Neoadjuvant Everolimus for Adult Giant Mesenteric Cystic Lymphangioma with mTOR Pathway Activation.

Cystic lymphangioma are rare benign vascular or lymphatic tumors, diagnosed mostly in newborns or children, that may become life-threatening because of local invasiveness. Surgical "en-bloc" resection with negative margins is the only curative treatment, but some patients are diagnosed with unresectable tumors. We describe the case of a young adult with giant unresectable mesenteric lymphangioma. Extensive pathological characterization as well as whole exome and transcriptome sequencing enabled us to identify mTOR pathway activation within endothelial tumor cells. The patient was treated with everolimus and experienced major partial response, leading to the surgical resection of the residual lesions. This case highlights the importance of molecular characterization of adult cystic lymphangioma for mTOR pathway activation because multidisciplinary therapeutic approaches, including neoadjuvant everolimus and secondary surgery, can lead to complete cure of this rare condition. KEY POINTS: The case of an adult patient diagnosed with giant unresectable mesenteric cystic lymphangioma, in which activation of the mTOR pathway was documented at both the pathological and transcriptomic levels, is reported. This patient showed major partial response to the mTOR inhibitor everolimus, which led to the successful resection of residual tumor lesions after 9 months of treatment. This report shows that mTOR targeting should be considered as neoadjuvant treatment in adult large cystic lymphangioma, as it can lead to complete surgery and cure of this rare condition.

The use of sirolimus in the treatment of giant cystic lymphangioma: Four case reports and update of medical therapy.

RATIONALE: Lymphatic malformations (LMs) are rare and benign anomalies resulting from the defective embryological development of the primordial lymphatic structures. Due to their permeative growth throughout all tissue layers, treatment is often challenging. Small asymptomatic lesions can be conservatively managed, while symptomatic lesions require active management. Surgery has been historically considered the treatment of choice, but today less invasive therapeutic options are preferred (sclerotherapy, laser therapy, oral medications). However, there are not uniform therapeutic protocols. Sirolimus is an oral medication that has been reported to be effective in the recent literature. Here we present the case of 4 newborns with giant multicystic lymphangioma treated with oral sirolimus after surgical resection had failed. PATIENT CONCERNS: At birth the LMs were clinically appreciated as giant masses involving different organs and structures. DIAGNOSES: All patients had a prenatal diagnosis of giant multicystic lymphangioma confirmed at histological and cytological analysis. INTERVENTIONS: Patients were treated with oral sirolimus after unsuccessful surgical resection. OUTCOMES: In all patients, sirolimus determined an overall reduction of the mass and a global involution from the macro- to the microcystic composition. Sirolimus was safe and poor disadvantages had been observed. The main and isolated adverse effect at laboratory analysis was progressive dyslipidemia, with increasing levels of total cholesterol and triglycerides. LESSONS: To date, our experience with sirolimus in the management of LMs is favorable. We recommend the use of sirolimus after unsuccessful surgical excision have been tried or when the surgical approach is not feasible. A multidisciplinary follow-up is needed to monitor disease evolution.

Intralesional Injection of OK-432 in Cystic Hygroma.

BACKGROUND: Lymphangiomas are congenital malformations of the lymphatic system with characteristic dilated endothelium-lined spaces. It is vulnerability to infection or chemical irritants cause spontaneous reduction in size and in some cases complete resolution. Intralesional injection of OK-432 or Picibanil (lyophilized incubation mixture of Group A Streptococcus pyogenes of human origin) is slowly gaining recognition as its safety and efficacy standards have shown to avoid complications resulting from surgical interventions. The objective of this study was to evaluate the clinical outcomes of cystic hygroma patients who received OK-432 injections. METHODS: In between 2011 and 2013, six patients with cystic hygroma received intralesional injection of OK-432. All the patients were assessed clinically and radiologically either via ultrasound, computer tomography (CT) or magnetic resonant imaging (MRI) prior to and after receiving the injections. Patients' response towards treatment was classified as total shrinkage, marked shrinkage (greater than 50% reduction in size), slight shrinkage (less than 50% reduction in size) or non-responsive to treatment. RESULTS: Mean duration of follow-up was 12 months. Total shrinkage was achieved in one patient, marked shrinkage in three patients and one patient experienced mild shrinkage. Only one out of the six patients showed no response to treatment. None of the patients in this study experienced serious complications or adverse effects post intralesional injection of OK-432. CONCLUSIONS: Intralesional OK-432 injection is an effective and safe alternative in treating cystic hygroma.

Spontaneous resolution of a recurrent axillary cystic hygroma following acute infection.

We report a case of spontaneous resolution of a recurrent axillary cystic hygroma in a 4-year-old boy. He presented with a 1-year history of a cystic lump in the left axilla, which intermittently changed in size. Ultrasound suggested it was a lipoma, with raised suspicions of vascular malformation. Scans were discussed in a multidisciplinary meeting and provisional diagnosis of lymphocele or slow flow lymphovascular malformation was made. It was surgically excised and histology confirmed the lesion to be a cystic hygroma. However, it recurred within 3 weeks. The patient was booked for aspiration and treatment with sclerotic agent OK 432. He developed acute infection in the cystic hygroma a week before surgical intervention and was treated with antibiotics for 5 days by his general practitioner. Acute infection led to complete spontaneous resolution of the cystic hygroma within a week. There are no other reported cases in which recurrent cystic hygroma has resolved after a week of acute infection.

