Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial.

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.

Hemolymphangioma involving bones and bladder detected on 68Ga-NEB PET/CT: A rare case report.

RATIONALE: Hemolymphangioma is a rare developmental defect of combined vasal and lymphatic vasculature. It is very rare that hemolymphangioma affects the bones and bladder simultaneously, and this condition has never been reported in PubMed. PATIENT CONCERNS: A 12-year-old male has a history of hospitalization for recurrent episodes of chyluria of 8 years duration and progressively worsening gross hematuria with right hip pain for 6 months. DIAGNOSIS: Chylous test of urine fluid was positive. There was no organic disease in the kidneys. Ga-NOTA-Evans Blue (NEB) positron emission tomography/computed tomography (PET/CT) images demonstrated clearly several round and strip-shaped low-density shadows with mildly increased radioactive uptake in both bladder wall and pelvis, including sacral, pubic, and ischial bones. Histopathological analysis of biopsy on pubic and ischial bones confirmed the diagnosis of hemolymphangioma. INTERVENTIONS: The patient received treatment with traditional Chinese medicine. OUTCOMES: At the 6-month follow-up visit, the patient's symptoms of chyluria, hematuria, and pain were all mitigated. LESSONS: Hemolymphangioma is a rare benign disease. Ga-NEB PET/CT is a specific method for the lymphatic system, and it might provide more accurate and comprehensive information about the disorder of the lymphatic system compared with CT and magnetic resonance imaging. When patients suffer from suspected lesions of the lymphatic system, Ga-NEB PET/CT might be recommended.

Lymphangioma Circumscriptum Post Radiotherapy for Penile Cancer Treated with CO2 Laser.

Lymphangioma circumscriptum (LC) is a rare, benign condition, predominantly characterized by the malformation of lymphatic skin vessels. Its onset may be congenital or due to secondary causes such as radiotherapy, infections, or surgical procedures. We present the case of a 55-year-old patient with a pathologic history of squamous cell carcinoma of the penis followed by radical penectomy. Due to metastasis to the locoregional lymph nodes, the entire affected area was subsequently treated with radiation therapy, receiving a total dose of 55.8 Gray. Eight years after this treatment, translucent vesicles filled with a clear liquid appeared on the scrotum. Histopathology confirmed the diagnosis of LC and therapy with CO2 laser was applied, resulting in a favorable outcome. LC of the scrotum may present a long-term radiotherapy-induced complication of this site. Our clinical experience showed that the CO2 laser was the therapy of choice as the vesicles entirely disappeared and healed as white scar-like lesions.

[Urological pathology of lymphatic origin]. / Patología urológica de origen linfático.

OBJECTIVES: Lymphatic disease is a rarely cause of some very unspecific genitourinary manifestations, assuming a diagnostic challenge in most cases. The aim of this paper is to warn about the possible etiology of these urological lymphatic presentations and discuss its management. METHODS: Retrospective review of clinical data in pediatric patients with urological pathology of lymphatic origin between 2008-2014. Three patients, two boys and a girl, were included. The complaints were: redundant prepuce, inguinal scrotal tumor and urinary incontinence. Clinical, diagnosis and treatment protocol is described. RESULTS: The first case is a male with genital lymphedema presented at birth as a redundant prepuce and the subsequent emergence of lower limb lymphedema, treated with compression bandages. The second case, a groin lymphangioma which debuted as a sudden painless inguinal tumor simulating a cord cyst, it was sclerosed and treated with OK- 432. Finally, a preteen who consulted for involuntary leakage of urine, genital lymphedema likely primary cause (lymphodisplasia) or malformation was diagnosed, which improved with two Lipiodol® embolization. CONCLUSIONS: Genitourinary manifestations can be the debut of more complex lymphatic pathology, so it is necessary to consider this cause, uncommon and nonspecific. Its management must be conservative initially by compression bandages, OK-432 or embolization with Lipiodol®.

