- Email: [email protected]
Symptom Resolution and Volumetric Reduction of Abdominal Lymphatic Malformations With Sclerotherapy
j o u r n a l o f s u r g i c a l r e s e a r c h j a n u a r y 2 0 1 9 ( 2 3 3 ) 2 5 6 e2 6 1
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Association for Academic Surgery
Symptom resolution and volumetric reduction of abdominal lymphatic malformations with sclerotherapy Helen J. Madsen, MD,a,b,c,* Aparna Annam, DO,b,c,d Roger Harned, MD,b,c,d Taizo A. Nakano, MD, LO,b,c,e Lauren O. Larroque, RN, BSN, CPN,a,b and Ann M. Kulungowski, MDa,b,c a
Division of Pediatric Surgery, Children’s Hospital Colorado, Aurora, Colorado Division of Pediatric Surgery, Children’s Hospital Colorado, Vascular Anomalies Center, Aurora, Colorado c Division of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado d Department of Radiology, Children’s Hospital Colorado, Interventional Radiology, Aurora, Colorado e Department of Oncology, Children’s Hospital Colorado, Center for Cancer and Blood Disorders, Aurora, Colorado b
article info
abstract
Article history:
Background: Lymphatic malformations (LMs) are congenital and arise from errors in
Received 2 March 2018
vascular embryogenesis. LMs are categorized by cyst size as microcystic, macrocystic, or
Received in revised form
combined. Abdominal LMs are rare. Surgical resection of abdominal LMs has been the
20 June 2018
mainstay of therapy, but recurrence and morbidity are high. We sought to determine the
Accepted 11 July 2018
effectiveness of sclerotherapy treatment for abdominal LM.
Available online xxx
Methods: A single-center, retrospective review from 2014 to 2018 was conducted evaluating pediatric patients with abdominal LM.
Keywords:
Results: Ten patients were included, n ¼ 9 had macrocystic LM and one patient had combined
Abdominal
disease. The average age at first treatment was 6.8 y. The most common presenting symptoms
Lymphatic malformation
were abdominal distention, pain, infection, and anemia. Preprocedural imaging was per-
Lymphangioma
formed for all patients; median pretreatment volume was 1572.9 cm3 (range, 67.2-13,226.4).
Sclerotherapy
LMs were accessed using ultrasound guidance and injected with opacified doxycycline. Pa-
Doxycycline
tients received a mean of 7.1 sclerotherapy injections. Complications included intraperitoneal
Pediatric
doxycycline extravasation (n ¼ 1), managed conservatively, and LM infection (n ¼ 1), treated with intravenous antibiotics and drainage. One patient went on to surgical resection due to inability gain stable intracystic access; follow-up ultrasonography showed no recurrence. Postprocedural imaging was available in n ¼ 8. Volume decreased by 96.7% after sclerotherapy. The median remaining volume was 0 cm3 (range, 0-599.7) (P ¼ 0.016). Postsclerotherapy magnetic resonance imaging was obtained in n ¼ 6, with complete resolution in 83.3%. All patients had resolution of presenting symptoms. Follow-up duration was 12.3 mo. Conclusions: Initial results demonstrate that sclerotherapy is an effective and durable treatment for symptom resolution and volume reduction of abdominal LM. ª 2018 Elsevier Inc. All rights reserved.
