lesions are often too numerous to individually target, and therefore the mass of microcysts must be treated by way of overdistention with sclerosants. A conglomerate of microcysts is often in fluid continuity, and needle access of one can allow for the treatment of an entire network of cysts ( Fig. 5c–f ). However, if this is not the case, injecting into each separate cyst may not be practically feasible, and it is never clear in advance if any particular access point will extend into the network or not. Owing to these considerations, the sclerosant of choice for microcystic LMs is bleomycin. ²⁷ A proposed mechanism of action in sclerotherapy is endothelial damage through disruption of tight junctions. ²⁸ It produces less inflammation and swelling than doxycycline and therefore is less likely to cause nontarget injury in the occurrence of extravasation, which allows for the above-detailed approach. This also makes bleomycin useful for treating both macro- and microcystic LMs that involve critical structures, such as the orbit and the airway, where swelling is not likely to be tolerated.

For mixed lesions, sclerotherapy is recommended for macrocystic components first. Repeat imaging is performed if there is a persistent lesion after initial treatment. If the primary remaining component is macrocystic, repeat sclerotherapy may be performed; if it is microcystic, sclerotherapy with bleomycin or medical therapy may be used. Surgical resection is an option for very persistent lesions.

Rarely, LMs occur in the abdomen. Treatment is recommended as abdominal LMs may lead to complications such as bowel obstruction or volvulus. ²² Macrocystic abdominal LMs are treated with doxycycline sclerotherapy. Drain placement and serial sclerotherapy may be performed for large LMs. Potential pitfalls include the possibility of misdiagnosis (differential includes cystic malignancy) and complications from peritoneal spillage of sclerosant. ²⁹

The most commonly quoted complications of sclerotherapy are skin necrosis and nerve damage. The highest complication rates have been associated with ethanol, which is now rarely used. An adverse effect unique to bleomycin is skin hyperpigmentation both locally at the injection site and remotely in areas of contact with adhesives: the microtrauma of tape removal leads to deposition of circulating bleomycin into the tissue, resulting in a brown hemosiderin discoloration. Therefore, the use of adhesive tapes on the skin should be minimized before and after bleomycin sclerotherapy, and when necessary (or if applied accidentally), all tape should be removed with care and the use of adhesive removers. Pulmonary toxicity is a known concern with intravenous administration of bleomycin, usually seen with >400 units lifetime dose. ²⁷ No reported cases of pulmonary fibrosis with intralesional bleomycin injections have been reported, and so pulmonary function testing is no longer routinely performed. ³⁰ Of note, since bleomycin can also be used in large intravenous doses by oncologists treating lymphomas and other malignancies, many hospital pharmacies treat even sclerosant-dose amounts of the medication with chemotherapy precautions. We do not routinely refer to bleomycin as a chemotherapeutic agent in the setting of treating vascular malformations.

Sclerotherapy Technique

Sclerotherapy is typically performed as an outpatient procedure in the interventional radiology suite. Patients are placed under general anesthesia. Prophylactic antibiotics against skin flora such as cefazolin are given, as well as intravenous ketorolac for pain control. Patients being treated for cervicofacial LMs are always intubated for airway protection.

Macrocystic LMs

Lesions are accessed directly with a small (25-gauge) needle under ultrasound guidance. The cystic content is aspirated nearly to completion, taking care not to lose needle access. The sclerosant mixture is prepared, its volume typically half of what was aspirated in to avoid overdistension and extravasation. Doxycycline, which is in powder form, is reconstituted in normal saline mixed with iodinated contrast and local anesthetics to achieve a concentration of 5 to 20 mg/mL. Doxycycline has a dose limit of 20 mg/kg of body weight, although single doses as high as 300 mg are considered safe regardless of patient weight. ³¹ Through the same needle access, the sclerosant is administered through fluoroscopy to monitor for extravasation.

Very large macrocystic lesions may be directly accessed with small-bore (6–8 Fr) catheters. For macrocysts that are likely to contain more than 100 mL of fluid content, we will often place a 6-Fr pigtail catheter and admit the patient postprocedurally. This allows for serial doxycycline administration without exceeding daily dosing limits. The sclerosant is left to dwell within the lesion for 4 to 6 hours and then drained out of the catheter to a standard gravity bag. The injection of sclerosant can be repeated daily until the output falls below 10% of the original fluid volume, ³² although our practice has had success with a less stringent threshold of about 25%, reducing both the total number of anesthesia events and hospital admission days. We usually remove the drain immediately after instilling the final sclerosant dose, allowing for hospital discharge within 24 hours of the final session.

