RARE DISEASE
Rare lymphatic malformation
Rare lymphatic malformation
Rare lymphatic malformation
Synonyms: LM, Lymphangioma
Synonyms: LM, Lymphangioma
Synonyms: LM, Lymphangioma
Drug discovery
9
drugs
With orphan designations
Overview
Lymphatic malformations (LMs) are rare congenital anomalies caused by abnormal development of lymphatic vessels, often linked to somatic mutations in PIK3CA, KRAS, or BRAF [1][2][7]. They manifest as macrocystic (>1 cm) or microcystic (<1 cm) fluid-filled lesions, commonly in the head/neck (45-60%) or abdominal regions [5][9]. Symptoms include swelling, pain, infections, and functional/cosmetic impairment, diagnosed via MRI and genetic testing [1][5].
Burden
Morbidity: Recurrent infections (35–45% of cases), chronic pain, and disfigurement impair daily function [5][8][16].
Quality of life: Parental QOL scores are significantly lower in complex cases, particularly with orbital or multisite involvement [8].
Healthcare utilization: Requires lifelong multidisciplinary care, with recurrence rates up to 53% after surgery [3][17].
Citations are integrated parenthetically as [n].
Therapies
Sclerotherapy: First-line for macrocysts using ethanol or doxycycline foam, achieving >50% lesion reduction in 80% of cases [3][5][11].
mTOR inhibitors: Sirolimus improves quality of life and reduces lesion size in 52–89% of patients [2][14].
Targeted therapies: PI3Kα inhibitors (e.g., alpelisib) and RAS/MAPK pathway inhibitors show promise in clinical trials [1][14].
Categories: rare circulatory system diseases, rare developmental anomalies during embryogenesis
Research Papers
1,051 drug discovery papers about Rare lymphatic malformation, with 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,051 drug discovery papers about Rare lymphatic malformation, with 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-09-24 | Pediatric scrotal lymphatic malformation: a 15-case series and a proposed diagnostic and management algorithm.
To investigate the clinical characteristics, risks of misdiagnosis, and diagnostic and management strategies for pediatric scrotal lymphatic malformation. A retrospective analysis was conducted on clinical data (demographics, symptoms, diagnostic work-up, and treatment) of 15 pediatric cases with scrotal lymphatic malformation treated at our institution between 2012 and 2025. Additionally, a targeted literature review of previously reported cases with diagnostic challenges was performed. All lesions showed a characteristic extratesticular distribution outside the tunica vaginalis. The overall accuracy rates of preoperative color Doppler ultrasound and clinical diagnosis were only 46.7% (7/15) and 40.0% (6/15), respectively. Furthermore, 26.7% (4/15) of cases had an indeterminate preoperative diagnosis, and 33.3% (5/15) were completely misdiagnosed. Surgical excision was performed in all patients, achieving complete resection in 10 cases and incomplete resection in 5 cases. Over a follow-up period ranging from 3 months to 6 years (mean, 22 months), 3 cases developed ipsilateral scrotal or inguinal recurrence, and 1 case presented with a gluteal lymphatic malformation one year postoperatively. A literature review identified an additional 12 reported cases with incorrect or indeterminate preoperative diagnoses. Indeterminate diagnosis was the largest category (41.7%), and among the definite misdiagnoses, hydrocele was the most common (25%), which closely mirrored the pattern observed in our series. Pediatric scrotal lymphatic malformation is a rare entity that is highly prone to misdiagnosis and recurrence. Based on our 15-case series and reported cases, we propose a diagnostic and management algorithm integrating clinical evaluation, stepwise imaging, surgical excision, and selective sclerotherapy to improve diagnostic accuracy and optimize surgical outcomes.
2026-06-20 | Acquired lymphangioma circumscriptum following radiotherapy: A late onset presentation
Lymphangioma circumscriptum also known as microcystic lymphatic malformation is a rare hamartomatous malformation characterized by the presence of translucent, discrete or grouped vesicles (frogspawn). It constitutes 4% of all the vascular tumors. Lymphangioma circumscriptum can result from congenital or acquired abnormalities of the lymphatic system. The classic lesion is a rare malformation that usually appears at birth or can develop in early childhood. The pathogenesis of acquired lymphangioma circumscriptum that can occur later in life mainly involves lymphatic system disturbances commonlyattributed to surgical procedures, radiation therapy or infections leading to lymphatic damage or obstruction. Diagnosis is confirmed by biopsy followed by histopathological examination. Superficial and deep lymphangioma lesions may be difficult to treat. Some of the treatment options include surgical excision, lasers, sclerotherapy etc. which have shown varying success. The treatment of choice for any type of lymphangioma lesions is surgical excision with wide local excision of the affected lymphatic channels.
2026-03-11 | Small bowel lymphatic malformation: Clinical presentation and a comprehensive literature review.
Small bowel lymphatic malformations are rare benign tumors of the lymphatic system, accounting for < 1% of intra-abdominal lymphatic malformations. They pose diagnostic challenges due to nonspecific presentations and are often misdiagnosed. To analyze clinical features, management, and outcomes of small bowel lymphatic malformations in adults through a case report and scoping review. A 47-year-old female with chronic abdominal pain underwent laparoscopic resection of an ileal lymphatic malformation. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews-guided scoping review of 97 adult cases (1991-2024) was conducted, extracting demographics, diagnostics, management, and outcomes. The cohort included 41 case reports and 2 case series (46% female, mean age 45.6 years), most commonly presenting with abdominal pain (74%), gastrointestinal bleeding (39%), or asymptomatic masses (9%). Lesions were predominantly in the jejunal mesentery (52%), with a mean size of 9.2 cm. Computed tomography identified lesions in 87% of cases, showing multiloculated cystic masses (78%). Surgical resection was the primary treatment (91%), with segmental bowel resection most frequent (65%). Complications occurred in 24% (infections: 13%), and recurrence in 11% (linked to incomplete resection). Complete excision achieved symptom resolution in 93%. Small bowel lymphatic malformations are rare but may cause significant morbidity. Surgical resection is curative, with laparoscopy emerging as a viable approach. Preoperative diagnosis remains challenging; heightened imaging awareness and complete excision are critical to prevent recurrence.
2025-06-03 | Atypical location of a lymphangioma in the thymic cavity in an adult: case report and review of the literature
Introduction: Lymphangiomas are rare primary tumours of the anterior mediastinum in adults. They are usually asymptomatic. In other cases, there may be a cervical mass or signs of mediastinal compression such as exertional dyspnoea or dysphagia. The diagnosis is made with certainty by histology. Surgery is the main curative treatment. Case report: We report the case of a 34-year-old female patient who presented with a painless anterior cervico-mediastinal mass associated with dyspnoea. Cervico-thoracic imaging revealed a non-compressive mass in the thymic cavity, suggestive of a thymoma but not excluding a lymphoma. Biology and histology after scannoguided biopsy were negative. Further histological examination following surgical biopsy revealed the vascular nature of the mass, consistent with lymphangioma. Conclusion: Lymphangiomas are rarely seen in adults, particularly in the anterior mediastinum. Our observation of a lymphangioma found in the thymic cavity adds to the other cases found in the literature. This could lead us to include it in the nosological panel of an anterior cervico-mediastinal mass found in adults. Furthermore, as its diagnosis is essentially histological, we could also consider surgery as a means of diagnosis in addition to the therapeutic aspect, especially in cases of diagnostic doubt.
2023-11-29 | Diagnostic and Therapeutic Challenges of a Large Tongue Lymphangioma in a Child: A Case Report.
Lymphangiomas are rare, painless, benign tumors in infancy or early childhood resulting from a congenital malformation of the lymphatic vessels with variable clinical appearance. We report the case of a six-year-old male child who presented with a micronodular surface of the tongue, a burning sensation, difficulties during swallowing and mastication, as well as speech disturbances. Histological examination of the excised tongue specimen showed an angiomatous lesion of the lamina propria that comprised many wide thin-walled spaces. MRI examination revealed an area of disparate T2 signal maximum diameter of 2-3 cm with cystic texture in the middle and frontal left part of the tongue. The lesion was diagnosed as a lymphangioma and was managed through pre-operative embolization and surgery. Tongue lymphangiomas may lead to aesthetic problems, functional issues (like dysphagia, airway obstruction, and speech difficulties), psychological disturbances, poor oral hygiene, and occasional bleeding associated with oral trauma. A major fraction of patients also experience infections, often leading to a significant increase in lesion size. A combination of preoperative embolization and surgical excision could be chosen considering its large size and the age of the patient, and to further eliminate the possibility of recurrence. Early diagnosis and radical treatment are critical in its management.
small molecules
2026-09-17 | Precision Medicine for Somatic Mutation-Driven Vascular Anomalies.