Sildenafil in Cystic Hygroma.

Cystic hygroma is a benign congenital malformation of the lymphatic system. Most of the cystic hygromas are found in the neck; other rare locations include axilla, mediastinum, and limbs. Symptoms range from mere presence of lesions to gross morbidity secondary to compression of adjacent organs, infection, hemorrhage etc. Treatment is primarily aimed at complete surgical resection. Other treatment modalities include sclerotherapy, radiotherapy and laser ablation as well as medical therapy with sirolimus but recurrence rate is high. We present a neonate with right sided cystic hygroma whose lesion settled completely with sildenafil.

Total clinical regression of an orbital macrocystic lymphatic malformation following intralesional sodium tetradecyl sulphate injection.

Lymphatic malformations are usually managed by observation, although significant cosmetic abnormalities, compressive optic neuropathy, risk of amblyopia, exposure keratopathy, or elevated intraocular pressure mandate treatment. We report the case of a 10-year-old boy with a deep orbital macrocystic lymphatic malformation that was successfully treated with intralesional injection of sodium tetradecyl sulphate, a sclerozing agent mainly used in the treatment of small varicose veins in the lower extremity.

Retiform hemangioendothelioma developed on the site of an earlier cystic lymphangioma in a six-year-old girl.

Retiform hemangioendothelioma (RH) is a rare low-grade malignancy angiosarcoma, with a high rate of local recurrence and a low metastatic risk. A 6 year-old girl with a large cervical cystic lymphangioma diagnosed by ultrasound and Doppler ultrasound, which showed a large multiloculated anechoic cyst with no flow. The lymphangioma was treated with injections of Picibanil (OK-432). The tumor regressed, but after a year, she developed a poorly limited infiltrated plaque spreading out regularly over her chest, back, and shoulder. The biopsy showed a poorly limited dermal and subcutaneous vascular proliferation composed of elongated arborising vessels lined with ovoid endothelial cells in a hobnail pattern. In addition, the deep part of the lesion showed typical features of a papillary intralymphatic angioendothelioma pattern (PILA) or Dabska tumor. The endothelial cells strongly expressed podoplanin (D2-40). A diagnosis of RH with focal areas of PILA was reached. The girl died 8 months after surgery of hypovolemic shock in a context of diffuse lymphangiomatosis with pulmonary localization. To our knowledge, RH has hardly ever been described in children. This entity exhibits a continuum with the PILA, sharing not only morphological and immunohistochemical similarities but also its ability to develop in a context of a vascular anomaly, particularly a lymphangioma. The role of Picibanil in the development of this tumor can be discussed.

[Severe iatrogenic airway obstruction due to lingual lymphangioma]. / Obstruction iatrogène sévère de la voie aérienne par un lymphangiome lingual.

Lymphangioma of the tongue is a rare and benign tumour involving congenital and cystic abnormalities derived from lymphatic vessels. Treatment modalities include surgery and a large number of different intralesional injections of sclerosing agents. Presently, OK-432 (Picibanil(®)) is the preferred sclerosant and when administered intralesionally will result in inflammation, sclerosis, and cicatricial contraction of the lesion. We report a case of microcystic lymphangioma of the tongue in a 5-year-old boy treated with an intralesional injection of OK-432. In the immediate postoperative period, the patient suffered severe diffuse swelling, progressive upper airway obstruction with inspiratory stridor, and respiratory distress requiring emergency fiberoptic nasotracheal intubation. Although OK-432 injections are found to be safe and effective as a first line of treatment for lymphangiomas, local swelling with potentially life-threatening airway compromise should be anticipated, especially when treating lesions near the upper airway.

Intralesional bleomycin injection treatment for vascular birthmarks: a 5-year experience at a single United Kingdom unit.

BACKGROUND: The authors present their experience using an established chemotherapeutic agent as a scarless treatment for vascular birthmarks. One hundred sixty-four of more than 600 patients seen in the authors' center received intralesional bleomycin injection over 5 years. METHODS: Patient demographics, clinical response, treatment, and complication details were recorded prospectively. Respiratory surveillance was provided by adult and pediatric pulmonologists. Eighty-one venous malformations, 39 hemangiomas, 26 lymphatic malformations, 10 mixed malformations, two arteriovenous malformations, two cystic hygromas, two capillary malformations, and two angiokeratomas underwent intralesional bleomycin injection. RESULTS: The authors observed that 45.7 percent of patients completed treatment in a mean of 3.8 sessions and mean duration of 107 days. Complete resolution occurred in 56.0 percent, with a 93.3 percent overall response rate, and 82.7 percent of lesions demonstrated complete response or significant improvement. Three patients developed transient skin hyperpigmentation. One patient each developed skin ulceration, blistering, infection, swelling, headache, bruising, and rash. One patient required intubation following treatment of a panfacial and thoracic lymphatic malformation. A full recovery ensued. No patients developed pulmonary fibrosis. One venous malformation recurred. CONCLUSIONS: The authors' single-site multidisciplinary team has successfully treated complex and recurrent vascular anomalies with acceptable complication and recurrence profiles. These findings represent the authors' experience and provide a reference for the management of these challenging lesions.

Effects and mechanism of OK-432 therapy in various neck cystic lesions.

CONCLUSION: Our results confirmed that OK-432 therapy is simple, easy, safe, and effective and can be used as a substitute for surgery in the treatment of benign neck cysts. In OK-432 therapy, inflammatory cytokines may play important roles in shrinkage of the cystic spaces. OBJECTIVE: The aim of this study was to evaluate the outcome and mechanism of action of OK-432 therapy in benign neck cysts. METHODS: We tried OK-432 therapy in 83 patients with benign neck cysts between April 1997 and August 2009. We aspirated as much of the fluid content of each cystic lesion as possible, and then replaced the volume of aspirated fluid with about half the volume of OK-432 solution. We evaluated the mechanism of action of OK-432 in 43 of the patients. The intracystic fluid in the cysts was aspirated before and after OK-432 therapy, and cytokine production in each aspirate was analyzed by ELISA. RESULTS: Disappearance of the lesion was observed in 63 of 83 patients (76%). Marked reduction was observed in 13 of the 83 patients (16%). Partial reduction was observed in two patients (2%) and no response was seen in five (6%). Local discomfort at the injection site and low-grade fever were side effects observed in half of the patients, but such problems resolved within a few days. No local scarring or deformity of the injected sites occurred in any patient. We performed OK-432 therapy on an outpatient basis without hospitalization. Levels of various cytokines, including tumor necrosis factor, interleukin-8, interleukin-6, interferon gamma, and vascular endothelial growth factor, were significantly elevated in each aspirate after OK-42 therapy.

Treatment of cystic hygroma by intralesional bleomycin injection: experience in 70 patients.

BACKGROUND/AIM: Cystic hygroma is a congenital malformation of the lymphatic system. Surgical excision is the treatment of choice, but injection of a sclerosing agent into the cyst is an alternative procedure. The aim of this study was to review the results after cystic hygroma treatment using intralesional bleomycin injection over a 16-year period at a tertiary hospital for pediatric patients in Thailand. MATERIALS AND METHODS: Medical records of patients with cystic hygroma treated by intralesional bleomycin injection between 1992 and 2007 were reviewed. Bleomycin at dosages of 0.3-0.6 mg/kg was injected into the cysts and repeated injections were performed at an interval of 2-6 weeks. Clinical outcomes were reviewed and analyzed. RESULTS: Seventy patients, 42 males and 28 females aged between one month and 14 years were treated with intralesional bleomycin injections. An excellent response (complete clinical resolution) was obtained in 33 cases (47.1%). A good response (partial reduction >50% of the mass) was achieved in 25 cases (35.8%). A poor result (no clinical response or mass reduction <50%) was noted in (17.1%). Adverse reactions including fever, local swelling, redness and pain at the site of injection occurred in 30 cases (42.9%). These reactions persisted for only a few days. Three cases died. Two girls in the poor results group died from pneumonia, respiratory failure and septicemia after bleomycin injection and partial surgical removal. The third one in the excellent results group developed thyroid carcinoma with metastasis at the opposite side to the first cystic hygroma. She died at another hospital from intracarotid artery injury with uncontrolled bleeding during left radical neck dissection. CONCLUSION: Intralesional bleomycin injection is useful for the treatment of cystic hygroma. It should be used in patients with large cystic masses and extensive invasion to reduce the risk of injury to vital organs.

Palmar and flagellate hyperpigmentation following low dose intralesional injection of bleomycin for cystic hygroma.

A 1(1/2)-year-old boy developed hyperpigmentation of the palms and feet along with flagellate pigmentation over the trunk following intralesional injection of bleomycin for cystic hygroma. We present this case to highlight the possibility of cutaneous pigmentation being induced by bleomycin in low doses through non-intravenous administration.

[Treatment of lymphangiomas with picibanil in the first year of life]. / Behandlung von Lymphangiomen mit Picibanil im ersten Lebensjahr.

BACKGROUND: The therapeutic gold standard of cystic hygroma is its complete resection. Because of its growth pattern and its main location in the head and neck region complete resection is not always possible. An alternative is the local injection of Picibanil, but only few cases have been published about its use in infants. PATIENTS/METHOD: We retrospectively analyzed the data of 8 infants (age: 2 weeks-12 months) who got Picibanil therapy because of cystic hygroma in the time period 2002 until 2006. Follow up ranged from 3 months up to 3 years. RESULTS: During the postoperative period all patients had local swelling, in 4 cases accompanied with local inflammation and fever. Tumor reduction of >50% was obtained in 7 of 8 patients. CONCLUSIONS: Local injection of Picibanil in infants with cystic hygroma seems to be a safe alternative to surgical therapy, especially when complete tumor resection means damage of important neighbouring structures. Prospective trials are necessary to confirm the better outcome after therapy with Picibanil compare to primary surgery.