The treatment of microcystic and combined lymphangiomas, especially in the head and neck region, is still a challenge because the lymphangiomas do not respond to conventional therapies and their recurrence rate is high, regardless of the treatment choice. Complete surgical resection is the main treatment of lymphangiomas, but because of localization perioperative complications, such as bleeding, neural damage and airway obstruction are common disadvantages of this method. Bleomycin-based sclerotherapy is another common therapeutic approach, in which the lymphocysts are aspirated, and 25% to 50% of their volumes are replaced with a sclerotisant drug. This is an effective treatment in cases in which the vessels are large enough for an intravascular or intracystic injection, but because of the small size of vessels and cysts, the microcystic and combined lymphangiomas are not suitable for sclerotherapy. Delivery of drugs for treating sclerosis to endothelial cells can be achieved by electroporation (electrochemotherapy), even for capillary malformations. A congenital, rapidly growing combined lymphangioma of the left cervicofacial region was treated with one session of bleomycin-based electrochemotherapy. Seven months after treatment, the growth-corrected target volume decrease was 63% and the dislocation of the trachea and blood vessels previously observed had ceased. We suggest that bleomycin-based electrochemotherapy is a feasible alternative treatment option for capillary malformations.
Lymphangiomas are rare, benign, congenital malformations of lymphatic vessels. The incidence of lymphangiomas is reported to be from 1.2 to 2.8 per 1000 newborns.1 The most common localization of lymphangiomas is the cervicofacial region (95%), where vital structures can be compressed and infiltrated.1 Spontaneous regression is not probable for microcystic (0%) and combined types (2%) of lymphangiomas,2 and these types exhibit a high recurrence and complication rate, such as hemorrhage (15%) or infection (27%), which can cause sudden enlargement, airway obstruction, or death.2,3 Complete surgical resection is the best treatment of lymphangiomas, but in lesions infiltrating main blood vessels, complete resection is not possible, and it may result in serious complications.4–6 Bleomycin-based sclerotherapy is an effective treatment of lymphangiomas in cases in which the vessels are large enough for an intravascular or intracystic injection. This therapy is not suitable for microcystic and combined lymphangiomas because of the small size of the vessels and cysts.
During reversible electroporation, the application of short-term, high-intensity electric pulses induces transient permeabilization of cell membranes, which enables the delivery of large hydrophilic molecules, such as bleomycin, to the cytosol. The combination of reversible electroporation and intratumoral bleomycin injection (referred to as bleomycin-based electrochemotherapy or electrosclerotherapy) facilitates drug delivery to endothelial cells, resulting in sclerosis of the vessels and cyst and, eventually, the regression of the lesion.
Representative Case Report
A congenital, rapidly growing soft-tissue mass was observed on the left side of the neck and cheek of a term infant boy. MRI revealed a prominent, heterogeneous, lobulated, multicystic mass. The trachea, left jugular vein, and common carotid artery were dislocated and compressed (Fig 1 A–C). The T1-weighted, contrast-enhanced magnetic resonance (MR) images revealed 1 large, high-lipid cyst (2 × 2 cm) at the level of the thyroid cartilage (Fig 1 A and B). The whole lesion volume was calculated by manual contouring and found to be 72.32 cm3. Because of the location of the tumor and the small size of the vessels, neither complete resection by surgery nor traditional bleomycin sclerotherapy was suitable. Because of the rapid growth of the tumor, which could increase the risk of airway obstruction, ischemia, and feeding difficulties, our multidisciplinary board decided to perform electrochemotherapy on the mixed lymphangioma. Transmucosal application of electrode application to avoid scarring was ruled out because of the high risk of mucosal swelling with consequential airway obstruction, considerable postoperative pain,7 and feeding problems.8
The first electrochemotherapy session was performed when the child was 4 months old, according to the European Standard Operating Procedures of Electrochemotherapy (ESOPE) criteria.9,10 The treatment was conducted under general anesthesia by using intratumoral injection of bleomycin (1000 IU/mL). Because this is a first case of using electrochemotherapy in a child with a lymphangioma, no guideline exists about the bleomycin dosage. In lymphangiomas, the advised dose of bleomycin is 0.3 to 0.5 mg/kg for sclerotherapy. In our case, 0.5 mg/kg was calculated and used for the treatment according to the weight of the infant and information from the drug database of the National Institute of Pharmacy and Nutrition11 (5.4 mg = 8100 IU, which is equivalent to 0.5 mg/kg). According to the ESOPE guideline, the intratumoral bleomycin dose would have been 18 000 IU on the basis of the tumor volume9 ; namely, a reduced dose of bleomycin was used in our case. The ESOPE guideline was developed for cancer treatment in adults.9 It should be noted that Groselj et al12 presented recently that the antitumor effectiveness of electrochemotherapy is comparable when using a standard or reduced bleomycin dose.
Electrochemotherapy was performed by using a Cliniporator electric pulse generator (IGEA, s.r.l., Carpi, Italy) and row needle electrodes.9,13 With every application, 8 consecutive pulses with a duration of 100 microseconds and a voltage-to-electrode distance ratio of 1000 V/cm were used for electroporation. During the first session of electrochemotherapy, 68 applications were performed to cover the whole lesion by the electric field. The average current was 5.27 A (2–14 A). Only 1 cyst (>2 cm) was aspirated, and the standard method (sclerotherapy) was used. During treatment, a biopsy was taken for a histopathological examination, which was used to confirm the diagnosis of lymphangioma. Eight months after the first electrosclerotherapy session, a second session was performed with the same technique under intraoperative ultrasonography guidance. In this session, the anterior triangle was treated close to the main vessels. During the second session of electrochemotherapy, 74 applications were performed; the average current was 5.55 A (2–13 A). Follow-up included visits with the patient on a weekly basis in the first month and, after the first 3 months, every fourth week. During routine checkups, the general state of health, the mental and physical development of the child, the size and density of the lesion, and skin scars were examined. The patient’s parents gave their written informed consent before treatments.
Therapeutic Response Evaluation
To follow the therapeutic response, imaging evaluations were performed before treatment, 7 months after the first electrochemotherapy session, and 5 months after the second electrochemotherapy session. The lesion volume in units of cubic centimeters was manually determined from T2-weighted MR slices. To evaluate objectively the therapeutic response, we corrected the absolute target volume reduction according to the growth of the infant. To measure the growth rate of the infant, the contralateral healthy parotid gland volume was determined by manual delineation in both time points.
Despite prominent postoperative edema, the treatment was well tolerated by the patient, and breastfeeding was constant. In this case, no perioperative complications were experienced. One and 2 months after treatment, erysipelas evolved on the cheek and was resolved with antibiotic therapy. During subsequent visits, a constant decrease in the volume of the lymphangioma was observed. Five months after the first electrochemotherapy, a distinct decrease in the tumor volume was revealed with physical examination (Fig 2). Seven months after the first electrochemotherapy treatment, a significant decrease of the multicystic mass and, most importantly, the restoration of the dislocated trachea and compressed vessels were indicated in MR images (Fig 1D). The volume of the cystic mass was reduced to 48.09 cm3 from 72.32 cm3. The absolute target volume decrease was 33.5%. The normal right parotid gland growth was from 3.40 to 6.08 cm3; therefore, a 78.8% physiologic growth rate of the parotid and the child was determined. On the basis of that calculation, a 63% growth-corrected target volume decrease was achieved. To prevent the potential progression of the untreated area, a second treatment was performed 8 months after the first session of electrochemotherapy. One year after the first session, the symmetry of the face was completely restored (Fig 2). After 17 months’ follow-up, no recurrence was observed. The mental and physical development of the child remained age appropriate. Small skin scars and slight hyperpigmentation caused by the application of the electrodes remained visible on the treated area.
Electrochemotherapy is a commonly used local treatment of cutaneous metastases and primary skin cancer of any histology.14–16 In several recently published reports, treatment of benign vascular malformations with bleomycin-based electrochemotherapy is described. McMorrow et al17 reported a case in which a venous malformation was managed successfully with intratumoral delivery of bleomycin by using electrochemotherapy and referred to the procedure as bleomycin-based electrosclerotherapy. Endothelial cells are valid targets for electroporation, especially for vessels with diameters <5 mm.18 Therefore, electrochemotherapy, which is the combination of electroporation delivery of intratumoral bleomycin, facilitates drug delivery to endothelial cells even in microcystic cases, which leads to sclerosis of the vessels and cyst and regression of the tumor (Fig 3).19 Moreover, electric pulses have an important immediate vascular effect that reduces blood flow transiently and prevents washout of the drug.18 In case of benign vascular lesions, the aim of electrochemotherapy is to enhance the sclerosing effect.20 In our case, the growth-corrected target volume decrease was 63% after one session of electrochemotherapy. This response was considered to be good, taking into account that the lesion was benign, and, accordingly, complete eradication was not necessary. Our major goal, to restore the position of the trachea and vessels, was achieved. The symmetry of the face was also restored, which is important for the social development of the child.
In our case, bleomycin-based electrochemotherapy proved to be safe and effective in the treatment of a combined lymphangioma. Bleomycin-based electrochemotherapy should be considered as a feasible alternative treatment option for microcystic and combined lymphangiomas for infants. Because this is the first use of bleomycin electrosclerotherapy in the management of capillary lymphangiomas in an infant, further studies are needed concerning the efficacy and safety of the method.
The authors wish to thank otolaryngologist Dr Vass Gábor for his highly capable assistance during the surgery.
Ms Dalmády conceptualized the treatment, drafted the initial manuscript, and reviewed and revised the manuscript; Ms Csoma and Ms Bottyán managed and controlled the patient as dermatologists, revised the results, and reviewed and revised the manuscript; Ms Besenyi valued the results, designed the radiologic imaging, and reviewed and revised the manuscript; Ms Oláh managed the patient as an oncologist, coordinated and supervised the treatment, designed the interpretation of the results, revised the results, and reviewed and revised the manuscript; Mr Kemény coordinated and supervised the treatment, analyzed and revised the results, critically reviewed the manuscript for important intellectual content, and revised the final version of the article; Ms Kis designed the treatment and the evaluation of the results, performed the surgery as a plastic surgeon, expert of electrochemotherapy, and head of the Hungarian electrochemotherapy team, critically reviewed the manuscript for important intellectual content, and revised and modified the final version of the article; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: Funded by grant GINOP-2.3.2-15-2016-00015 (Ms Kemény), grant EFOP-3.6.1-162016-00008 (Ms Csoma), and the János Bolyai Research Scholarship from the Hungarian Academy of Sciences (Ms Csoma).
European Standard Operating Procedures of Electrochemotherapy
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.