Vascular anomalies, including proliferative vascular tumours and structural malformations, are largely driven by postzygotic somatic mutations that constitutively activate key signalling pathways, mainly the PI3K/AKT/mTOR and RAS/MAPK pathways. This molecular understanding has shifted clinical management from empiric interventions towards precision medicine. In this review, the interactions between somatic mosaicism, germline predispositions (e.g., PTEN hamartoma tumour syndrome), and microenvironmental risk factors in the context of lesional progression are described. We synthesized data on genotype‒phenotype correlations-such as PIK3CA mutations in lymphatic and venous malformations, KRAS/MAP2K1 mutations in arteriovenous malformations, and cerebral cavernous malformation (CCM) complex dysfunctions in cerebral cavernous anomalies-while fundamentally differentiating the mechanistic dependencies of true malformations from those of proliferative tumours. Targeted therapies, including mTOR, PI3Kα, and MEK inhibitors, have exhibited significant clinical efficacy in the treatment of pathway-specific anomalies. Despite these advances, therapeutic resistance and drug dependency persist. Future directions include the development of integrated diagnostic frameworks combining tissue biopsies with longitudinal cell-free DNA (cfDNA) monitoring, optimizing dual-pathway combination strategies, and advancing cellular models to reshape the management of vascular anomalies.
2026-08-25 | Resolution of Refractory Chylous Effusions With Targeted MEK Inhibition in NRAS Q61R-Driven Kaposiform Lymphangiomatosis: A Case Report.
Kaposiform lymphangiomatosis (KLA) is a rare and aggressive lymphatic anomaly characterised by chylous effusions, respiratory failure and poor prognosis. Diagnosis is often challenging and delayed due to the mosaic distribution of causative somatic mutations. A previously well four-year-old girl presented with pleural and pericardial effusions and methicillin-sensitive Staphylococcus aureus bacteraemia. She was treated with intravenous antibiotics, and chest and pericardial drains were inserted. Despite these measures, she developed high-volume, refractory chylous effusions. Management included dietary modification, as well as trials of octreotide and intravenous methylprednisolone, neither of which reduced chyle output. Magnetic resonance lymphangiography demonstrated diffuse abdominal and thoracic lymphatic abnormalities. She was subsequently treated with sirolimus, which was associated with reduced pleural and pericardial chylous drainage but ongoing clinical deterioration. Cell-free DNA analysis of pleural fluid identified a somatic NRAS variant (NM_002524.5 (NRAS):c.182A > G (p.Gln61Arg)). In the absence of histopathology, a presumed diagnosis of NRAS Q61R-driven KLA was made based on clinical, radiologic and molecular findings. She was started on trametinib, a MEK inhibitor. Over the subsequent 7 weeks, she was weaned from respiratory support and parenteral nutrition, transitioned to a fat-containing diet and experienced resolution of clinically significant effusions, allowing discharge home. This case highlights the diagnostic challenges of complex lymphatic anomalies, demonstrates the utility of cell-free DNA analysis from effusions in identifying pathogenic somatic variants and underscores the therapeutic potential of targeted MEK inhibition in NRAS Q61R-driven KLA.
2026-08-12 | Recurrent Hematuria Unveiling Renal Lymphangioma: A Diagnostic Challenge in a Patient with von Willebrand Disease
Abstract Renal lymphangioma is a rare benign lymphatic malformation that may present with hematuria and flank pain. We report the case of a 16-year-old female with type 2A von Willebrand disease who developed recurrent macroscopic hematuria and left lumbar pain. Imaging revealed a multiloculated intrarenal cystic lesion consistent with renal lymphangioma. After recurrence of symptoms and failure of conservative management, percutaneous intrarenal sclerotherapy with doxycycline was performed under factor replacement, resulting in complete symptom resolution and no recurrence on follow-up. This case highlights the diagnostic challenge in coagulopathic patients and supports sclerotherapy as an effective minimally invasive treatment.
2026-07-30 | Binding of RAS to PI3Kα regulates developmental and KRASG12D-induced lymphangiogenesis.
Complex lymphatic anomalies (CLAs) are rare diseases characterized by the abnormal development of lymphatic vessels. CLAs can be caused by somatic activating mutations in KRAS (e.g., KrasG12D), which stimulate MAPK and PI3K signaling. While KRAS/MAPK signaling is known to play a critical role in CLA pathogenesis, the contribution of KRAS/PI3Kα signaling remains unclear. To investigate the role of RAS-activation of PI3Kα in CLAs, we analyzed mice carrying two missense mutations in the RAS-binding domain of p110α, the catalytic subunit of PI3Kα. These two mutations block the interaction between p110α and RAS but do not affect its kinase activity. Disruption of RAS-mediated PI3Kα activation in lymphatic endothelial cells reduced lymphatic vessel branching but did not affect lymphatic valve formation. In KrasG12D mutant mice, blocking RAS activation of p110α reduced the pathological enlargement of lymphatic vessels, but failed to prevent KrasG12D-induced lymphatic valve loss. Similar results were observed following p110α deletion in KrasG12D mutant mice. Together, these findings demonstrate that KrasG12D drives distinct disease phenotypes through separate downstream pathways. KRAS/PI3Kα signaling promotes pathological lymphatic vessel enlargement, whereas KRAS/MAPK signaling disrupts lymphatic valve formation.
2026-06-29 | Uncommon Presentation of a Macrocystic Lymphatic Malformation in a Seven-Year-Old Boy: A Case Report.
Macrocystic lymphatic malformations (old terminology: cystic hygromas) are considered a relatively rare condition; they mostly appear in the first two years of life. Cervical neck masses are a common presenting complaint in children to pediatric outpatient departments, the most common causes being infectious/inflammatory conditions of cervical lymph nodes. In this report, we aim to bring light to the fact that rarer causes like secondarily infected or hemorrhagic lymphatic malformations may also present similarly. Here, we present the case of a seven-year-old boy who had been asymptomatic before, presenting with a 10-day history of sudden-onset neck swelling associated with an upper respiratory tract infection. Treating the upper respiratory tract infection with an oral antibiotic also helped the cystic mass involute, showing that a secondary infection was the precipitating factor in the sudden increase in size of the cyst. Management options for these lymphatic malformations are between sclerotherapy and surgical excision according to indications. In this case, the size has resolved considerably with antibiotics so that the child does not require an active intervention at present and is planned to be under close radiological follow-up.
proteins
2023-11-02 | Efficacy of OK-432 sclerotherapy for different types of lymphangiomas: a review and meta-analysis.
This study aims to perform a meta-analysis to figure out the efficacy of OK-432 sclerotherapy between Macrocystic (MAC) lymphangiomas and Microcystic (MIC) lymphangiomas. We conducted a systematic review and meta-analysis to clarify the relationship between OK-432 and lymphangiomas. PubMed and ISI Web of Science were searched from inception to May 2022. Joanna Briggs Institute (JBI) manual was used to evaluate the risk of bias. We calculated pooled Relative Risks (RR) and 95% Confidence Interval (95% CI) using random effects model to evaluate the relations between OK-432 and lymphangiomas. A total of 11 studies (including 352 cases) about OK-432 sclerotherapy for lymphangioma were included in the current meta-analyses. The results suggested that the efficacy of OK-432 was significantly in MAC lesions than in MIC (RR=1.51, 95% CI 1.298-1.764), with significant moderate degrees of heterogeneity among 11 studies (I2=51.2%, p=0.025). Subgroup analyses suggested that there was significant association in both retrospective studies (RR=1.26, 95% CI 1.03-1.53) and classification (by 1 cm) (RR=1.37, 95% CI 1.04-1.80) were associated with the efficacy of OK-432. To our knowledge, our study represents the first meta-analysis examining the efficacy of OK-432 in the treatment of different types of LMs. However, the regional differences and the age differences of the subjects are the main limitations of this study and should be avoided in further research. Our results suggested that OK-432 sclerotherapy for macrocystic lymphangiomas was more effective.
2022-12-05 | A fetus with large mediastinal cystic lymphatic malformation managed with prenatal serial thoracocentesis and postnatal sclerotherapy.
We report a very rare case of large fetal mediastinal cystic lymphatic malformation (cLM), formerly called lymphangioma, that was managed with prenatal serial thoracocentesis and postnatal sclerotherapy. A fetal pericardial effusion-like lesion gradually increased the size until it occupied more than half of the thoracic cavity. Thoracocentesis was performed three times, namely at 31 and 35 weeks of gestation, and also just before the delivery for decompression. The characteristic shape changes of the lesion were observed after thoracocentesis. A boy delivered by planned cesarian section at term required respiratory support after birth. Postnatal magnetic resonance imaging (MRI), which showed a large cystic lesion with septa and hemorrhage without solid components, led to the diagnosis of cLM. The fluid from the cyst continued to be drained. Neonatal sclerotherapy using OK-432 was effective and the infant recovered well. Fetal thoracocentesis may be useful for the diagnosis and management of a large mediastinal cLM.
2020-02-12 | A single-center experience in the management of head and neck lymphangiomas.
Lymphangiomas are relatively uncommon head and neck region lymphatic malformations. Although surgery can be still considered the mainstay of treatment, sclerotherapy by OK-432 is becoming a widespread treatment option. The aim of this article is to present and discuss the management and outcomes of a series of cases of lymphangiomas. All patients with lymphangiomas who were treated from 2010 to 2018 were reviewed. The following data were recorded: age, gender, subtype, staging, type of treatment, outcome, and recurrence. Fifteen patients (9 females, 6 males) were included with 2 microcystic and 13 macrocystic lymphangiomas. Six patients underwent surgery with excision (5 with a complete success, one with a fair success), whereas the remaining 9 subjects underwent sclerotherapy by OK-432 (6 with a complete success, 3 with a fair success). No postoperative complications were observed. All modes of treatment are important in properly selected patients affected by lymphangiomas. OK-432 therapy is a safe and effective option in the treatment of head and neck lymphangiomas.
2019-08-06 | [Experience with OK-432 in lymphatic vascular malformations in a hospital from northern Mexico].
Lymphatic vascular malformations (LVM) or formerly called lymphangiomas are congenital malformations present in about 1 out of 6000 to -16000 births. The most relevant classification system for lymphangioma management is based on the size of the cysts. Spontaneous resolution is uncommon; thus, expectant management is not recommended. The classic treatment is excisional surgery, but it can affect adjacent structures or have relapses, so, sclerosing substances like OK-432 are being studied. The majority of the studies are small in number of patients and are from Japan; the largest studies in Mexico are focused on specific lesions (macrocystic) or a determined anatomical region. To date, there are no studies of the population of the north of Mexico. The experience with OK-432 was described through a retrospective, descriptive study in patients with LVM, from 2011 to 2016, in a reference hospital of northern Mexico. A total of 26 patients with LVM were treated with OK-432. The majority of the lesions were macrocystic (69 %), microcystic (19 %) and mixed (12 %). From the total number of patients, 11 fully healed, and 72 % of the study population had >50 % reduction in lesion size, with only 2 applications. There were no recurrences. Complications were reported in 2 patients who had skin hyperpigmentation. OK-432 probed to be an effective treatment for LVM in a reference hospital in the north of Mexico. Las malformaciones vasculares linfáticas (MVL), anteriormente llamadas linfangiomas, son malformaciones congénitas que se presentan en uno de cada 6,000 a 16,000 nacimientos. El sistema de clasificación más útil para el manejo del linfangioma se basa en el tamaño de los quistes. La resolución espontánea es infrecuente, por lo que el tratamiento expectante no se recomienda. El tratamiento clásico es la cirugía de escisión, pero puede afectar a estructuras vecinas o haber recidivas, por lo que se empezaron a estudiar sustancias esclerosantes, como el OK-432. La mayoría de los estudios incluyen pocos pacientes; los más grandes realizados en México se enfocan a lesiones específicas (macroquísticas) o únicamente a una región anatómica. Hasta la fecha, no existen estudios del uso de este fármaco en la población del norte de México. Se describe la experiencia con OK-432 mediante un estudio retrospectivo, descriptivo, en los pacientes con MVL, de 2011 a 2016, en un hospital de referencia del norte de México. Veintiséis pacientes con MVL recibieron tratamiento con OK-432. La mayoría fueron macroquísticos (69%), microquísticos (19%) y mixtos (12%). Del total de pacientes, 11 presentaron curación total. El 72% de la población estudiada tuvo una reducción de > 50% del tamaño de las lesiones con solo dos aplicaciones de tratamiento; no se presentaron recidivas. Se reportaron complicaciones en dos pacientes (hiperpigmentación de la piel). El manejo con OK-432 demostró ser efectivo para el tratamiento de las MVL en un hospital de referencia del norte de México.
2019-06-05 | Management of Gorham Stout disease with skull-base defects: Case series of six children and literature review
Gorham-Stout disease (GSD) is a rare lymphatic disorder which results in bone destruction. Defects of the skull base are difficult to manage, we describe cases to better understand the disease and discuss treatment. Retrospective study including all patients treated for GSD skull-base defects. Medical records, clinical, imaging and treatment data were studied. A systematic review of the literature included case reports of the diseases for further analysis. 6 patients (5 males, 1 female) were included. Mean age at diagnosis was 3.5 years (range 0–10). Follow-up was of 5.2 years. Patients were divided into Naso-temporal (NT) and Vertebro-temporal (VT) groups following anatomical location. NT patients (4 patients) all had petrous defects extending anteriorly, including sphenoid, ethmoidal and mandibular defects. They all had cerebro-spinal fluid leak (CSF) and recurrent meningitis (range from 3 to 7). Two of those patients had sequelae including deafness, paralysis and epilepsy. VT patients (2 patients) all had temporal, occipital bone and cervical vertebrae defects. None had CSF leaks but both died from medullar compression (preceded by tetraparesis in one case). Overall, five out of six patients had type I Chiari malformation. Interferon seemed to be the most efficient medical treatment. Surgery included petrectomy, endonasal surgery for CSF leak management and neurosurgery for medullar management but could not guarantee long-term effects. Main issues in skull base defects are CSF leaks and medullar compressions. Surgical treatment is necessary in both cases but can only be satisfactory if general medical treatment can stabilise the disease.
gene therapies
2026-09-14 | Surgical case of mediastinal lymphangioma in an adult
症例は70歳女性．画像検査で偶発的に前縦隔腫瘤を認め，精査・加療目的に当科紹介となった．造影CT検査では右前縦隔心膜脂肪組織内にφ4.1 cmの境界明瞭かつ分葉状の腫瘤を認め，右横隔膜や前胸壁に接するように存在しており周囲への浸潤所見は認めなかった．耐術能に問題なく診断・治療目的に手術の方針とした．完全鏡視下にて手術を施行し，十分な切除断端を確保の上，縦隔腫瘍摘出術を施行した．病理診断では多囊胞性病変でかつ囊胞壁にD2-40陽性像を認めたことから縦隔リンパ管腫と診断された．周術期合併症は認めず，術後1年6ヵ月時点で無再発生存中である．
2026-07-23 | Giant Omental Lymphangioma Presenting With Abdominal Pain and Intra-Cystic Hemorrhage in an Adult: A Case Report.
Lymphangiomas are benign tumors of lymphatic origin that usually arise in the neck and axilla during childhood; intra-abdominal involvement is rare, and an omental origin in an adult is exceptional. Because imaging features are non-specific, preoperative diagnosis is difficult, and intra-cystic hemorrhage can transform an otherwise indolent lesion into a surgical emergency. We report the case of a 46-year-old man who presented with sudden right lower-quadrant abdominal pain and a soft, mobile, tender right-abdominal mass. Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) revealed a giant (approximately 25 cm), thin-walled, multilocular cystic mass containing a hematoma, with enhancement of the cyst walls but not the internal component, and feeding vessels arising from the greater omentum. Tumor markers were normal apart from mildly elevated carbohydrate antigen (CA) 125. Because malignancy could not be excluded, open resection was performed; the tumor arose from the greater omentum without invading adjacent organs and was completely excised. Histopathology confirmed an omental lymphangioma. The acute presentation was attributable to intra-cystic hemorrhage with a focal, self-sealed rupture superimposed on an indolent lesion. Because cross-sectional imaging cannot reliably distinguish lymphangioma from other cystic lesions, an immunohistochemical panel combining lymphatic and vascular endothelial markers (D2-40, CD31) with mesothelial markers (calretinin, WT-1) was decisive in excluding a mesothelial-lined cyst and mesothelioma. Omental lymphangioma should be considered in the differential diagnosis of a giant intra-abdominal multilocular cystic mass in adults, including those presenting acutely, and complete excision is both diagnostic and curative.
2026-07-16 | Mesenteric cystic lymphangioma in an adult female - a case report
Background: Lymphangiomas are benign vascular proliferations composed of malformed lymphatics, located in the head, neck, and axilla. Incidence in adults and at the retroperitoneal location is rare. Case presentation: We present a 34-year woman with a 7-day history of abdominal distention, colicky pain, and vomiting. Physical examination shows a non-tender, diffusely enlarged abdomen and absent bowel sounds. She underwent a magnetic resonance imaging (MRI), which confirmed 18.0 x 14.3 x 8.5 cm, multi-loculated mass extending along the mesentery of the small intestine. On histopathological examination cystic lymphangioma was the final diagnosis. Cystic lymphangioma is an unusual lesion associated with genetic and chromosomal abnormalities. Radiological investigations play a key role in pre-operative diagnosis. Final diagnosis can be obtained only after histopathological evaluation. Conclusion: This report adds to current knowledge on this pathology in atypical sites by providing thorough insights into clinical aspects, MRI results, and the histopathological correlation.
2026-07-10 | Natural History of Fetal Non-Nuchal Lymphatic Malformations: A Single Center Retrospective Study.
To document the natural history and complications of second- and third-trimester non-nuchal lymphatic malformations (LM) and identify predictors of these complications. We conducted a single-centre retrospective review of fetuses diagnosed with LMs between January 2015 and January 2024. Lesion size was quantified using the lymphatic malformation volume ratio (LVR): LVR = 0.523 x width x length x height (cm3) / head circumference (cm). Outcomes and LVR growth trends were analyzed using Student's t-test and a linear mixed-effects model. Eighteen cases were included (10 cervical, 8 axillary). Uncomplicated cervical LMs grew at 0.3 cm2/week (p < 0.001). Intralesional bleeding (n = 3) was associated with LVR > 11 cm2 and significantly higher growth rates (2.6 vs. 0.3 cm2/week; p = 0.005). All cases with LVR > 5 cm2 required subsequent tracheostomy after birth. Axillary LMs grew at 0.21 cm2/week. One case with bleeding had LVR 4.4 cm2. Median LVR was significantly lower in vaginal deliveries compared with complicated births (2.0 vs. 7.3 cm2; p = 0.03). All LVR > 4 cm2 led to delivery complications. Higher LVR predicts haemorrhage and airway intervention in cervical LMs, and delivery complications in axillary LMs. These exploratory observations warrant confirmation in larger prospective cohorts.
2026-06-16 | A case series of radiologically misdiagnosed visceral lymphatic malformations.
Visceral lymphatic malformation (LM) was rare and was easily misdiagnosed on imaging. This study aims to explore the clinicopathological and imaging findings of a series of visceral LM. The clinicopathological and imaging [computed tomography (CT) and/or magnetic resonance imaging (MRI)] findings of 11 radiologically misdiagnosed visceral LM were reviewed. The median age was 34 years old, with a sex ratio (male:female) of 1.2:1. Most were asymptomatic and found incidentally. Their locations were the lung, liver, spleen, and pancreas. They were all cystic masses, with or without septa, and mainly showed fluid attenuation on unenhanced CT (one filled with gas), hypo-signal intensity (SI) on T1WI, and hyper-SI on T2WI with/without internal hypo-SI fibrous septa. The septa showed mild to moderate enhancement. These masses were misdiagnosed as congenital pulmonary airway malformation (CPAM), hepatic mesenchymal hamartoma, splenic cyst, pancreatic intraductal papillary mucinous neoplasms (IPMN), mucinous cystadenoma, serous cystadenoma, and pancreatic ductal adenocarcinoma. They were all excised surgically. The positive rates of D2-40, CD31, and F8 staining were 100%, 100%, and 83.3%, respectively. Visceral LM were all cystic masses (multicysts or unilocular); mainly showed hypo-attenuation on unenhanced CT, hypo-SI on T1WI, and hyper-SI on T2WI with internal thin and uniform hypo-SI septa showing mild to moderate enhancement. It commonly expressed D2-40, CD31, and F8. LM should be reminded of the differentiation of visceral cystic mass.
other
2022-12-15 | Lymphangioma of the Oral and Maxillofacial Region: A Report of Three Cases
Lymphangiomas, or lymphatic malformations (LM), are benign malformations of the lymphatic system characterized by abnormal proliferation of lymphatic vessels. It was first described by Virchow in 1854. They occur rarely in the oral cavity and involve the tongue dorsum more often. Though complete surgical excision is the gold standard and most desirable management, certain limitations restrict this approach. Laser therapy, cryotherapy, electrocautery, sclerotherapy, and intralesional injections of steroids and Bevacizumab are other treatment options in such cases. Here, we present three cases of diverse forms of lymphatic malformations treated with two different modalities of treatment.
2019-12-02 | CHAPLE syndrome uncovers the primary role of complement in a familial form of Waldmann's disease.
Primary intestinal lymphangiectasia (PIL) or Waldmann's disease was described in 1961 as an important cause of protein-losing enteropathy (PLE). PIL can be the sole finding in rare individuals or occur as part of a multisystemic genetic syndrome. Although genetic etiologies of many lymphatic dysplasia syndromes associated with PIL have been identified, the pathogenesis of isolated PIL (with no associated syndromic features) remains unknown. Familial cases and occurrence at birth suggest genetic etiologies in certain cases. Recently, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and PLE (the CHAPLE syndrome) has been identified as a monogenic form of PIL. Surprisingly, loss of CD55, a key regulator of complement system leads to a predominantly gut condition. Similarly to other complement disorders, namely paroxysmal nocturnal and hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), CHAPLE disease involves pathogenic cross-activation of the coagulation system, predisposing individuals to severe thrombosis. The observation that complement system is overly active in CHAPLE disease introduced a novel concept into the management of PLE; anti-complement therapy. While CD55 deficiency constitutes a treatable subgroup in the larger pool of patients with isolated PIL, the etiology remains to be identified in the remaining patients with intact CD55.
2017-06-30 | The Origins of Lymphatic Vessels
Work on the lymphatic system began in the 17th century, and by the beginning of the 19th century, the anatomy of most of the lymphatic system had been described. One of the most important questions in this field has been the determination of the embryological origin of the lymphatic endothelium. Two theories were proposed. The first suggested the lymphatic endothelium derived by sprouting from venous endothelium, the so-called centrifugal theory. The second, the so-called centripetal theory, suggested that lymphatic endothelium differentiates in situ from primitive mesenchyme and secondarily acquires connection with the vascular system. More recent evidence has provided support for both hypotheses. The lymphatic system is implicated in interstitial fluid balance regulation, immune cell trafficking, edema, and cancer metastasis. However, the sequence of events that initiate and coordinate lymphatic vessel development (lymphangiogenesis) remains obscure. In effect, the understanding of physiological regulation of lymphatic vasculature has been overshadowed by the greater emphasis focused on angiogenesis, and delayed by a lack of specific markers, thereby limiting this field to no more than a descriptive characterization. New insights into lymphangiogenesis research have been due to the discovery of lymphatic-specific markers and growth factors of vascular endothelial growth factor (VEGF) family, such as VEGF-C and VEGF-D. Studies using transgenic mice overexpressing VEGF-C and VEGF-D have demonstrated a crucial role for these factors in tumor lymphangiogenesis. Knowledge of lymphatic development has now been redefined at the molecular level, providing an interesting target for innovative therapies.
2015-10-26 | Expression of Vascular Endothelial Growth Factor Receptors in Benign Vascular Lesions of the Orbit
Purpose
Vascular lesions of the orbit, although not malignant, can cause morbidity because of their location near critical structures in the orbit. For the same reason, they can be challenging to remove surgically. Anti-vascular endothelial growth factor (VEGF) drugs are increasingly being used to treat diseases with prominent angiogenesis. Our study aimed to determine to what extent VEGF receptors and their subtypes are expressed on selected vascular lesions of the orbit.
Design
Retrospective case series of all orbital vascular lesions removed by one of the authors (JAG) at the Mayo Clinic.
Participants
A total of 52 patients who underwent removal of vascular orbital lesions.
Methods
The pathology specimens from the patients were retrieved, their pathologic diagnosis was confirmed, demographic and clinical information were gathered, and sections from vascular tumors were stained with vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor type 1 (VEGFR1), vascular endothelial growth factor receptor type 2 (VEGFR2), and vascular endothelial growth factor receptor type 3 (VEGFR3).
Main Outcome Measures
The existence and pattern of staining with VEGF and its subtypes on these lesions.
Results
There were 28 specimens of venous malformations, 4 capillary hemangiomas, 7 lymphatic malformations, and 6 lymphaticovenous malformations. All samples stained with VEGF, 55% stained with VEGFR1, 98% stained with VEGFR2, and 96% stained with VEGFR3. Most (94%) of the VEGFR2 staining was diffuse.
Conclusions
Most orbital vascular lesions express VEGF receptors, which may suggest a future target for nonsurgical treatment.
2013-07-11 | Role of podoplanin expression in squamous cell carcinoma of upper aerodigestive tract.
Podoplanin, a type-1 transmembrane glycoprotein, was originally named due to its expression in renal podocytes of rats. It was subsequently detected in a variety of normal human tissues, including lymphatic endothelium. Although podoplanin has been identified as the endogenous ligand of C-type lectin-like receptor 2 (CLEC-2) on platelets, its physiological functions and pathways remain largely unknown. A role in lymphangiogenesis has been suggested, since podoplanin-deficient mice were found to die at birth with a phenotype of dilated, malfunctioning lymphatic vessels and lymphedema. Podoplanin is invariably expressed in some tumors, such as lymphangioma, seminoma and follicular dendritic cell tumor, but tumor cell expression of podoplanin is highly variable in squamous cell carcinoma (SCC). It has been found that high podoplanin expression is associated with lymph node metastasis and poor prognosis in SCC of the upper aerodigestive tract. Now there is growing evidence that podoplanin is also involved in carcinogenesis, cell motility, tumor invasiveness, platelet aggregation and hematogenous metastasis. Additionally, animal studies confirmed some in vivo effects of podoplanin-overexpressing tumors, including formation of more tumor lymphatic vessels, larger lymph node metastases, more platelet aggregation, and more pulmonary metastases. Several recently developed anti-podoplanin antibodies, such as NZ-1, P2-0 and hP2-0, have been shown to attenuate podoplanin-induced platelet aggregation and prevent experimental hematogenous metastasis in nude mice. These antibodies may be applied in preclinical and clinical studies to evaluate the possibility of podoplanin-targeted therapy.
cell therapies
2026-09-24 | Pediatric scrotal lymphatic malformation: a 15-case series and a proposed diagnostic and management algorithm.
To investigate the clinical characteristics, risks of misdiagnosis, and diagnostic and management strategies for pediatric scrotal lymphatic malformation. A retrospective analysis was conducted on clinical data (demographics, symptoms, diagnostic work-up, and treatment) of 15 pediatric cases with scrotal lymphatic malformation treated at our institution between 2012 and 2025. Additionally, a targeted literature review of previously reported cases with diagnostic challenges was performed. All lesions showed a characteristic extratesticular distribution outside the tunica vaginalis. The overall accuracy rates of preoperative color Doppler ultrasound and clinical diagnosis were only 46.7% (7/15) and 40.0% (6/15), respectively. Furthermore, 26.7% (4/15) of cases had an indeterminate preoperative diagnosis, and 33.3% (5/15) were completely misdiagnosed. Surgical excision was performed in all patients, achieving complete resection in 10 cases and incomplete resection in 5 cases. Over a follow-up period ranging from 3 months to 6 years (mean, 22 months), 3 cases developed ipsilateral scrotal or inguinal recurrence, and 1 case presented with a gluteal lymphatic malformation one year postoperatively. A literature review identified an additional 12 reported cases with incorrect or indeterminate preoperative diagnoses. Indeterminate diagnosis was the largest category (41.7%), and among the definite misdiagnoses, hydrocele was the most common (25%), which closely mirrored the pattern observed in our series. Pediatric scrotal lymphatic malformation is a rare entity that is highly prone to misdiagnosis and recurrence. Based on our 15-case series and reported cases, we propose a diagnostic and management algorithm integrating clinical evaluation, stepwise imaging, surgical excision, and selective sclerotherapy to improve diagnostic accuracy and optimize surgical outcomes.
2026-06-20 | Acquired lymphangioma circumscriptum following radiotherapy: A late onset presentation
Lymphangioma circumscriptum also known as microcystic lymphatic malformation is a rare hamartomatous malformation characterized by the presence of translucent, discrete or grouped vesicles (frogspawn). It constitutes 4% of all the vascular tumors. Lymphangioma circumscriptum can result from congenital or acquired abnormalities of the lymphatic system. The classic lesion is a rare malformation that usually appears at birth or can develop in early childhood. The pathogenesis of acquired lymphangioma circumscriptum that can occur later in life mainly involves lymphatic system disturbances commonlyattributed to surgical procedures, radiation therapy or infections leading to lymphatic damage or obstruction. Diagnosis is confirmed by biopsy followed by histopathological examination. Superficial and deep lymphangioma lesions may be difficult to treat. Some of the treatment options include surgical excision, lasers, sclerotherapy etc. which have shown varying success. The treatment of choice for any type of lymphangioma lesions is surgical excision with wide local excision of the affected lymphatic channels.
2026-03-11 | Small bowel lymphatic malformation: Clinical presentation and a comprehensive literature review.
Small bowel lymphatic malformations are rare benign tumors of the lymphatic system, accounting for < 1% of intra-abdominal lymphatic malformations. They pose diagnostic challenges due to nonspecific presentations and are often misdiagnosed. To analyze clinical features, management, and outcomes of small bowel lymphatic malformations in adults through a case report and scoping review. A 47-year-old female with chronic abdominal pain underwent laparoscopic resection of an ileal lymphatic malformation. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews-guided scoping review of 97 adult cases (1991-2024) was conducted, extracting demographics, diagnostics, management, and outcomes. The cohort included 41 case reports and 2 case series (46% female, mean age 45.6 years), most commonly presenting with abdominal pain (74%), gastrointestinal bleeding (39%), or asymptomatic masses (9%). Lesions were predominantly in the jejunal mesentery (52%), with a mean size of 9.2 cm. Computed tomography identified lesions in 87% of cases, showing multiloculated cystic masses (78%). Surgical resection was the primary treatment (91%), with segmental bowel resection most frequent (65%). Complications occurred in 24% (infections: 13%), and recurrence in 11% (linked to incomplete resection). Complete excision achieved symptom resolution in 93%. Small bowel lymphatic malformations are rare but may cause significant morbidity. Surgical resection is curative, with laparoscopy emerging as a viable approach. Preoperative diagnosis remains challenging; heightened imaging awareness and complete excision are critical to prevent recurrence.
2025-06-03 | Atypical location of a lymphangioma in the thymic cavity in an adult: case report and review of the literature
Introduction: Lymphangiomas are rare primary tumours of the anterior mediastinum in adults. They are usually asymptomatic. In other cases, there may be a cervical mass or signs of mediastinal compression such as exertional dyspnoea or dysphagia. The diagnosis is made with certainty by histology. Surgery is the main curative treatment. Case report: We report the case of a 34-year-old female patient who presented with a painless anterior cervico-mediastinal mass associated with dyspnoea. Cervico-thoracic imaging revealed a non-compressive mass in the thymic cavity, suggestive of a thymoma but not excluding a lymphoma. Biology and histology after scannoguided biopsy were negative. Further histological examination following surgical biopsy revealed the vascular nature of the mass, consistent with lymphangioma. Conclusion: Lymphangiomas are rarely seen in adults, particularly in the anterior mediastinum. Our observation of a lymphangioma found in the thymic cavity adds to the other cases found in the literature. This could lead us to include it in the nosological panel of an anterior cervico-mediastinal mass found in adults. Furthermore, as its diagnosis is essentially histological, we could also consider surgery as a means of diagnosis in addition to the therapeutic aspect, especially in cases of diagnostic doubt.
2023-11-29 | Diagnostic and Therapeutic Challenges of a Large Tongue Lymphangioma in a Child: A Case Report.
Lymphangiomas are rare, painless, benign tumors in infancy or early childhood resulting from a congenital malformation of the lymphatic vessels with variable clinical appearance. We report the case of a six-year-old male child who presented with a micronodular surface of the tongue, a burning sensation, difficulties during swallowing and mastication, as well as speech disturbances. Histological examination of the excised tongue specimen showed an angiomatous lesion of the lamina propria that comprised many wide thin-walled spaces. MRI examination revealed an area of disparate T2 signal maximum diameter of 2-3 cm with cystic texture in the middle and frontal left part of the tongue. The lesion was diagnosed as a lymphangioma and was managed through pre-operative embolization and surgery. Tongue lymphangiomas may lead to aesthetic problems, functional issues (like dysphagia, airway obstruction, and speech difficulties), psychological disturbances, poor oral hygiene, and occasional bleeding associated with oral trauma. A major fraction of patients also experience infections, often leading to a significant increase in lesion size. A combination of preoperative embolization and surgical excision could be chosen considering its large size and the age of the patient, and to further eliminate the possibility of recurrence. Early diagnosis and radical treatment are critical in its management.
small molecules
2026-09-17 | Precision Medicine for Somatic Mutation-Driven Vascular Anomalies.
Vascular anomalies, including proliferative vascular tumours and structural malformations, are largely driven by postzygotic somatic mutations that constitutively activate key signalling pathways, mainly the PI3K/AKT/mTOR and RAS/MAPK pathways. This molecular understanding has shifted clinical management from empiric interventions towards precision medicine. In this review, the interactions between somatic mosaicism, germline predispositions (e.g., PTEN hamartoma tumour syndrome), and microenvironmental risk factors in the context of lesional progression are described. We synthesized data on genotype‒phenotype correlations-such as PIK3CA mutations in lymphatic and venous malformations, KRAS/MAP2K1 mutations in arteriovenous malformations, and cerebral cavernous malformation (CCM) complex dysfunctions in cerebral cavernous anomalies-while fundamentally differentiating the mechanistic dependencies of true malformations from those of proliferative tumours. Targeted therapies, including mTOR, PI3Kα, and MEK inhibitors, have exhibited significant clinical efficacy in the treatment of pathway-specific anomalies. Despite these advances, therapeutic resistance and drug dependency persist. Future directions include the development of integrated diagnostic frameworks combining tissue biopsies with longitudinal cell-free DNA (cfDNA) monitoring, optimizing dual-pathway combination strategies, and advancing cellular models to reshape the management of vascular anomalies.
2026-08-25 | Resolution of Refractory Chylous Effusions With Targeted MEK Inhibition in NRAS Q61R-Driven Kaposiform Lymphangiomatosis: A Case Report.
Kaposiform lymphangiomatosis (KLA) is a rare and aggressive lymphatic anomaly characterised by chylous effusions, respiratory failure and poor prognosis. Diagnosis is often challenging and delayed due to the mosaic distribution of causative somatic mutations. A previously well four-year-old girl presented with pleural and pericardial effusions and methicillin-sensitive Staphylococcus aureus bacteraemia. She was treated with intravenous antibiotics, and chest and pericardial drains were inserted. Despite these measures, she developed high-volume, refractory chylous effusions. Management included dietary modification, as well as trials of octreotide and intravenous methylprednisolone, neither of which reduced chyle output. Magnetic resonance lymphangiography demonstrated diffuse abdominal and thoracic lymphatic abnormalities. She was subsequently treated with sirolimus, which was associated with reduced pleural and pericardial chylous drainage but ongoing clinical deterioration. Cell-free DNA analysis of pleural fluid identified a somatic NRAS variant (NM_002524.5 (NRAS):c.182A > G (p.Gln61Arg)). In the absence of histopathology, a presumed diagnosis of NRAS Q61R-driven KLA was made based on clinical, radiologic and molecular findings. She was started on trametinib, a MEK inhibitor. Over the subsequent 7 weeks, she was weaned from respiratory support and parenteral nutrition, transitioned to a fat-containing diet and experienced resolution of clinically significant effusions, allowing discharge home. This case highlights the diagnostic challenges of complex lymphatic anomalies, demonstrates the utility of cell-free DNA analysis from effusions in identifying pathogenic somatic variants and underscores the therapeutic potential of targeted MEK inhibition in NRAS Q61R-driven KLA.
2026-08-12 | Recurrent Hematuria Unveiling Renal Lymphangioma: A Diagnostic Challenge in a Patient with von Willebrand Disease
Abstract Renal lymphangioma is a rare benign lymphatic malformation that may present with hematuria and flank pain. We report the case of a 16-year-old female with type 2A von Willebrand disease who developed recurrent macroscopic hematuria and left lumbar pain. Imaging revealed a multiloculated intrarenal cystic lesion consistent with renal lymphangioma. After recurrence of symptoms and failure of conservative management, percutaneous intrarenal sclerotherapy with doxycycline was performed under factor replacement, resulting in complete symptom resolution and no recurrence on follow-up. This case highlights the diagnostic challenge in coagulopathic patients and supports sclerotherapy as an effective minimally invasive treatment.
2026-07-30 | Binding of RAS to PI3Kα regulates developmental and KRASG12D-induced lymphangiogenesis.
Complex lymphatic anomalies (CLAs) are rare diseases characterized by the abnormal development of lymphatic vessels. CLAs can be caused by somatic activating mutations in KRAS (e.g., KrasG12D), which stimulate MAPK and PI3K signaling. While KRAS/MAPK signaling is known to play a critical role in CLA pathogenesis, the contribution of KRAS/PI3Kα signaling remains unclear. To investigate the role of RAS-activation of PI3Kα in CLAs, we analyzed mice carrying two missense mutations in the RAS-binding domain of p110α, the catalytic subunit of PI3Kα. These two mutations block the interaction between p110α and RAS but do not affect its kinase activity. Disruption of RAS-mediated PI3Kα activation in lymphatic endothelial cells reduced lymphatic vessel branching but did not affect lymphatic valve formation. In KrasG12D mutant mice, blocking RAS activation of p110α reduced the pathological enlargement of lymphatic vessels, but failed to prevent KrasG12D-induced lymphatic valve loss. Similar results were observed following p110α deletion in KrasG12D mutant mice. Together, these findings demonstrate that KrasG12D drives distinct disease phenotypes through separate downstream pathways. KRAS/PI3Kα signaling promotes pathological lymphatic vessel enlargement, whereas KRAS/MAPK signaling disrupts lymphatic valve formation.
2026-06-29 | Uncommon Presentation of a Macrocystic Lymphatic Malformation in a Seven-Year-Old Boy: A Case Report.
Macrocystic lymphatic malformations (old terminology: cystic hygromas) are considered a relatively rare condition; they mostly appear in the first two years of life. Cervical neck masses are a common presenting complaint in children to pediatric outpatient departments, the most common causes being infectious/inflammatory conditions of cervical lymph nodes. In this report, we aim to bring light to the fact that rarer causes like secondarily infected or hemorrhagic lymphatic malformations may also present similarly. Here, we present the case of a seven-year-old boy who had been asymptomatic before, presenting with a 10-day history of sudden-onset neck swelling associated with an upper respiratory tract infection. Treating the upper respiratory tract infection with an oral antibiotic also helped the cystic mass involute, showing that a secondary infection was the precipitating factor in the sudden increase in size of the cyst. Management options for these lymphatic malformations are between sclerotherapy and surgical excision according to indications. In this case, the size has resolved considerably with antibiotics so that the child does not require an active intervention at present and is planned to be under close radiological follow-up.
proteins
2023-11-02 | Efficacy of OK-432 sclerotherapy for different types of lymphangiomas: a review and meta-analysis.
This study aims to perform a meta-analysis to figure out the efficacy of OK-432 sclerotherapy between Macrocystic (MAC) lymphangiomas and Microcystic (MIC) lymphangiomas. We conducted a systematic review and meta-analysis to clarify the relationship between OK-432 and lymphangiomas. PubMed and ISI Web of Science were searched from inception to May 2022. Joanna Briggs Institute (JBI) manual was used to evaluate the risk of bias. We calculated pooled Relative Risks (RR) and 95% Confidence Interval (95% CI) using random effects model to evaluate the relations between OK-432 and lymphangiomas. A total of 11 studies (including 352 cases) about OK-432 sclerotherapy for lymphangioma were included in the current meta-analyses. The results suggested that the efficacy of OK-432 was significantly in MAC lesions than in MIC (RR=1.51, 95% CI 1.298-1.764), with significant moderate degrees of heterogeneity among 11 studies (I2=51.2%, p=0.025). Subgroup analyses suggested that there was significant association in both retrospective studies (RR=1.26, 95% CI 1.03-1.53) and classification (by 1 cm) (RR=1.37, 95% CI 1.04-1.80) were associated with the efficacy of OK-432. To our knowledge, our study represents the first meta-analysis examining the efficacy of OK-432 in the treatment of different types of LMs. However, the regional differences and the age differences of the subjects are the main limitations of this study and should be avoided in further research. Our results suggested that OK-432 sclerotherapy for macrocystic lymphangiomas was more effective.
2022-12-05 | A fetus with large mediastinal cystic lymphatic malformation managed with prenatal serial thoracocentesis and postnatal sclerotherapy.
We report a very rare case of large fetal mediastinal cystic lymphatic malformation (cLM), formerly called lymphangioma, that was managed with prenatal serial thoracocentesis and postnatal sclerotherapy. A fetal pericardial effusion-like lesion gradually increased the size until it occupied more than half of the thoracic cavity. Thoracocentesis was performed three times, namely at 31 and 35 weeks of gestation, and also just before the delivery for decompression. The characteristic shape changes of the lesion were observed after thoracocentesis. A boy delivered by planned cesarian section at term required respiratory support after birth. Postnatal magnetic resonance imaging (MRI), which showed a large cystic lesion with septa and hemorrhage without solid components, led to the diagnosis of cLM. The fluid from the cyst continued to be drained. Neonatal sclerotherapy using OK-432 was effective and the infant recovered well. Fetal thoracocentesis may be useful for the diagnosis and management of a large mediastinal cLM.
2020-02-12 | A single-center experience in the management of head and neck lymphangiomas.
Lymphangiomas are relatively uncommon head and neck region lymphatic malformations. Although surgery can be still considered the mainstay of treatment, sclerotherapy by OK-432 is becoming a widespread treatment option. The aim of this article is to present and discuss the management and outcomes of a series of cases of lymphangiomas. All patients with lymphangiomas who were treated from 2010 to 2018 were reviewed. The following data were recorded: age, gender, subtype, staging, type of treatment, outcome, and recurrence. Fifteen patients (9 females, 6 males) were included with 2 microcystic and 13 macrocystic lymphangiomas. Six patients underwent surgery with excision (5 with a complete success, one with a fair success), whereas the remaining 9 subjects underwent sclerotherapy by OK-432 (6 with a complete success, 3 with a fair success). No postoperative complications were observed. All modes of treatment are important in properly selected patients affected by lymphangiomas. OK-432 therapy is a safe and effective option in the treatment of head and neck lymphangiomas.
2019-08-06 | [Experience with OK-432 in lymphatic vascular malformations in a hospital from northern Mexico].
Lymphatic vascular malformations (LVM) or formerly called lymphangiomas are congenital malformations present in about 1 out of 6000 to -16000 births. The most relevant classification system for lymphangioma management is based on the size of the cysts. Spontaneous resolution is uncommon; thus, expectant management is not recommended. The classic treatment is excisional surgery, but it can affect adjacent structures or have relapses, so, sclerosing substances like OK-432 are being studied. The majority of the studies are small in number of patients and are from Japan; the largest studies in Mexico are focused on specific lesions (macrocystic) or a determined anatomical region. To date, there are no studies of the population of the north of Mexico. The experience with OK-432 was described through a retrospective, descriptive study in patients with LVM, from 2011 to 2016, in a reference hospital of northern Mexico. A total of 26 patients with LVM were treated with OK-432. The majority of the lesions were macrocystic (69 %), microcystic (19 %) and mixed (12 %). From the total number of patients, 11 fully healed, and 72 % of the study population had >50 % reduction in lesion size, with only 2 applications. There were no recurrences. Complications were reported in 2 patients who had skin hyperpigmentation. OK-432 probed to be an effective treatment for LVM in a reference hospital in the north of Mexico. Las malformaciones vasculares linfáticas (MVL), anteriormente llamadas linfangiomas, son malformaciones congénitas que se presentan en uno de cada 6,000 a 16,000 nacimientos. El sistema de clasificación más útil para el manejo del linfangioma se basa en el tamaño de los quistes. La resolución espontánea es infrecuente, por lo que el tratamiento expectante no se recomienda. El tratamiento clásico es la cirugía de escisión, pero puede afectar a estructuras vecinas o haber recidivas, por lo que se empezaron a estudiar sustancias esclerosantes, como el OK-432. La mayoría de los estudios incluyen pocos pacientes; los más grandes realizados en México se enfocan a lesiones específicas (macroquísticas) o únicamente a una región anatómica. Hasta la fecha, no existen estudios del uso de este fármaco en la población del norte de México. Se describe la experiencia con OK-432 mediante un estudio retrospectivo, descriptivo, en los pacientes con MVL, de 2011 a 2016, en un hospital de referencia del norte de México. Veintiséis pacientes con MVL recibieron tratamiento con OK-432. La mayoría fueron macroquísticos (69%), microquísticos (19%) y mixtos (12%). Del total de pacientes, 11 presentaron curación total. El 72% de la población estudiada tuvo una reducción de > 50% del tamaño de las lesiones con solo dos aplicaciones de tratamiento; no se presentaron recidivas. Se reportaron complicaciones en dos pacientes (hiperpigmentación de la piel). El manejo con OK-432 demostró ser efectivo para el tratamiento de las MVL en un hospital de referencia del norte de México.
2019-06-05 | Management of Gorham Stout disease with skull-base defects: Case series of six children and literature review
Gorham-Stout disease (GSD) is a rare lymphatic disorder which results in bone destruction. Defects of the skull base are difficult to manage, we describe cases to better understand the disease and discuss treatment. Retrospective study including all patients treated for GSD skull-base defects. Medical records, clinical, imaging and treatment data were studied. A systematic review of the literature included case reports of the diseases for further analysis. 6 patients (5 males, 1 female) were included. Mean age at diagnosis was 3.5 years (range 0–10). Follow-up was of 5.2 years. Patients were divided into Naso-temporal (NT) and Vertebro-temporal (VT) groups following anatomical location. NT patients (4 patients) all had petrous defects extending anteriorly, including sphenoid, ethmoidal and mandibular defects. They all had cerebro-spinal fluid leak (CSF) and recurrent meningitis (range from 3 to 7). Two of those patients had sequelae including deafness, paralysis and epilepsy. VT patients (2 patients) all had temporal, occipital bone and cervical vertebrae defects. None had CSF leaks but both died from medullar compression (preceded by tetraparesis in one case). Overall, five out of six patients had type I Chiari malformation. Interferon seemed to be the most efficient medical treatment. Surgery included petrectomy, endonasal surgery for CSF leak management and neurosurgery for medullar management but could not guarantee long-term effects. Main issues in skull base defects are CSF leaks and medullar compressions. Surgical treatment is necessary in both cases but can only be satisfactory if general medical treatment can stabilise the disease.
gene therapies
2026-09-14 | Surgical case of mediastinal lymphangioma in an adult
症例は70歳女性．画像検査で偶発的に前縦隔腫瘤を認め，精査・加療目的に当科紹介となった．造影CT検査では右前縦隔心膜脂肪組織内にφ4.1 cmの境界明瞭かつ分葉状の腫瘤を認め，右横隔膜や前胸壁に接するように存在しており周囲への浸潤所見は認めなかった．耐術能に問題なく診断・治療目的に手術の方針とした．完全鏡視下にて手術を施行し，十分な切除断端を確保の上，縦隔腫瘍摘出術を施行した．病理診断では多囊胞性病変でかつ囊胞壁にD2-40陽性像を認めたことから縦隔リンパ管腫と診断された．周術期合併症は認めず，術後1年6ヵ月時点で無再発生存中である．
2026-07-23 | Giant Omental Lymphangioma Presenting With Abdominal Pain and Intra-Cystic Hemorrhage in an Adult: A Case Report.
Lymphangiomas are benign tumors of lymphatic origin that usually arise in the neck and axilla during childhood; intra-abdominal involvement is rare, and an omental origin in an adult is exceptional. Because imaging features are non-specific, preoperative diagnosis is difficult, and intra-cystic hemorrhage can transform an otherwise indolent lesion into a surgical emergency. We report the case of a 46-year-old man who presented with sudden right lower-quadrant abdominal pain and a soft, mobile, tender right-abdominal mass. Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) revealed a giant (approximately 25 cm), thin-walled, multilocular cystic mass containing a hematoma, with enhancement of the cyst walls but not the internal component, and feeding vessels arising from the greater omentum. Tumor markers were normal apart from mildly elevated carbohydrate antigen (CA) 125. Because malignancy could not be excluded, open resection was performed; the tumor arose from the greater omentum without invading adjacent organs and was completely excised. Histopathology confirmed an omental lymphangioma. The acute presentation was attributable to intra-cystic hemorrhage with a focal, self-sealed rupture superimposed on an indolent lesion. Because cross-sectional imaging cannot reliably distinguish lymphangioma from other cystic lesions, an immunohistochemical panel combining lymphatic and vascular endothelial markers (D2-40, CD31) with mesothelial markers (calretinin, WT-1) was decisive in excluding a mesothelial-lined cyst and mesothelioma. Omental lymphangioma should be considered in the differential diagnosis of a giant intra-abdominal multilocular cystic mass in adults, including those presenting acutely, and complete excision is both diagnostic and curative.
2026-07-16 | Mesenteric cystic lymphangioma in an adult female - a case report
Background: Lymphangiomas are benign vascular proliferations composed of malformed lymphatics, located in the head, neck, and axilla. Incidence in adults and at the retroperitoneal location is rare. Case presentation: We present a 34-year woman with a 7-day history of abdominal distention, colicky pain, and vomiting. Physical examination shows a non-tender, diffusely enlarged abdomen and absent bowel sounds. She underwent a magnetic resonance imaging (MRI), which confirmed 18.0 x 14.3 x 8.5 cm, multi-loculated mass extending along the mesentery of the small intestine. On histopathological examination cystic lymphangioma was the final diagnosis. Cystic lymphangioma is an unusual lesion associated with genetic and chromosomal abnormalities. Radiological investigations play a key role in pre-operative diagnosis. Final diagnosis can be obtained only after histopathological evaluation. Conclusion: This report adds to current knowledge on this pathology in atypical sites by providing thorough insights into clinical aspects, MRI results, and the histopathological correlation.
2026-07-10 | Natural History of Fetal Non-Nuchal Lymphatic Malformations: A Single Center Retrospective Study.
To document the natural history and complications of second- and third-trimester non-nuchal lymphatic malformations (LM) and identify predictors of these complications. We conducted a single-centre retrospective review of fetuses diagnosed with LMs between January 2015 and January 2024. Lesion size was quantified using the lymphatic malformation volume ratio (LVR): LVR = 0.523 x width x length x height (cm3) / head circumference (cm). Outcomes and LVR growth trends were analyzed using Student's t-test and a linear mixed-effects model. Eighteen cases were included (10 cervical, 8 axillary). Uncomplicated cervical LMs grew at 0.3 cm2/week (p < 0.001). Intralesional bleeding (n = 3) was associated with LVR > 11 cm2 and significantly higher growth rates (2.6 vs. 0.3 cm2/week; p = 0.005). All cases with LVR > 5 cm2 required subsequent tracheostomy after birth. Axillary LMs grew at 0.21 cm2/week. One case with bleeding had LVR 4.4 cm2. Median LVR was significantly lower in vaginal deliveries compared with complicated births (2.0 vs. 7.3 cm2; p = 0.03). All LVR > 4 cm2 led to delivery complications. Higher LVR predicts haemorrhage and airway intervention in cervical LMs, and delivery complications in axillary LMs. These exploratory observations warrant confirmation in larger prospective cohorts.
2026-06-16 | A case series of radiologically misdiagnosed visceral lymphatic malformations.
Visceral lymphatic malformation (LM) was rare and was easily misdiagnosed on imaging. This study aims to explore the clinicopathological and imaging findings of a series of visceral LM. The clinicopathological and imaging [computed tomography (CT) and/or magnetic resonance imaging (MRI)] findings of 11 radiologically misdiagnosed visceral LM were reviewed. The median age was 34 years old, with a sex ratio (male:female) of 1.2:1. Most were asymptomatic and found incidentally. Their locations were the lung, liver, spleen, and pancreas. They were all cystic masses, with or without septa, and mainly showed fluid attenuation on unenhanced CT (one filled with gas), hypo-signal intensity (SI) on T1WI, and hyper-SI on T2WI with/without internal hypo-SI fibrous septa. The septa showed mild to moderate enhancement. These masses were misdiagnosed as congenital pulmonary airway malformation (CPAM), hepatic mesenchymal hamartoma, splenic cyst, pancreatic intraductal papillary mucinous neoplasms (IPMN), mucinous cystadenoma, serous cystadenoma, and pancreatic ductal adenocarcinoma. They were all excised surgically. The positive rates of D2-40, CD31, and F8 staining were 100%, 100%, and 83.3%, respectively. Visceral LM were all cystic masses (multicysts or unilocular); mainly showed hypo-attenuation on unenhanced CT, hypo-SI on T1WI, and hyper-SI on T2WI with internal thin and uniform hypo-SI septa showing mild to moderate enhancement. It commonly expressed D2-40, CD31, and F8. LM should be reminded of the differentiation of visceral cystic mass.
other
2022-12-15 | Lymphangioma of the Oral and Maxillofacial Region: A Report of Three Cases
Lymphangiomas, or lymphatic malformations (LM), are benign malformations of the lymphatic system characterized by abnormal proliferation of lymphatic vessels. It was first described by Virchow in 1854. They occur rarely in the oral cavity and involve the tongue dorsum more often. Though complete surgical excision is the gold standard and most desirable management, certain limitations restrict this approach. Laser therapy, cryotherapy, electrocautery, sclerotherapy, and intralesional injections of steroids and Bevacizumab are other treatment options in such cases. Here, we present three cases of diverse forms of lymphatic malformations treated with two different modalities of treatment.
2019-12-02 | CHAPLE syndrome uncovers the primary role of complement in a familial form of Waldmann's disease.
Primary intestinal lymphangiectasia (PIL) or Waldmann's disease was described in 1961 as an important cause of protein-losing enteropathy (PLE). PIL can be the sole finding in rare individuals or occur as part of a multisystemic genetic syndrome. Although genetic etiologies of many lymphatic dysplasia syndromes associated with PIL have been identified, the pathogenesis of isolated PIL (with no associated syndromic features) remains unknown. Familial cases and occurrence at birth suggest genetic etiologies in certain cases. Recently, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and PLE (the CHAPLE syndrome) has been identified as a monogenic form of PIL. Surprisingly, loss of CD55, a key regulator of complement system leads to a predominantly gut condition. Similarly to other complement disorders, namely paroxysmal nocturnal and hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), CHAPLE disease involves pathogenic cross-activation of the coagulation system, predisposing individuals to severe thrombosis. The observation that complement system is overly active in CHAPLE disease introduced a novel concept into the management of PLE; anti-complement therapy. While CD55 deficiency constitutes a treatable subgroup in the larger pool of patients with isolated PIL, the etiology remains to be identified in the remaining patients with intact CD55.
2017-06-30 | The Origins of Lymphatic Vessels
Work on the lymphatic system began in the 17th century, and by the beginning of the 19th century, the anatomy of most of the lymphatic system had been described. One of the most important questions in this field has been the determination of the embryological origin of the lymphatic endothelium. Two theories were proposed. The first suggested the lymphatic endothelium derived by sprouting from venous endothelium, the so-called centrifugal theory. The second, the so-called centripetal theory, suggested that lymphatic endothelium differentiates in situ from primitive mesenchyme and secondarily acquires connection with the vascular system. More recent evidence has provided support for both hypotheses. The lymphatic system is implicated in interstitial fluid balance regulation, immune cell trafficking, edema, and cancer metastasis. However, the sequence of events that initiate and coordinate lymphatic vessel development (lymphangiogenesis) remains obscure. In effect, the understanding of physiological regulation of lymphatic vasculature has been overshadowed by the greater emphasis focused on angiogenesis, and delayed by a lack of specific markers, thereby limiting this field to no more than a descriptive characterization. New insights into lymphangiogenesis research have been due to the discovery of lymphatic-specific markers and growth factors of vascular endothelial growth factor (VEGF) family, such as VEGF-C and VEGF-D. Studies using transgenic mice overexpressing VEGF-C and VEGF-D have demonstrated a crucial role for these factors in tumor lymphangiogenesis. Knowledge of lymphatic development has now been redefined at the molecular level, providing an interesting target for innovative therapies.
2015-10-26 | Expression of Vascular Endothelial Growth Factor Receptors in Benign Vascular Lesions of the Orbit
Purpose
Vascular lesions of the orbit, although not malignant, can cause morbidity because of their location near critical structures in the orbit. For the same reason, they can be challenging to remove surgically. Anti-vascular endothelial growth factor (VEGF) drugs are increasingly being used to treat diseases with prominent angiogenesis. Our study aimed to determine to what extent VEGF receptors and their subtypes are expressed on selected vascular lesions of the orbit.
Design
Retrospective case series of all orbital vascular lesions removed by one of the authors (JAG) at the Mayo Clinic.
Participants
A total of 52 patients who underwent removal of vascular orbital lesions.
Methods
The pathology specimens from the patients were retrieved, their pathologic diagnosis was confirmed, demographic and clinical information were gathered, and sections from vascular tumors were stained with vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor type 1 (VEGFR1), vascular endothelial growth factor receptor type 2 (VEGFR2), and vascular endothelial growth factor receptor type 3 (VEGFR3).
Main Outcome Measures
The existence and pattern of staining with VEGF and its subtypes on these lesions.
Results
There were 28 specimens of venous malformations, 4 capillary hemangiomas, 7 lymphatic malformations, and 6 lymphaticovenous malformations. All samples stained with VEGF, 55% stained with VEGFR1, 98% stained with VEGFR2, and 96% stained with VEGFR3. Most (94%) of the VEGFR2 staining was diffuse.
Conclusions
Most orbital vascular lesions express VEGF receptors, which may suggest a future target for nonsurgical treatment.
2013-07-11 | Role of podoplanin expression in squamous cell carcinoma of upper aerodigestive tract.
Podoplanin, a type-1 transmembrane glycoprotein, was originally named due to its expression in renal podocytes of rats. It was subsequently detected in a variety of normal human tissues, including lymphatic endothelium. Although podoplanin has been identified as the endogenous ligand of C-type lectin-like receptor 2 (CLEC-2) on platelets, its physiological functions and pathways remain largely unknown. A role in lymphangiogenesis has been suggested, since podoplanin-deficient mice were found to die at birth with a phenotype of dilated, malfunctioning lymphatic vessels and lymphedema. Podoplanin is invariably expressed in some tumors, such as lymphangioma, seminoma and follicular dendritic cell tumor, but tumor cell expression of podoplanin is highly variable in squamous cell carcinoma (SCC). It has been found that high podoplanin expression is associated with lymph node metastasis and poor prognosis in SCC of the upper aerodigestive tract. Now there is growing evidence that podoplanin is also involved in carcinogenesis, cell motility, tumor invasiveness, platelet aggregation and hematogenous metastasis. Additionally, animal studies confirmed some in vivo effects of podoplanin-overexpressing tumors, including formation of more tumor lymphatic vessels, larger lymph node metastases, more platelet aggregation, and more pulmonary metastases. Several recently developed anti-podoplanin antibodies, such as NZ-1, P2-0 and hP2-0, have been shown to attenuate podoplanin-induced platelet aggregation and prevent experimental hematogenous metastasis in nude mice. These antibodies may be applied in preclinical and clinical studies to evaluate the possibility of podoplanin-targeted therapy.
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Drug Discovery Landscape
9 orphan drug designations for Rare lymphatic malformation.
9 orphan drug designations for Rare lymphatic malformation.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Alpelisib | small molecules | EMA | Novartis Europharm Limited | |
Alpelisib | small molecules | FDA | Novartis Pharmaceuticals Corporation | |
Sirolimus | small molecules | EMA | Raremoon Consulting Esp S.L. | |
Streptococcus pyogenes, group A, type 3, strain Su, inactivated | cell therapies | EMA | — | Premier Research Group S.L. |
sirolimus | small molecules | FDA | Palvella Therapeutics, Inc. | |
trans-4-[4-Amino-5-(7-methoxy-1H-indol-2-yl)-imidazo[5,1-f][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid, tromethamine salt | small molecules | FDA | Avalo Therapeutics, Inc. | |
picibanil | other | FDA | Protara Therapeutics Inc. | |
picibanil | other | FDA | Royds Pharmaceuticals, Inc. | |
Ethanol gel | small molecules | FDA | — | Orfagen |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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