* Corresponding author. University of Colorado School of Medicine, 13001 E 17th Place, Aurora, CO 80045, USA. Tel.: þ1720 979 5779; fax: þ1 303 724 2761. E-mail address: [email protected] (H.J. Madsen). 0022-4804/$ e see front matter ª 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2018.07.031
madsen et al sclerotherapy for lymphatic malformation
Introduction Pediatric lymphatic malformations (LMs) are congenital vascular anomalies that arise due to errors during vascular embryogenesis.1-4 LMs are rare with a prevalence of 1 in 20,000 children.5 The most common location for an LM is the head and neck, with only 10% occurring in the abdomen.2,5 Cystic LMs are categorized by the size of their lymphatic channels as either macrocystic, microcystic, or combined. In general, macrocystic LMs are those which can be accessed by a hypodermic needle and undergo visible decompression; however, the microcystic form comprises numerous small cysts that are difficult to enter with a needle. Combined LMs contain both macrocysts and microcysts.2 LMs can spontaneously regress, but this is the exception as most persist and can enlarge over time.1,2 Abdominal LMs typically present with vague abdominal complaints of pain and distention. They can also present acutely with vomiting, peritonitis, intestinal obstruction, or intestinal necrosis.6,7 Additional complications of intraabdominal LMs include anemia due to intracystic bleeding, sepsis due to bacterial translocation, and/or inability to empty dilated lymphatic channels, and chylous ascites.2 Historically, the first-line treatment for problematic LMs has been surgical resection.3,6,8-12 Regardless of location, LMs tend to be infiltrative, involve vital structures, and are poorly demarcated.3,13 Complete excision is difficult and can require staged interventions. Surgical principals for LM include limiting the resection to a defined anatomic area, performing as complete a resection as possible, preserving vital structures, and minimizing blood loss. Prolonged closed suction drainage is often needed for large resections involving soft tissues. Resection of intra-abdominal or mesenteric LM can require segmental bowel resection; consideration of postsurgical enteral length is essential.8,14,15 Expectant management of an abdominal LM is a viable option in some instances in an effort to avoid anesthesia in very young infants; however, treatment is preferred over observation to avoid the aforementioned complications.1,5 Sclerotherapy has become an important mainstay and alternative to surgical resection for the treatment of macrocystic lymphatic malformation.2,13,16-21 Sclerotherapy involves aspiration and subsequent injection of a sclerosant that causes scarring of cyst walls to one another. We sought to add to the collective experience for the treatment of abdominal lymphatic malformation with doxycycline, as the body of literature supporting this treatment remains sparse.11,15,18,19,22,23
Methods Study population After approval by the institutional review board with a waiver of consent, a retrospective review was conducted evaluating patients with macrocystic lymphatic malformation treated with doxycycline sclerotherapy from 2012 to 2018. The clinical records and imaging for presclerotherapy and postsclerotherapy treatment were reviewed for age, gender,
257
radiographic imaging, sclerotherapy intervention, hospital admissions, and follow-up information. Diagnosis of LM and classification of cyst size was based on magnetic resonance imaging (MRI) characteristics. Dimensions were calculated using width, height, and length at time of diagnosis. Follow-up data included imaging to determine presence and size of the LMs. Subjective data regarding symptom resolution was obtained from patients and families.
Technique Preprocedural MRI was used to plan the sclerotherapy intervention. Sclerotherapy was performed by an experienced interventional radiologist. General anesthesia was administered in all cases. For the initial treatment, ultrasound guidance was used to access the macrocysts with a needle. Under fluoroscopic guidance the needle was exchanged for a pigtail catheter. Cysts were aspirated and opacified doxycycline was injected via the pigtail catheters at a concentration of 10 mg/ mL. Volume injected was equal to the aspirated volume of each macrocyst, up to a typical maximum of 1000 mg per treatment. Each catheter was clamped for 8 h and left to gravity drainage after this 8 h period. The patients returned to interventional radiology for subsequent injections of sclerosant through the existing catheter during the same cycle. After a median of three sclerotherapy injections, the catheter was removed. The next cycle was initiated after 4-8 wk if imaging demonstrated the presence of continued macrocysts, or if the patient experienced a complication or increase in symptoms.
Statistical analysis Wilcoxon matched pairs signed-rank test was used to determine if the difference between pre- and post-treatment volume was significant. The difference was considered significant when P < 0.05. Calculations were performed in GraphPad Prism 7.0 (GraphPad Software Inc, La Jolla, California).