Microcystic LMs

Bleomycin is reconstituted in a 1:1 mixture of normal saline and contrast in advance by pharmacy. Its dosing is 1 unit/kg body weight, with maximum dose of 15 units per session. ²⁷ A microcyst is targeted with a small-bore needle under ultrasound guidance and injected with the bleomycin solution under fluoroscopy. Multiple cysts may need to be targeted. A purposeful overdistention technique is often employed to reach networked lesions, as extravasation with bleomycin is usually inconsequential unless significant focal volumes are deposited.

Postprocedurally, the patients are observed in the recovery unit. Doxycycline sclerotherapy remains painful for 1 to 2 hours after injection and requires analgesics in recovery. After discharge, over-the-counter anti-inflammatory medications are sufficient to manage pain as needed. LMs involving the airway must be observed carefully and may require prolonged airway intubation. Repeat sclerotherapy is often needed and is spaced 6 to 8 weeks apart to allow for the first inflammatory process to resolve before attempting to start another.

Surgery

Historically considered the first-line treatment for LMs, surgery continues to play an important albeit limited therapeutic role. Complete surgical resection is rarely achievable for lesions that cross multiple tissue planes and involve vital structures. Recurrence rate after incomplete resection is high (20–40%). ³³ Therefore, upfront surgical debulking is reserved for large neonatal cervicofacial LMs to reduce disease burden prior to sclerotherapy. Surgical resection may also be considered for lesions that are percutaneously inaccessible or that persist despite repeated sclerotherapy. It is worth noting that safe identification and dissection of neurovascular structures can be challenging in a previously sclerosed area, although this seems to be less of an issue when bleomycin is the sclerosant. Given the risks of facial nerve injury with post-sclerotherapy resection of craniofacial LMs, we exclusively utilize bleomycin for any malformations above the jawline if there is any conceivable potential for a surgical resection in the future.

Collaboration of multiple surgical specialties, including pediatric surgery, plastic surgery, otolaryngology, and orthopedic surgery, are important to optimize surgical outcome. Staged procedures may be necessary. Even if complete resection is not possible, surgical debulking may help improve function and cosmesis. In cases of large cervicofacial LMs, additional procedures such as tracheostomy and feeding tube placement should be considered. Complications of surgery can include nerve damage (e.g., facial and hypoglossal nerve injury during cervicofacial LM resections), scarring, lymphatic leakage, seroma formation, poor wound healing, and infection. The most common complication from LM resection, seroma formation lends itself well to cleaning up with doxycycline sclerotherapy.

Medical Therapy

Knowledge of the genetic mutations responsible for activating signaling pathways in LMs has led to the usage of targeted pharmacological interventions. Small molecule inhibitors that target the PI3K-AKT-mTOR pathway, well-known drug targets in cancer, have been repurposed for the treatment of LMs. Medical therapy is typically indicated for LMs that are either resistant to or not amenable to sclerotherapy or resection. In particular, diffuse microcystic LMs or LMs in challenging locations such as the base of the tongue, deep retropharyngeal space, or the region of the facial nerve, should prompt consideration for medical therapy.

Sirolimus (also known as rapamycin) is the most studied drug in the treatment of vascular anomalies. It is, however, used for this indication in an off-label fashion. It is a macrolide that inhibits mTOR, a protein kinase involved in cell growth and angiogenesis. Sirolimus has been well established as an immunosuppressant in organ transplant patients for decades but was first used for LMs in extensive and difficult-to-treat microcystic lesions in 2011. ³⁴ Since then, many studies have demonstrated efficacy and tolerability of sirolimus in patients with LMs. A pivotal phase II prospective trial showed improvement in quality of life, organ dysfunction, and lesion size after 1 year of sirolimus treatment, although none of the lesions resolved completely. ³⁵

Sirolimus requires good patient compliance to be effective. It is orally dosed twice daily and requires regular blood level checks, typically spaced weekly until steady-state level is met, at which point the frequency is decreased to every 2 to 4 weeks. The goal trough level is typically 10 to 15 ng/mL. ³⁶ The most common side effects include oral mucositis, dyslipidemia, leukopenia, gastrointestinal symptoms, and rash. ³⁷ Because sirolimus is prescribed at lower doses for patients with vascular anomalies compared to those with organ transplants, concern for immunosuppression is low. However, by protocol, most vascular anomalies patients on the medication still receive a weekly dose of sulfamethoxazole/trimethoprim for Pneumocystis jirovecii pneumonia prophylaxis.

Alpelisib is a PI3K inhibitor originally used for the treatment of PIK3CA -mutated breast cancer. In 2022, it was the first drug to be approved by the U.S. Food and Drug Administration for the treatment of PROS. It has been shown to reduce overgrowth and disease symptoms, ³⁸ although its effect on LMs specifically is not well-studied. Alpelisib is an oral drug with a side effect profile similar to that of sirolimus. It does not require drug level checks like sirolimus; however, regular monitoring of blood glucose is recommended as it can cause hyperglycemia in up to 12% of patients. ³⁹

Laser

Lymphatic microcysts can occur at the cutaneous or mucosal level. These microcysts, also referred to as vesicles, may spontaneously leak lymph or blood. Bacteria can readily enter through the vesicles and spread through the tissues, resulting in recurrent cellulitis. These superficial lesions can be treated with laser therapy. Carbon dioxide laser has been shown to improve pain and localized infections. ⁴⁰ Other types of lasers, such as neodymium-doped yttrium aluminum garnet and pulsed dye laser, may be used. ⁴¹ Repeated treatments may be necessary as recurrence is common. While generally safe and well-tolerated, laser therapy can cause hyperpigmentation or scarring. Topical sirolimus is another treatment option for lymphatic vesicles and can be used adjunctively to laser therapy. ⁴²

Complex Lymphatic Anomalies

Clinical Patterns of Complex Lymphatic Anomalies

CLAs are rare disease entities with highly variable and overlapping presentations. A combination of clinical, laboratory, and imaging studies is required to make a diagnosis. A high index of suspicion and familiarity with these conditions are important for timely diagnosis and management.

GSD, also known as vanishing bone disease, is characterized by the proliferation of LMs within bone resulting in progressive osteolysis. The disease is best conceptualized as a focal, locally aggressive lymphatic tumor. As such, it may extend into multiple bones locally but is not polyostotic in origin. GSD typically affects the axial skeleton: the vertebrae, ribs, skull, jaw, and clavicle are most commonly involved. Due to cortical destruction, patients can present with pathologic fractures, spinal instability, cerebrospinal fluid leaks from skull osteolytic lesions, as well as pleural and pericardial effusions. ⁴³ GSD can be rapidly progressive but also can spontaneously stabilize. Central lymphatics are not typically involved in GSD, although there can be communication between the mass lesion and surrounding lymphatics of any size.

GLA is characterized by multifocal LMs involving soft tissues, bones, liver, spleen, and lungs. GLA is often polyostotic, and the affected bones are often noncontiguous with an appendicular distribution compared to GSD's axial regional/monostotic distribution. The most common site is the ribs followed by the spine. Lesions are lytic, nonprogressive, and involve the medullary space. GLA is best conceptualized as a diffuse abnormality of the entire body's (or an entire body region's) lymphatics. Pleural effusions are present in 40 to 70% of patients ^{44 45} and frequently lead to respiratory problems. Thoracic involvement in GLA portends a poor prognosis in children, with mortality rate of 20%. ⁴⁴ Effusions can worsen with illness, including common viral infections, and at times of growth spurts and hormonal surges.

KLA is considered to be a more aggressive subset of GLA. Like GLA, KLA features multifocal LMs involving bones and viscera but is associated with much higher morbidity and mortality. The 5-year survival rate is 50%. ⁴⁶ KLA exhibits features of both neoplasia and malformation. Histologically, the disease is defined by the presence of proliferative spindle-shaped cells, in addition to malformed lymphatic channels on biopsy samples. However, obtaining a biopsy poses a substantial bleeding risk for KLA patients. KLA is associated with consumptive coagulopathy, also referred to as Kasabach–Merritt phenomenon, characterized by thrombocytopenia and hypofibrinogenemia. This is a distinguishing feature of KLA from other CLAs. Without treatment, KLA is progressive and can cause serious complications like hemorrhagic effusion, cardiorespiratory compromise, and multiorgan failure.

CCLA may represent a malformation of the thoracic duct and its tributaries, as it is a disorder characterized by abnormal central lymphatic flow. The thoracic duct and/or cisterna chyli are either obstructed or dysfunctional, causing chronic reflux and leakage of lymphatic fluid distally. Manifestations of CCLA include pleural and pericardial effusions, ascites, and lymphedema. Fluid is often chylous, although this can vary depending on where the fluid is sampled from. In addition, patients may develop pulmonary lymphangiectasis, protein-losing enteropathy, and cutaneous vesicles. Osseous lesions are not seen in CCLA, as the disorder is considered an isolated abnormality of the central conducting lymphatic channels themselves.

Imaging of Complex Lymphatic Anomalies

In cases of suspected CLAs, cross-sectional imaging of the chest, abdomen, pelvis, and spine is indicated. MRI is typically the preferred modality over CT to evaluate multifocal lymphatic abnormalities in CLAs because of its superior soft tissue differentiation and lack of ionizing radiation. CT can be helpful in assessing bony involvement. A specialized type of MR study performed by intranodal injection of gadolinium, known as MR lymphangiogram (MRL), is an important diagnostic tool for assessing the integrity of central lymphatics and for planning lymphatic interventions in CLA patients.

GSD

The key imaging finding is cortical destruction and progressive bone loss ( Fig. 8 ). Osteolysis is best demonstrated with radiography or CT. There is often an extension of LM in the soft tissue surrounding the affected bone, best seen on MRI. ¹⁹ This appears as infiltrative, T2-hyperintense lesions that enhance. GSD may have findings that overlap with GLA, including pleural effusion and splenic lesions. Depending on the location of the lesion and the directionality of flow in nearby lymphatics, MRL may demonstrate contrast flow into the lesion; however, visualized central lymphatics should be morphologically normal.

Fig. 8.

A 17-year-old male with Gorham-Stout disease. ( a ) Axial CT of the chest demonstrates lytic bone lesions of the right posterior ribs (arrow). The bony cortex is involved. ( b ) Left greater than right pleural effusions are also seen. ( c ) Sagittal T1-weighted MR image of the thoracolumbar spine demonstrates diffuse marrow signal changes in multiple contiguous vertebral bodies.

GLA

Unlike GSD, bone lesions in GLA involve the medullary cavity while the cortex is spared. Also, GLA does not exhibit infiltrative periosseous soft tissue masses or progressive osteolysis. Visceral organ involvement, particularly macrocystic LMs and splenic cysts, are more common in GLA than GSD ( Fig. 9 ). Pleural and pericardial effusions may be present, in which case MRL can be particularly helpful to identify a site of lymphatic leakage that is causing the effusions.

Fig. 9.

An 11-year-old male with generalized lymphatic anomaly. ( a ) Axial contrast-enhanced CT demonstrates a cystic lesion in the spleen (arrow) as well as right pleural effusion. ( b ) Coronal postcontrast MRI demonstrates enhancement of noncontiguous thoracic vertebral bodies (arrows). ( c ) 3D MIP MR lymphangiogram shows enhancement of innumerable collateral lymphatic channels below the diaphragm without visualization of a thoracic duct.

KLA

Similar to GLA, imaging findings of KLA include splenic cysts and noncontiguous lytic osseous lesions sparing the cortex. However, KLA tends to exhibit more extensive thoracic involvement, manifested by T2-hyperintense, enhancing soft tissue lesions in the mediastinum ( Fig. 10 ). Hemorrhagic pericardial and pleural effusions and ascites may be present. Owing to the severity of global lymphatic anomalies in KLA, MRL may demonstrate thoracic duct abnormalities, similar to CCLA.

Fig. 10.

A 7-year-old male patient with Kaposiform lymphangiomatosis. ( a ) A chest radiograph shows a widened mediastinum with bilateral interstitial opacities. Bilateral proximal humeri demonstrates multiple lytic lesions. ( b ) Axial chest CT with contrast demonstrates bilateral peribronchovascular thickening, bilateral paraspinal soft tissue thickening, and pericardial effusion. ( c ) Coronal abdominal CT with contrast shows multiple scattered hypoenhancing splenic lesions. ( d ) 3D MIP MR lymphangiogram shows ectatic cisterna chyli and thoracic duct with intact drainage to the venous angle. No lymphatic leaks are visualized. Clinically, this patient also had thrombocytopenia.

CCLA

Imaging manifestations of central lymphatic dysmotility in CCLA are wide-ranging. MRL is essential for the diagnosis of CCLA ( Fig. 11 ). Due to either functional or anatomic abnormality of the thoracic duct, there may be enlarged lymphatic channels or cysts distally in the thoracoabdominal cavity. Dynamic postcontrast phase can demonstrate progressive filling of the central lymphatic channels with contrast and identify areas of obstruction, reflux, and leakage. Leakage can occur in various compartments, resulting in pleural/pericardial effusion and ascites. Lymphedema and diffuse osseous changes may also be present.

Fig. 11.

A 22-year-old female with central conducting lymphatic anomaly. ( a ) Axial T2-weighted fat-saturated MR image shows large left pleural effusion with adjacent lung atelectasis and diffuse peribronchovascular thickening in the right lung. ( b ) Postcontrast MR lymphangiogram image shows no progression of contrast past the cisterna chyli with no demonstrable thoracic duct.

Imaging findings of multifocal lesions in CLAs may prompt clinicians to pursue a biopsy for a definitive diagnosis. However, the decision to biopsy must be weighed carefully against the risks, including bleeding (especially for KLA) and lymphatic leakage, both of which can be life-threatening. Biopsy of rib lesions in particular is not advised as this can lead to refractory pleural effusion.

MR Lymphangiogram Technique

Dynamic contrast-enhanced MR lymphangiography (DCE-MRL) first requires cannulation of bilateral inguinal lymph nodes. Using a high-frequency linear ultrasound probe, a small needle (25 gauge) is placed into a lymph node with the tip positioned at the junction of the cortex and medulla. The needle is attached to long but small-diameter extension tubing to reduce dead space. This is connected to a three-way stopcock and a prefilled syringe containing gadolinium. Any macrocyclic gadolinium-based contrast may be injected into the nodes, with a standard dose of 0.1 mmol/kg of body weight. Gadolinium is diluted in a 1:2 ratio with normal saline in younger children and in a 1:1 concentration in older children. ⁴⁷ However, in our practice, we will often dilute to 1:4 in neonates where total volumes are otherwise prohibitively low.

When lymph nodes are cannulated outside of the MRI suite, care should be taken to secure accesses and minimize manipulation during transfer to the table to avoid dislodgement from the lymph node, as this may result in a nondiagnostic study. We take care to put the patient on an MRI-safe transfer board, place all MRI-associated vital monitoring equipment onto the patient prior to nodal access, and secure the needles with large transparent adhesive film dressings prior to transport to MRI. Care must be taken not to bend the hips once needles are placed. For all these reasons, our standard protocol includes general anesthesia. Heavily T2-weighted and precontrast T1-weighted images should be obtained. Postcontrast dynamic T1-weighted sequences are obtained as gadolinium is injected by hand. The injection rate is at 0.01 mL/min to 0.04 mL/min so that the entire volume of contrast is administered over approximately 4 to 5 minutes. Normal saline is used to clear the dead space once the gadolinium has been infused. Contrast should be visible within the lymphatics soon after the onset of injection. From beginning to end, MRL procedures usually last between 60 and 90 minutes.

Management of Complex Lymphatic Anomalies

Multimodal therapies are often required for CLA patients. Therapies vary by the mechanism of lymphatic dysfunction and the location of active complications.

Image-Guided Interventions

Thoracic duct embolization is a minimally invasive technique for percutaneous management of lymphatic leakage. The procedure is a safe and effective alternative to surgical ligation of the thoracic duct. ⁴⁸ Thoracic duct embolization consists of three steps: (1) fluoroscopic intranodal lymphangiogram, (2) transabdominal catheterization of the thoracic duct via the cisterna chyli or lumbar tributaries, and (3) embolization with glue and/or endovascular coils. ⁴⁹

A fluoroscopic lymphangiogram, obtained by intranodal injection of ethiodized oil, provides excellent spatial resolution for visualizing lymphatic leaks with the advantage of multiple obliquities. Diagnostic lymphangiography can be inadvertently therapeutic, as ethiodized oil is itself an embolic that induces an inflammatory and granulomatous reaction, thereby blocking the site of lymphatic leakage. ⁵⁰ An isolated chylothorax variant in neonatal lymphatic flow disorders was completely resolved with ethiodized oil alone. ⁵¹ Given the relatively smaller caliber of lymphatic vessels in the neonatal population, this phenomenon is not unexpected.

Consequently, care should be taken to avoid injection of large volumes of ethiodized oil in pediatric patients, particularly neonates, as this may result in unwanted lymphatic obstruction and lymphedema. Furthermore, operators should be aware of any congenital cardiac anomalies to avoid nontarget embolization of ethiodized oil into the arterial circulation. ⁵² Water-soluble contrast should be used instead for active right-to-left cardiac shunts. Oil-based contrast can also cause pneumonitis and must be used with caution in patients with limited respiratory reserve. ⁵³ There is a weight-based maximum dose (0.25 mL/kg) in pediatric patients, and lethal respiratory compromise has been seen with large-volume injections. ⁵⁴

Limitations of fluoroscopic lymphangiography include exposure to ionizing radiation, long examination time, and limited information about the relationship of lymphatic ducts with surrounding structures. ⁵⁵ Thus, DCE-MRL is helpful prior to lymphatic interventions as it allows for visualization of a patient's overall lymphatic anatomy. Also, DCE-MR may be more sensitive in detecting leakages due to the relatively low viscosity of gadolinium compared to oil-based contrast. ⁴⁷

It may take several weeks to determine if a lymphatic embolization was successful. If the volume of leak has not decreased by at least 50% after a week, a repeat treatment may be needed. ⁵⁶ Early complications related to thoracic duct include anaphylaxis to ethiodized oil, and ethiodized oil emboli or glue migration into the systemic venous system. ⁵⁷ Delayed complications include worsening of leakage or change in location of the leak (e.g., development of chylous ascites following chylothorax treatment). While there are options available for the treatment of chylothorax, the conversion to chylous ascites often represents a dramatic worsening of the clinical scenario. For this reason, thoracic duct embolization should not be embarked upon lightly in any CLA: the etiology of disease is different from an iatrogenic chylous leak, and therefore the clinical response to standard treatments can be wildly beyond expectation as well. Sirolimus and other systemic therapies are often a better first-line approach than thoracic duct embolization.

Additional image-guided procedures include sclerotherapy for macro- and microcystic LMs and drainage of pleural effusion and ascites. Deep visceral LMs, which frequently occur in CLA patients, may not be percutaneously accessible or safe to perform sclerotherapy.

Fluoroscopic Lymphangiogram and Thoracic Duct Embolization Technique

General anesthesia is required due to the long procedure duration. Prophylactic wide-spectrum antibiotics are given to cover for skin flora and potential bowel transgression. Ultrasound-guided intranodal access is achieved, using the same technique as in the case of DCE-MRL, except ethiodized oil is injected into the nodes rather than gadolinium. A slow rate of injection (approximately 1 mL every 5–10 minutes) is important to avoid extravasation. ⁵⁸ The contrast can be administered via an anesthesia infusion pump set to a rate of 4 mL/hour and titrated as needed based on the opacification of the lymphatics. The volume of ethiodized oil is limited to 0.25 mL/kg and is not to exceed 10 mL in total. ⁵⁴

Intermittent fluoroscopy is used to document the progression of contrast to the thoracic duct. Particular attention should be paid to the terminal portion of the thoracic duct for anatomic variations, ectasia, reflux, collateralization, obstruction, or leakage. The cisterna chyli or a lumbar tributary is directly accessed transabdominally using a 21- to 22-gauge Chiba needle under fluoroscopic guidance. A right-sided approach is favored to avoid aortic transgression. A 0.014-inch or 0.018-inch relatively rigid guidewire with a flexible tip is advanced through the needle into the thoracic duct. A low-profile 2.0- to 2.4-Fr microcatheter is then advanced into the thoracic duct. The guidewire is removed, and iodinated contrast is injected to visualize the duct and assess for leakage. ⁵⁹

Once a leak is identified, the microcatheter is advanced past the site of leakage, and microcoils are deployed across the site of leakage. The coils act as a scaffold for the subsequent liquid embolic and prevent it from passing into the venous system. Note that unlike arterial or venous embolizations, the lack of blood within the lymphatic system requires complete cessation of flow for successful embolization, as there will be no subsequent thrombosis within a coil pack or Onyx cast. Both agents can be used as the exclusive embolic within the thoracic duct, so long as enough material is deposited to prevent flow and subsequent recanalization. For these reasons, the embolic of choice typically consists of a 2:1 or 1:1 mixture of ethiodized oil to n-butyl cyanoacrylate (n-BCA) glue, often injected caudally to deployed coils. ⁵⁹ In addition to its function as an adherent embolic, n-BCA is quite inflammatory and in effect acts as a sclerosant. Note that care must be taken not to dilute the glue further as polymerization in lymphatic fluid is relatively slow compared to in blood and can increase risks of venous embolization.

There are alternatives to the technique described earlier. A retrograde thoracic duct embolization was first described by Chung et al in a child who had prior surgical thoracic duct ligation, rendering a transabdominal approach impossible. ⁶⁰ The left brachial vein was accessed under ultrasound guidance to cannulate the terminal thoracic duct and embolize a lymphatic channel presumed to be the remnant thoracic duct. Alternatively, the terminal thoracic duct may be directly accessed percutaneously from the neck or supraclavicular region using ultrasound or fluoroscopic guidance when it is opacified with contrast. The duct can then be cannulated retrograde and embolization performed.

Surgery

Surgical interventions for CLAs may be supportive or targeted toward lymphatic pathology. Supportive procedures include chest tube placement and pleurodesis for pleural effusions. Surgical shunting of ascites into the venous circulation, known as a Denver shunt, is generally not recommended due to the risk of clogging and peritoneal infection. ⁷ In GSD and GLA patients, surgical stabilization of fractures may be performed.

Targeted surgical procedures include thoracic duct reimplantation. If the terminal thoracic duct is obstructed and fails to empty into the venous circulation, it can be resected and micro-anastomosed to a valved vein (e.g., the external jugular vein). ⁷ In cases of lymphatic leakage, thoracic duct ligation may temporize symptoms, although recurrence or redirection of fluid invariably occurs. Surgical debulking may be considered for large, disfiguring LMs. Complications of surgery include postoperative infection and lymphatic leakage. Generally, systemic therapies should be tried first before pursuing invasive interventions.

Medical Therapy

Thanks to advances in molecular understanding of CLAs, several medical therapies have been adopted from oncology to improve symptoms and slow disease progression. Sirolimus, the mainstay of medical therapy for vascular anomalies in general, is often a good starting point in patients with CLAs. ¹⁹ Sirolimus has demonstrated efficacy in GSD and GLA in particular, as shown by the reduction of pleural effusions and osseous LMs. Its benefits are mixed for KLA and less clear for CCLA. ⁴⁵ Once a patient undergoes genetic testing, medical therapy can then be adjusted to target his/her specific genetic mutation.

With the discovery of activating mutations in the RAS/MAPK pathway in CLA patients, MEK inhibitors have emerged as a key therapeutic option. These inhibit the mitogen-activated protein kinase in the RAS/MAPK pathway and have been used in treating cancers like melanoma and lung cancer. Trametinib is a MEK inhibitor that has been most studied in the context of CLAs and has shown success in treating GSD, KLA, and CCLA. ^{61 62 63} Close clinical monitoring is necessary with trametinib use, as its toxicities include rash, diarrhea, liver dysfunction, and rarely cardiac dysfunction and retinopathy. ⁶⁴ Further studies are needed with alternative MEK inhibitors that may have less toxicities.

Supportive therapies are important in the long-term management of CLAs. Patients with osseous LMs are treated with bisphosphonates or interferons to stabilize lytic osseous destruction. Bisphosphonates in particular are a crucial component of medical therapy in GSD, as so much of the clinical pathology is due to osteoclast activation and subsequent cortical osteolysis. KLA can be particularly difficult to treat given its progressive nature, but combination therapies including steroids and vincristine have been used to improve coagulopathy and effusions. Nonpharmacological adjunctive care includes compression garments, lymphatic massage and pump, physical therapy, counseling, nutritional assessment, would care, and pain control.

Conclusion

The interventional radiologist plays a vital role in the multidisciplinary care of LMs, both in diagnosis and treatment. Important interventions include sclerotherapy, intranodal access for MRLs, and thoracic duct embolization. Knowing the appropriate indications and potential complications of these procedures, as well as understanding how they fit into the broader therapeutic objective for each individual patient, is crucial.