OBJETIVOS: La patología linfática es infrecuente como causa de manifestaciones genitourinarias inespecíficas, suponiendo un reto diagnóstico en la mayoría de los casos. El objetivo de este trabajo es advertir sobre la posible etiología linfática de estas presentaciones urológicas y discutir su manejo. MATERIAL Y METODOS: Revisión retrospectiva de los datos clínicos de los pacientes pediátricos con patología urológica de origen linfático entre el año 2008-2014. Se incluyeron 3 pacientes, dos niños y una niña. Todos ellos se evaluaron para obtener un diagnóstico fiable. Los motivos de consulta fueron: prepucio redundante, tumoración inguino-escrotal e incontinencia urinaria. Se describe la clínica, el protocolo diagnóstico y el tratamiento de los mismos. CASOS CLINICOS: El primer caso se trata de un lactante varón con un linfedema genital que presentaba un prepucio redundante congénito y la aparición posterior de linfedema en el miembro inferior que es tratado con vendajes compresivos. El siguiente, un linfangioma inguinal que debutó con una tumoración inguinal indolora de aparición súbita simulando un quiste de cordón y tratado mediante esclerosis con OK-432. Por último, una preadolescente que consultó por escapes involuntarios de orina diagnosticada de linfedema genital de probable causa primaria (linfodisplasia) o malformativa que mejoró con dos embolizaciones de Lipiodol®. CONCLUSIONES: Las manifestaciones genitourinarias pueden ser el debut de una patología linfática más compleja, por ello es necesario tener presente esta etiología infrecuente e inespecífica. Su manejo inicialmente debe ser conservador, mediante vendajes compresivos, OK-432 o embolización con Lipiodol®.

Microcystic lymphatic malformations (lymphangioma circumscriptum) managed with fractional carbon dioxide laser ablation

Microcystic lymphatic malformation (lymphangioma circumscriptum) is the most common cutaneous lymphatic malformation, consisting of abnormal, dilated, and tortuous lymphatic vessels in the dermis and subcutaneous tissue. It is due to irregular vessel contraction with subsequent dilatation and fluid build-up that manifests clinically as multiple, grouped, small macroscopic superficial vesicles filled with clear or serosanguineous fluid. The lesions are frequently located over proximal limbs, axillae and chest but may occur on any part of the body. We report a case of lymphangioma circumscriptumin a four-year-old child, partially treated with fractional carbon dioxide laser ablation under local anesthesia. Most of the lesions resolved but the treated areas healed with hypertrophic scarring after one month, which was cosmetically acceptable. Compared to surgical excision, carbon dioxide laser ablation may provide less chances of contractures especially in areas overlying a joint and may be considered as an alternative to more invasive procedures.

Cryotherapy for massive vulvar lymphatic leakage complicated with lymphangiomas following gynecological cancer treatment.

Vulvar lymphatic leakage is a severe complication associated with gynecological cancer treatments. However, standard treatment strategies have not yet been determined. We encountered a rare case of a 76-year-old multiparous woman suffering from massive lymphatic fluid leakage from the entire vulva, and papules developed and were identified as lymphangiomas. A large amount of straw-colored discharge continued from all vulvar papules, which extended over the mons pubis. Nine years ago, the patient had undergone a radical hysterectomy with concurrent chemoradiation for uterine cervical cancer treatment. Her serum albumin level was 1.9 mg/dl, which was attributed to the loss of a large amount of lymph fluid due to leakage from the vulva. Her quality of life gradually decreased because of general fatigue and the need for frequent diaper exchanges every 2 h. The patient received a less-invasive treatment with cryotherapy using liquid nitrogen. She also received a multimodality treatment consisting of the intravenous administration of albumin, massage of the lower limbs and intensive rehabilitation. Cryotherapy was administered once a week for 3 months. Her discharge almost stopped and vulvar lymphangiomas decreased without any major complications. To the best of our knowledge, this is the first case report of massive lymphatic leakage complicated with vulvar lymphangiomas. Additionally, this case may represent the first successful treatment of vulva lymph leakage by cryotherapy without recurrence. Cryotherapy may have the potential to improve the quality of life as a less-invasive treatment for gynecological cancer survivors without serious complications.

Propranolol as an alternative treatment option for pediatric lymphatic malformation.

Lymphatic malformation (LM), which was previously termed lymphangioma, is a rare congenital malformation of the lymphatic system and its treatment is still challenging. Propranolol (beta blocker) has been recently developed as a first-line treatment of infantile hemangioma. Our study aimed to assess the effect of propranolol on pediatric LM and the relationship between its effectiveness and vascular endothelial growth factor (VEGF) family members (VEGF-A, C and D). Six Japanese patients with LM (age range: 10 months-19 years old; 2 macrocystic, 2 microcystic and 2 combined type) were enrolled. Oral propranolol was administered at 2 mg/kg/day. The efficacy of propranolol for LM was evaluated by the rate of volume change as calculated from MRI imaging and by symptomatic improvement. In all patients, there were no significant side effects. Patients 3 and 5 were classified as objective responders with tumor volume reduction of 30.6% and 22.9%, respectively, at 24 weeks. Patient 1 showed 8% tumor volume reduction and patient 6 showed symptomatic improvement, hence, both were classified as minimal responders. The other two patients were classified as non-responders. Plasma VEGF-A, C, and D levels were significantly higher in the LM group than in the controls (all P < 0.01 by Mann-Whitney test). VEGF-A and D levels at 24 weeks were significantly lower than those at pre-treatment (P = 0.031, 0.047 by Wilcoxon matched pairs test). Though further trials with this treatment must be carried out, we propose that propranolol may be an alternative therapy option for intractable LM.

Transumbilical scarless surgery with thoracic trocar: easy and low-cost / 대한외과학회지

PURPOSE: Single-site laparoscopic surgery has become increasingly common. We herein report an easy and low-cost thoracic trocar technique (TTT) for these types of procedures and recommend the simpler name "transumbilical scarless surgery" (TUSS) to minimize confusion in nomenclature. METHODS: We retrospectively reviewed patients who underwent TUSS by TTT using a thoracic trocar and surgical glove in our hospital between November 2011 and November 2012. Operating time, postoperative stay, and complications were detailed. RESULTS: A total of 101 TUSS by TTT were successfully performed, comprising appendectomy (n = 63), ovarian cyst excision (n = 7), splenectomy (n = 5), nephroureterectomy (n = 5), orchidopexy (n = 4), pyeloplasty (n = 3), nephrolithotomy (n = 2), orchiectomy (n = 2), varicocelectomy (n = 2), lymphangioma excision (n = 2), ureterectomy (n = 1), Morgagni diaphragmatic hernia repair (n = 1), ovarian detorsion (n = 1), antegrade continence enema (n = 1), intestinal resection anastomosis (n = 1), and intestinal duplication excision (n = 1). Kirschner wires were used for some organ traction. Nine patients required an additional port, but no major complications occurred. The postoperative stay (mean +/- standard deviation) was 3.2 +/- 1.4 days, and operating time was 58.9 +/- 38.3 minutes. CONCLUSION: We recommend the simpler name of TUSS to minimize confusion in nomenclature for all transumbilical single-incision laparoendoscopic surgeries. TTT is an easy and low-cost TUSS technique.

Bipolar radiofrequency-induced interstitial thermoablation for oral cavity vascular malformations: Preliminary results in a series of 5 children.

We report our assessment of the effectiveness of bipolar radiofrequency-induced interstitial thermoablation (BRIT) for the treatment of certain oral cavity vascular malformations in 5 children. Two of these patients had lymphangiomatous macroglossia (LM), 1 had lymphangioma circumscriptum (LC), and 2 had a venous malformation (VM). Each patient underwent BRIT at least twice; treatment was delivered at 4- to 8-week intervals according to each patient's circumstances. The 2 patients with LM required three treatment sessions; although their tongue volume decreased after each session, both still required a partial glossectomy to achieve a satisfactory reduction in volume. The patient with LC underwent two BRIT treatments, which reduced the size of the lesion by half; the remainder was excised. The 2 patients with a VM (1 buccal and 1 lingual) responded well to BRIT, and their malformations almost completely disappeared. Our early results with BRIT suggest that it is an effective treatment for oral cavity vascular malformations-more so for patients with venous rather than lymphangiomatous lesions.

Looking at appearance of urine before performing a renal biopsy in nephrotic syndrome.

Chyluria results from an abnormal connection between lymphatic bed and urinary tract, causing lymph leakage into the urine. The clinical picture often begins with the appearance of cloudy, milky urines accompanied by monolateral flank pain, malnutrition, weight loss and weakness. We report a case of chyluria that occurred in a young woman who was referred to our unit for nephrotic-range proteinuria. Before performing a renal biopsy, we found that urine analysis demonstrated a massive lipiduria. Therefore, we collected urine samples from each kidney with a selective ureteral catheterization, demonstrating a monolateral source of lipids and proteins. We suspended the renal biopsy and performed a lymphography that showed an inherited lymphangioma on the left lumbar lymphatic bed. Sclerosing solution instillation, renal pedicle lymphatic disconnection or laser therapy are invasive therapeutical options that may cause severe adverse effects. Instead of these procedures, a conservative therapy based on a low-fat diet supplemented with medium-chain triglycerides was chosen. This dietetic schedule was followed by complete resolution of proteinuria and lipiduria. The patient progressively gained body weight and improved quality of life. No relapses were observed after 3 years of follow-up. This case emphasizes the possible role of a noninvasive therapeutical option for patients with chyluria.

A case of mediastinal lymphangioma successfully treated with Kampo medicine.

OBJECTIVE: The authors report a case of mediastinal lymphangioma successfully treated with Kampo medicine. METHODS: A 2-year-old boy with an axillary soft mass consulted our clinic. Physical examination findings were normal except for axillary elastic swelling. The neck and chest magnetic resonance imaging scan (MRI) showed a multilocular mass starting from a cervical lesion and extending above the carina. RESULTS: After 9 months of Kampo administration, MRI showed marked regression of mediastinal lymphangioma. CONCLUSIONS: It was found that Kampo medicine might be safe and effective as an alternative choice of treatment for lymphangiomas.

Infected giant lymphangioma circumscriptum treated with a combination therapy.

Lymphangioma circumscriptum is an uncommon benign disorder of skin and subcutaneous tissues characterized by dilated lymphatic channels. It is an uncommon vascular tumor and it rarely becomes infected. We report a 20-year-old man who had an infected giant tumor in his left thigh. After an extensive resection and radiofrequency energy therapy, he recovered well with an acceptable cosmetic result. We followed up the patient for 2 years without any recurrence.

Lymphatic malformations: a proposed management algorithm.

OBJECTIVE: The aim of this study was to develop a management algorithm for cervicofacial lymphatic malformations, based on the authors' experience in managing these lesions as well as current literature on the subject. STUDY DESIGN AND METHODS: A retrospective medical record review of all the patients treated for lymphatic malformations at our institution during a 10-year period (1998-2008) was performed. DATA COLLECTED: age at diagnosis, location and type of lesion, radiologic investigation performed, presenting symptoms, treatment modality used, complications and results achieved. RESULTS: 14 patients were identified. Eight (57%) male and six (43%) female. There was an equal distribution between the left and right sides. The majority (71%) of cases were diagnosed within the first year of life. The majority of lesions were located in the suprahyoid region. The predominant reason for referral was an asymptomatic mass in 7 cases (50%) followed by airway compromise (36%) and dysphagia (14%). Management options employed included: observation, OK-432 injection, surgical excision and laser therapy. In 5 cases (36%) a combination of these were used. CONCLUSION: Historically surgical excision has been the management option of choice for lymphatic malformations. However due to the morbidity and high complication rate associated this is increasingly being questioned. Recent advances in sclerotherapy e.g. OK-432 injection have also shown significant promise. Based on experience in managing these lesions as well as current literature the authors of this paper have developed an algorithm for the management of cervicofacial lymphatic malformations.