Results Ten patients underwent sclerotherapy as the primary treatment of their abdominal LM. Diagnosis for all patients was based on pretreatment imaging, MRI was used in n ¼ 9 and CT was used in n ¼ 1. One patient was diagnosed prenatally with ultrasonography and confirmed with postnatal MRI. Average age at diagnosis was 6.8 y (range, 0-17 y). Nine patients were male. Common presenting symptoms were abdominal distention (n ¼ 5), abdominal pain (n ¼ 5), infection (n ¼ 2), and anemia (n ¼ 1). Macrcocystic LM was identified in nine patients; one patient had a combined LM. Patient characteristics, LM type, and symptoms are presented in (Table 1). Nine patients were treated solely with sclerotherapy. Sclerotherapy was unable to be performed in one patient due to inability to achieve a stable intracystic location after two distinct, failed attempts. This patient underwent resection of the mesenteric LM with a 5 cm segmental small intestinal
258
j o u r n a l o f s u r g i c a l r e s e a r c h j a n u a r y 2 0 1 9 ( 2 3 3 ) 2 5 6 e2 6 1
Table 1 e Patient demographics. Patient
Age (y)
Gender
Presenting symptom(s)
LM classification Macrocystic
1
13
Male
Abdominal pain, nausea/vomiting
2
11
Male
Abdominal pain, infection
Combined
3
3
Male
Abdominal distention
Macrocystic
4
17
Male
Abdominal pain and distention
Macrocystic
5
2
Female
Abdominal pain & distention, constipation, decreased appetite
Macrocystic
6
0
Male
Prenatal imaging
Macrocystic
7
7
Male
Abdominal pain, infection
Macrocystic
8
1.4
Male
Abdominal distention, constipation, anemia, poor feeding
Macrocystic
9
1.25
Male
Abdominal distention
Macrocystic
Male
Incidental finding
Macrocystic
10
12
resection and primary anastomosis. The patient was discharged on postoperative day 3 on a regular diet. A variable number of sclerotherapy injections were performed on each patient, with a range of 2-16 (average, 7.1 injections). The cumulative total dose of doxycycline was on average 5577 mg (range 370-17,900 mg). Details of the sclerotherapy treatment course are presented in (Table 2), (Fig. 1). Successive sclerotherapy injections were performed via existing indwelling pigtail catheters for a median of three injections (range, 1-7) per cycle. Postprocedural imaging was available in 80% (8/10) of patients. All patients (in whom imaging was available posttreatment) experienced LM volume reduction. The LM locations were abdominal (n ¼ 6) and mesenteric (n ¼ 4). The median pretreatment volume was 1572.9 cm3 (range, 67.213,226.4) and the median remaining volume was 0 cm3 (range, 0-599.7), (P ¼ 0.016). Statistical analysis excluded patients 2, 3 (follow-up imaging pending), and patient 6 (surgical resection). Ultrasonography was performed for patient 6 showing complete resolution after surgical resection. Notably, three
patients (patient 3, 4, and 10) have not yet completed their sclerotherapy courses. These patients are doing clinically well but have evidence of residual LM on ultrasound imaging that is amenable to sclerotherapy and will continue to undergo sclerotherapy treatment. Patient 2 has not followed up for postsclerotherapy imaging, so need for further treatment versus resolution of the LM is not able to be determined. Volumetric details are presented in (Table 3), (Fig. 2). Complications during sclerotherapy included intraperitoneal extravasation of doxycycline (n ¼ 1), which was treated conservatively, and infection of the LM (n ¼ 1), treated with intravenous antibiotics successfully. Patients were followed up in clinic for symptom monitoring from the date of first treatment for a median of 376.5 d (range, 38-612). Follow-up imaging was available in 8 of 10 patients and was performed an average of 402 d (range, 71-819) from the first treatment.
Discussion
Table 2 e Details on sclerotherapy treatment course. Patient
Number of sclerotherapy injections
Total dosage of doxycycline (mg)
1
11
2
2
6200 370
3
9*
5900
4
13*
18,400
5
6
4800
6 (surgery)
2y
7
4
2200
8
16
12,100
9
3
0
1700
10
4
*
4000
Average
7.1
5577
*
Sclerotherapy treatment ongoing. y Failed sclerotherapy attempts.
Historically, the treatment of LM was surgical. In recent years, sclerotherapy has become the mainstay of treatment for macrocystic lesions. Sclerotherapy is favored over surgical resection due to greater effectiveness and lower morbidity.16,24 Sclerotherapy preserves vital structures such as intestines, nerves, arteries, and veins. Incomplete surgical resection or debulking procedures result in re-expansion or “recurrence.” The perceived “recurrence” is due to growth and expansion of affected lymphatics in the remaining, seemingly normal appearing tissue.10 Partial resection has “recurrence” rates approaching 100%. Complete surgical excision is difficult as resection is limited to macroscopically visibly affected tissue; recurrence as high as 27% is documented in cases of complete excision.9,25 Surgery also is morbid and complication rates as high as 33% have been reported.9 Common complications include bleeding, infection, and damage to neurovascular structures.2,9,12 Prolonged closed suction drains are often needed in the resection bed due to lymphatic leakage and for seroma prevention, adding to postoperative pain. Surgically resected abdominal LM can result in chylous
madsen et al sclerotherapy for lymphatic malformation
259
Fig. 1 e Sclerotherapy technique performed by interventional radiology. (A) Injection of contrast through needle to ensure position in cyst before placement of pigtail catheter. (B) Injection of sclerosant with Isovue through existing catheters.
ascites due to transected lymphatics, resulting in patient morbidity and mortality.26 The success of sclerotherapy for LM in the literature is largely based on case report studies conducted on craniofacial LM, necessitating extrapolation of data for abdominal LMs.16,24,27-29 This study adds to a sparse body of literature, as just two other studies have focused on abdominal LM treated with doxycycline sclerotherapy.18,19 Our study finds sclerotherapy to be effective, with significant LM volume reduction. We report complete resolution rate of the macrocystic LM in 83% of cases. The symptom resolution was observed in 100% of our patient with durability of about a year. To date, we have had no recurrence of the LMs. Prior studies reported most recurrences in the first year, with some up to 10 y.9,25 Our cohort continues to be followed for recurrence to ensure durability of effect. A critical factor for sclerotherapy success is the classification of the LM. Macrocystic malformations are more effectively treated by sclerotherapy than combined or microcystic
Table 3 e Volume of LM before and after sclerotherapy treatment. Patient
Pre-treatment volume (cm3)
Post-treatment volume (cm3)
1
1338.1
0
2
388.5
Not available
3
2443.9
Not available*
4
13,226.4
5
2517.1
6 (surgery)
599.7* 0
67.2
0
7
1807.6
0
8
1952.5
0
9
1271.6
0
10
963.1
151.3*
Average *
2597.6 (3820.1)
Sclerotherapy treatment ongoing.
107.3 (224.3)
LM.1,16,24,27 In this study, one combined LM underwent successful sclerotherapy for the macrocysts. Follow-up imaging is pending in this case, but patient’s symptoms have decreased considerably. One patient failed sclerotherapy and required surgery. Interestingly, the sclerotherapy failure was not predicted by the classification of the LM (macrocystic) or mesenteric location.18 Mobility of the cyst, not discernible on cross-sectional imaging, was cited as the reason for failure, as no stable intracystic access could be established for sclerotherapy. Cyst mobility was not observed in the other cases. Prior studies do not indicate the size or volume of the LMs undergoing treatment. Compared with prior investigations, our patients underwent more sclerotherapy injections19 and received a higher mean dose of doxycycline.18 We theorize the discrepancies are either technical, related to our patients having larger LM, or a combination. Similar to other studies, sclerosant extravasation occurred in one patient, which was managed expectantly without any adverse effects.2,18 Another patient experienced infection of the LM midway through their treatment. We were not able to rule out sclerotherapy as a cause; however, infection of LM is a common complication.1,2 Skin ulceration, the most common complication of doxycycline sclerotherapy, was not observed in our series.2 Doxycycline, a tetracycline antibiotic, was our agent of choice due to its safety profile.2,3,16,18,22,23,30 Doxycycline is the agent of choice for sclerotherapy of macrocystic LM in our institution. The mechanism of action of doxycycline is unclear. Theories include inhibition of matrix metalloproteinases and suppression of factors associated with lymphangiogenesis.1,23 There is no standard dose for doxycycline and the total dosage for sclerotherapy is related to a patient’s intracystic LM volume. Our study has several limitations. The sample size is small and retrospective in nature. In addition, not all patient followup or sclerotherapy treatment courses have been completed leading to some gaps in the data. Sclerotherapy treatment is considered complete when there is total resolution of the LM on imaging; residual LM that is amenable to sclerotherapy requires further treatment to prevent re-expansion of the LM. In conclusion, our results indicate that doxycycline
260
j o u r n a l o f s u r g i c a l r e s e a r c h j a n u a r y 2 0 1 9 ( 2 3 3 ) 2 5 6 e2 6 1
Fig. 2 e Abdominal lymphatic malformation treated with sclerotherapy. (A) T2-weighted magnetic resonance imaging (MRI) showing large abdominal, macrocystic lymphatic malformation (stars). (B) Postsclerotherapy MRI showing resolution.
sclerotherapy is effective for volume reduction and durable symptom resolution in abdominal LM. Many patients have no residual or visible LM after treatment. Doxycycline sclerotherapy should be considered first-line treatment for macrocystic abdominal LM.
Acknowledgment Authors’ contributions: H.J.M. participated in study design and performed acquisition and analysis/interpretation of data and drafted the article. A.M.K. participated in study conception and design, analysis and interpretation of the data, and critical revisions of the article. A.A., R.H., T.A.N., and L.O.L. performed critical revisions of the article.
Disclosures The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. The authors have no conflicts of interest to report. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
references
1. Perkins JA, Manning SC, Tempero RM, et al. Lymphatic malformations: review of current treatment. Otolaryngol Head Neck Surg. 2010;142:795e803. 2. Greene AK, Perlyn CA, Alomari AI. Management of lymphatic malformations. Clin Plast Surg. 2011;38:75e82. 3. Renton JP, Smith RJH. Current treatment paradigms in the management of lymphatic malformations. Laryngoscope. 2011;121:56e59.
4. Fliegelman LJ, Friedland D, Brandwein M, Rothschild M. Lymphatic malformation: predictive factors for recurrence. Otolaryngol Head Neck Surg. 2000;123:706e710. 5. Oliveira C, Sacher P, Meuli M. Management of prenatally diagnosed abdominal lymphatic malformations. Eur J Pediatr Surg. 2010;20:302e306. 6. Steyaert H, Guitard J, Moscovici J, Juricic M, Vaysse P, Juskiewenski S. Abdominal cystic lymphangioma in children: benign lesions that can have a proliferative course. J Pediatr Surg. 1996;31:677e680. 7. Konen O, Rathaus V, Dlugy E, et al. Childhood abdominal cystic lymphangioma. Pediatr Radiol. 2002;32:88e94. 8. Goh BKP, Tan Y-M, Ong H-S, et al. Intra-abdominal and retroperitoneal lymphangiomas in pediatric and adult patients. World J Surg. 2005;29:837e840. 9. Hancock BJ, St-Vil D, Luks FI, Di Lorenzo M, Blanchard H. Complications of lymphangiomas in children. J Pediatr Surg. 1992;27:220e224. 10. Lei Z-M, Huang X-X, Sun Z-J, Zhang W-F, Zhao Y-F. Surgery of lymphatic malformations in oral and cervicofacial regions in children. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;104:338e344. 11. Alqahtani A, Nguyen LT, Flageole H, Shaw K, