Management for lymphatic malformation in infants: a single center experience

Background:Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.Methods:We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel.Results:These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status.Conclusions:Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.Funding:R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.Clinical trial number:NCT03941782

A term, large-for-gestational age boy is transferred from an outside hospital with a right anterior chest wall mass noted since birth. His mother is a healthy 33-year-old gravida 4, para 4 woman with good prenatal care and normal prenatal laboratory values who had an uncomplicated pregnancy and elective cesarean delivery. None of the patient’s siblings or family members have had similar masses.On physical examination the patient is well-appearing and moving all 4 extremities spontaneously without obvious limitations. Vital signs on admission to the hospital are normal. There is a nontender, boggy, fluctuant, flesh-colored, grapelike mass from his right nipple to the midaxillary line that extends to the right upper arm, with dimpling of the skin throughout the right upper extremity (Fig 1). No bruit is heard over the lesion. There is no palpable bony abnormality. Radial pulses are 2+. Capillary refill is less than 2 seconds. His lungs are clear to auscultation. The cardiovascular examination reveals a normal heart rate, rhythm, S1, and S2 and no murmurs. The abdomen is soft, nontender, and nondistended, with no palpable masses or hepatosplenomegaly.Chest radiography is normal. Complete blood cell count with differential count is normal. Ultrasonography of the right superolateral chest shows a multiloculated fluid collection with undulating borders measuring 6 × 1.7 cm. Magnetic resonance imaging (MRI) with contrast of the chest and right upper extremity reveals a multiloculated macrocystic mass in the superficial right chest wall, additional cysts in the right arm, and a partially cystic right mediastinal mass (Figs 2 and 3). MRI also shows multiple cysts in both kidneys (Fig 4). Review of the findings from MRI and genetic testing reveal the diagnoses.The differential diagnosis includes lymphatic malformation, venous malformation, vascular tumor, arteriovenous malformation, arteriovenous fistula, and capillary malformation. The patient was diagnosed as having lymphatic malformation. In addition, rapid genome sequencing revealed de novo pathogenic variant of PKD1 mutation, supporting an incidental second diagnosis of autosomal dominant polycystic kidney disease (ADPKD).Lymphatic malformations are a type of vascular anomaly. The International Society for the Study of Vascular Anomalies stratifies vascular anomalies into vascular tumors (benign, locally aggressive or borderline, and malignant) and vascular malformations (simple, combined, anomalies of major named vessels, and vascular malformations associated with other anomalies). (1)(2) Lymphatic malformations are low-flow, nonmalignant vascular malformations of the lymphatic system with dilated lymphatic channels or cysts thought to occur during lymphatic development.Lymphatic malformations can affect 1 location or can be loculated and/or multifocal (eg, lymphangiomatosis). (3) Lymphatic malformation is an umbrella term that includes all subtypes of lymphatic malformations, including cystic lymphatic malformations (macrocystic, microcystic, or mixed), generalized lymphatic anomalies such as kaposiform lymphangiomatosis, channel-type lymphatic malformation, acquired progressive lymphatic anomaly (acquired progressive lymphangioma), and primary lymphedema. Lymphatic malformations can affect any area of the body but most commonly occur in the head and neck regions, followed by the extremities. (4) They are classified as macrocystic, microcystic, or mixed. Most are noted at birth or within the first 2 years after birth.Superficial lymphatic malformations or deep vascular lesions may have no skin discoloration. In contrast, superficial arterial, capillary, or venous vascular anomalies can appear red, pink, violaceous, or blue, depending on the mix of oxygenated (arterial) or deoxygenated (venous) blood. Superficial lymphatic malformations can have clear vesicles or pitting of the skin or appear bruised if bleeding occurs within the malformation. Venous malformations are often bluish, soft, and compressible papules. Capillary malformations are often pink, red, or purple flat macules or patches. High-flow malformations, such as arteriovenous malformations and arteriovenous fistulas, can have a palpable bruit or thrill. Vascular anomalies can cause overgrowth and swelling in the affected area, which could cause pain.Lymphatic malformations can be associated with other anomalies. Gorham-Stout syndrome, also known as vanishing bone disease, is a rare condition characterized by proliferation of lymphatic vessels adjacent to single or multiple bones, leading to osteolysis and resorption of bone, oftentimes the ribs, spine, pelvis, skull, clavicle, or jaw. (5) Several PIK3CA-related overgrowth spectrum conditions also have lymphatic malformations, such as Klippel-Trenaunay syndrome, a rare congenital syndrome characterized by cutaneous capillary malformations (port-wine stain), vascular or lymphatic malformations, and limb overgrowth. (1)(6) Many patients with lymphatic malformations have an activating somatic PIK3CA gene mutation. (7) This was not the case for our patient.Diagnosis of vascular malformation or neoplasm is often made clinically and confirmed by imaging. For initial imaging, the 2019 American College of Radiology Appropriateness Criteria for Clinically Suspected Vascular Malformation of the Extremities deems magnetic resonance angiography with and without contrast, MRI with and without contrast, computed tomographic (CT) angiography with contrast, and duplex Doppler ultrasonography as appropriate for suspected vascular malformation of the extremity presenting with physical deformity. (8) However, because our patient also had a suspected abnormality in the chest wall, MRI or magnetic resonance angiography with and without contrast would be the best initial study to better evaluate deeper lesions than ultrasonography and better evaluate soft tissue contrast than CT angiography.The presence of renal cysts initially raised concern for underlying lymphangiomatosis. Lymphangiomatosis is the term used to describe lymphatic malformations in multiple organs. (3) It can affect any region of the body, although it is most common in the neck, axilla, retroperitoneum, and mediastinum. Renal lymphangiomatosis in pediatric patients is rare but should be included in the differential diagnosis for conditions such as ADPKD, nephroblastomatosis, lymphoma, and hydronephrosis with perinephric urinoma. (9) Several case reports describe initial misdiagnosis of renal lymphangiomatosis as ADPKD. Imaging and genetic testing can help differentiate between renal lymphangiomatosis and ADPKD. In renal lymphangiomatosis, renal cysts are central in the renal sinus, whereas in ADPKD, renal cysts are peripheral and parenchymal, as was seen with this patient. (9) In addition, the patient’s rapid genome sequencing reveals de novo pathogenic variant of PKD1 mutation, which supports a diagnosis of ADPKD being a separate etiology for renal cysts from that underlying the lymphatic malformations in the chest and right upper extremity. Differentiation between renal lymphangiomatosis and ADPKD can affect the treatment regimen and prognosis. A case report describing an infant with biopsy-proven bilateral renal lymphangiomatosis with 1-year follow-up suggests a self-limiting course in some patients, although it can expand before regression. (10) Successful treatment for renal lymphangiomatosis with sclerotherapy has been described. (3)(9)A case report describing an adult with comorbid lymphangiomatosis and ADPKD hypothesized a link between ADPKD and lymphangiomas as cystic pathologies sharing common genetic and congenital processes; however, no genetic mechanism has been identified. (11)ADPKD is the most common hereditary kidney disease, with a prevalence of 1:1,000 to 1:2,500. Patients with ADPKD develop cysts in the kidney parenchyma, which often leads to end-stage kidney disease by age 50 to 60 years. Our patient’s incidental diagnosis of ADPKD is atypical for several reasons. There was no family history, he developed cysts in the neonatal period, and his presenting complaint was lymphatic malformations. Our patient had a de novo PKD1 mutation, the most common mutation seen in ADPKD. Patients with PKD1 mutations have a less favorable kidney prognosis than patients with PKD2 mutations, who have end-stage kidney disease in their 70s and 80s. The Predicting Renal Outcomes in Polycystic Kidney Disease score combines predictive genetic factors with clinical information to predict risk of progression to end-stage kidney disease for patients with ADPKD in patients older than 35 years. (12) ADPKD is typically diagnosed using renal ultrasonography in patients with an affected first-degree relative. Genetic analysis can be useful in very young patients without a family history of ADPKD, as in our patient, who was found to have a de novo PKD1 mutation.Symptoms from lymphatic malformations vary depending on location of involvement and extent of invasion. Management varies depending on location, size and symptoms (including compression or obstruction of adjacent structures), infection, and interference with quality of life, including cosmetic concerns. Generally, microcystic lymphatic malformations are more challenging to treat than are macrocystic lymphatic malformations because they are less accessible for aspiration or sclerosing. (1)Observation for potential spontaneous regression can be appropriate for small lymphatic malformations without compromise of other systems. (13) Compression dressing is a conservative, first-line option for symptomatic treatment of lymphatic malformations limited to the extremities to prevent pain or growth of the malformation. (4) Treatment options for large or symptomatic lymphatic malformations include sclerotherapy, endovenous laser ablation, radiofrequency ablation, and surgical resection. Drug therapy with sirolimus, sildenafil, or propranolol has been described in case reports. Antibiotics should be used to treat infected lymphatic malformations.Clinical trials in adults with ADPKD show that angiotensin-converting enzyme inhibitors and possibly vasopressin antagonists decrease renal cyst growth. (14) A randomized controlled trial with tolvaptan, a selective vasopressin antagonist, for pediatric ADPKD is underway for children aged 12 to 17 years; results are not yet available. (15) Schaefer et al suggest angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for management of hypertension and proteinuria in the setting of pediatric ADPKD. (15) In addition, there is limited evidence that statin therapy slows the progression of structural kidney disease in children and young adults with ADPKD. (16)The patient was evaluated by a multidisciplinary team including surgery, hematology/oncology, nephrology, genetics, and interventional radiology; he was referred for sclerotherapy but was lost to follow-up.Five months later he presented with cough and was diagnosed as having a parainfluenza infection. Chest radiography revealed airway compromise; CT showed that the intrathoracic extent had dramatically increased, resulting in mediastinal shift and tracheal narrowing (Fig 5). Dark, sanguineous fluid was drained from the lesion, and sclerotherapy was performed using bleomycin. The postsclerotherapy radiograph showed mass reduction and improved lung expansion.Persistent hypertension was treated with enalapril. Repeated renal ultrasonography, compared with postnatal imaging, showed an enlarging right cyst and a new left cyst. Intrathoracic sclerotherapy was repeated 40 days later. Further treatment will be required.

Management of LMs still remains a challenge especially for those suffering from complications such as acute airway compression. In this study, we retrospectively evaluated the efficacy and safety of percutaneous lauromacrogol foam sclerotherapy for the patients with acute airway compression caused by lymphatic malformations (LMs) in infants. Five cases of infants with acute airway compression caused by LMs were treated with lauromacrogol foam sclerotherapy in the radiology department from February 2013 to August 2015 at Wuhan Medical and Healthcare Center for Women and Children, China. By CT examination and the DSA imaging, LMs were diagnosed and progressed cervical and sublingual LMs combined with hemorrhages were observed and suppression of the trachea was noticed as well, resulting in the difficulty with breathing and feeding. For all the patients, we extracted most cyst liquid from the LMs to reduce the surface tension and alleviate the respiratory pressure symptoms under the guidance of ultrasound. Subsequently, the lauromacrogol foam was injected percutaneously into the cyst of LMs. The dose of the agent was determined according to the size of the LMs, which was 3-8 ml in our study. After treatment, autonomous respiration and independent eating were observed. When the procedures were completed after 16 cycles, the cyst cavity became atrophic and then nearly vanished. During the follow-up period (a minimum of three months and a maximum of two years), 4 patients were clinically proved to be cured and one patient was significantly improved. There was no recurrence, serious complications, or adverse reactions. Our study demonstrated that percutaneous sclerotherapy combined with lauromacrogol foam is a safe, effective therapy for acute airway compression caused by LMs, especially giving a good cosmetic result.

To discuss the treatment effect of infant lymphatic malformations (LMs) located in the head and neck. Fourty-six LMs located in the head and neck between 2009 and 2013 were retrospectively analyzed. There were 26 males and 20 females, aged from 9 months to 4 years, with a median age of 1.8 years. Phase Isurgical resection was performed in 28 cases. The low concentrations of pingyangmycin was injected in 18 cases, and Phase II surgical resection was performed in 6 cases after 6 months, because of the large tumors and a wide range of invasion. Two post-operative complications were found, one was minor paralyses of mandibular branch of facial nerve, manifestied as mouth askew. Another was injured accessory nerve, manifestied as right upper limb lifting weakness, which improved after rehabilitation treatment. Surgical treatment is effective to LMs. In order to avoid serious complications, the huge LMs and microcystic LMs may be given local injection of pingyangmycin after puncture fluid, and phase II surgical resection secondly if necessary.

Lymphatic malformations (LMs) are challenging to manage, particularly those involving the cervicofacial region and airway. Traditional therapy is sclerotherapy and/or resection. We aim to establish the emerging therapeutic role of sirolimus. Institutional review board-approved retrospective review. All patients treated for cervicofacial LM with sirolimus at Boston Children's Hospital, Massachusetts, from November 2012 to October 2016 were included. Chart review included response to therapy (defined as reduction in LM bulk by clinical photographs and radiologic imaging), type of LM (microcystic, macrocystic, mixed), extent of disease, duration of therapy, patient/parent-reported quality-of-life, airway status (tracheostomy dependence), and complications (opportunistic infection, hemorrhage, other). Follow-up and clinical outcomes were included up until October 2016. Nineteen patients were treated with sirolimus for cervicofacial LM from November 2012 to October 2016 at Boston Children's Hospital. Seven patients remain on uninterrupted sirolimus. Of 12 patients who stopped therapy, seven have resumed due to recurrence of symptoms. All patients demonstrated reduction in LM bulk, ranging from modest to significant. All patients with mucosal vesicles (n = 14) resolved or improved on sirolimus. Six patients developed cellulitis, and four had bleeding within the LM during treatment. No patients developed opportunistic or systemic bacterial infection. The use of sirolimus in the management of cervicofacial LM often is efficacious, with limited adverse events. Long-term follow-up, durability of response, and coordination of sirolimus prior to procedural therapies need further study. 4. Laryngoscope, 128:269-276, 2018.

BackgroundLymphatic malformation (LM) is a form of congenital vascular malformation with a low incidence. Although LM has been studied, no consensus has emerged regarding its cause or treatment.MethodsIn this study, we retrospectively evaluated 40 patients who visited our vascular anomalies center for the treatment of cervicofacial LM, which is a common manifestation of LM. The medical records of patients over a period of 12 years were reviewed and analyzed for commonalities regarding the diagnosis and the results of treatment.ResultsSuspected cervicofacial LM was confirmed through imaging studies. No difference in incidence was observed according to sex, and 73% of patients first presented with symptoms before the age of two years. The left side and the V2–V3 area were most commonly affected. No significant differences in incidence were observed among the macrocystic, microcystic, and combined types of LM. A total of 28 out of 36 patients received sclerotherapy as the first choice of treatment, regardless of the type of lesion. Complete resolution was achieved in only 25% of patients.ConclusionsLM is important to confirm the diagnosis early and to choose an appropriate treatment strategy according to the stage of the disease and each individual patient's symptoms. When treatment is delayed or an incorrect treatment is administered, patient discomfort increases as the lesion gradually spreads. Therefore, more so than is the case for most other diseases, a team approach on a case-by-case basis is important for the accurate and appropriate treatment of LM.

Background: Lymphatic malformations are developmental defects of the lymphatic system. They are frequently present at birth and are most commonly found in the head and neck regions. The aim of the study was to investigate the clinical presentation of head and neck Lymphatic malformations in relation to, age, gender, color and site of distribution. Methods: This is a retrospective descriptive study, where the record of the patient diagnosed as lymphatic malformation at the Department of Oral and Maxillofacial Surgery at Khartoum Teaching Dental Hospital, during the period of 2005 to 2008 where retrieved and analysed. Result: A cervicofacial lymphatic malformation was found more common in females than in males with a ratio of 11:9. The mean age was 14 ± 10 years, with lip and tongue being the most common sites, followed by the buccal mucosa in the intraoral site and neck in the posterior triangle was the most common site for extraoral site (30%). It was found that the bluish color was the commonest presenting color in oral lymphangioma followed by red pink color. Conclusion: Females are more affected than males, while infants and children were more affected than other age groups. The bulks of the patients were presented with soft swelling, blue to normal colour in the lip, neck and in the tongue. Further prospective studies are needed to evaluate the clinic picture and treatment outcome.

Surgical excision as primary treatment modality for extensive cervicofacial lymphatic malformations in children

The cervicofacial lymphatic malformations (LMs) often have poor outcomes due to their microcystic component and diffuse infiltration. Mostly, traditional treatments are inadequate for these refractory cases. Recent researches have shown that sirolimus is effective in the treatment of complicated LMs, however, there is still no standard strategy. To evaluate the efficacy and safety of intermittent oral sirolimus in treating refractory cervicofacial LMs as a second-line treatment. Fifteen pediatric patients of refractory cervicofacial LMs were retrospectively analyzed in this study. All the cases had received traditional therapy before, but could not completely control the symptoms and eliminate lesions. As a remedy, sirolimus was then proceeded with an intermittent administration regimen, that is 3 continuous months as a course and started the next course after 1 month interval. The clinical characteristics, imaging data of patients, the changes in the signs and symptoms observed, and associated adverse effects were collected and analyzed. The patients initiated sirolimus therapy at the average age of 2.3 years (range 28 days-8 years 9 months). At the end point of the study, 2 patients remained on sirolimus in continuous courses of treatment. Of 13 patients who withdrawn therapy, 4 had restarted due to recurrence of symptoms and re-expansion of LMs. All patients demonstrated reduction in residual LMs and complete disappearance of symptoms during treatment, and 2 patients with complete resolution on imaging. Toxicity was tolerant in this series. There was no patient develop opportunistic or systemic bacterial infection. Sirolimus is commended as a second-line treatment to treat intractable cervicofacial LMs after failure of traditional therapy. The intermittent administration regimen is efficacious to completely control symptoms and partially reduce residual lesions with good tolerance and limited side effects.

To determine the efficacy and safety of the immunostimulant OK-432 (Picibanil) as a treatment option in the management of children with cervicofacial lymphatic malformations. A prospective, randomized, multi-institutional phase II clinical trial at 27 U.S. academic medical centers. 182 patients with lymphatic malformations (LM) were enrolled between January 1998 and November 2004. Of the 151 patients with complete case report forms, 117 patients were randomized into immediate or delayed treatment groups; 34 patients were nonrandomized and assigned to the open-label group. Treatment consisted of a four-dose intralesional injection series of OK-432 at eight-week intervals. Patients randomized into the delayed treatment group served as observational controls for spontaneous regression. Response to therapy was measured radiographically by quantitating change in lesion size and graded as complete (90%-100%), substantial (60%-89%), intermediate (20%-59%), or none (<20%). Of 117 patients randomized with intent-to-treat, 68% demonstrated a complete or substantial response to OK-432 immunotherapy. Response data for macrocystic LM were higher, with a complete or substantial response in 94% of patients; 63% of patients with mixed macrocystic-microcystic LM responded to treatment; no patients with microcystic LM responded to treatment. Spontaneous resolution occurred in less than 2% of patients. Median follow-up of 2.9 years demonstrated a 9% recurrence rate. Major adverse effects related to therapy occurred in 11 patients. As compared to historical surgical data on LM, OK-432 immunotherapy is more effective (P < .001) and has a lower morbidity (P < .001). OK-432 immunotherapy is an effective, safe, and simple treatment option for the management of macrocystic cervicofacial LM. ClinicalTrials.gov Identifier: NCT00010452.

Pulmonary Lymphangioma

Many children with cervicofacial lymphatic malformations have facial skeletal abnormalities. This study qualitatively and quantitatively evaluated these bony mandibular abnormalities. Retrospective chart review. Patients with craniofacial lymphatic malformations presenting to a vascular anomalies center during a 2-year period were included. An age-matched control population was found on the Picture Archiving and Communication System database. Three-dimensional reconstructions were created from computed tomography and magnetic resonance imaging. Qualitative observations and quantitative measurements were taken of the gonial angle, mandibular anterior dentoalveolar height, and anterior condylar displacement. There were 23 controls. A total of 21 patients with "beard" distribution malformations were studied; 10 had unilateral and 11 had bilateral disease.Qualitatively, a few patterns emerged: outward ramal flaring, anterior displacement of the mandible, relative ipsilateral facial "hypertrophy," and anterior positioning of the maxilla and orbit. The open-bite deformity was a common finding leading to malocclusion and oral incompetence. Quantitatively, in 67 nondiseased sides, the average gonial angle was 131 degrees (standard deviation [SD] = 6.8), whereas in 32 diseased sides, the average angle was 152 degrees (SD = 14.0, P < 3.8E-09). With half-beard malformations, the diseased side averaged 153.9 and the nondiseased side averaged 140.8 (P = .008). The average condylar displacement was 8.5 mm versus 5.9 mm (diseased vs. nondiseased), and the average mandibular dentoalveolar height to face ratio was 0.37 (control = 0.34). Cervicofacial lymphatic malformations in the "beard" distribution are associated with significant bony abnormalities leading to both functional and aesthetic sequelae. Our study is the first quantitative analysis of these changes. This is the first step in planning for dentofacial orthopedics, orthodontics, and orthognathic surgery.

To evaluate the morphologic properties of advanced lymphatic malformations of the head and neck and to investigate possible therapeutic interventions by intralesional endoscopy. This case study analyzes the outcome of intralesional endoscopy of lymphatic malformations of the head and neck and discusses the results of this approach. Academic medical center. Endoscopy was performed on 4 patients with cervicofacial lymphatic malformations. Endoscopy of lymphatic malformations. The endoscopic inspection and assessment of the lesions revealed detailed information about morphologic aspects like the structure of intralesional septa, internal vascularization, and intercystic correspondence and channel networks. Anatomic landmarks could be followed on their intralesional courses. Intralesional endoscopy of lymphatic malformations provides insight into the morphologic properties of the lesion and is a useful supplementary tool during conventional surgical intervention and for sclerosing therapy. The technique allows a detailed assessment of these lesions and opens a broad spectrum of therapeutic options.

This article aimed to present a series of surgically treated lymphatic malformations of the cervicofacial region in a population of children and adolescents during a 13-year period. The medical records of all children and adolescents with cervicofacial lymphatic malformations, treated surgically at our department from 1998 to 2011, were reviewed retrospectively. Eighteen patients with 20 lymphatic malformations located within the soft tissues of the cervicofacial region were identified. All patients were submitted to surgical treatment (excision or resection with conventional scalpel or radiosurgery) to address complications (ulceration, bleeding, impaired mastication and feeding, airway obstruction) and/or aesthetic issues. Recurrence was noted in 2 of our patients. Accurate diagnosis based on history, clinical examination, and adequate imaging techniques is the key to the optimal treatment of cervicofacial lymphatic malformations; surgical intervention remains the treatment of choice for these lesions.

Lymphatic malformations: A proposed management algorithm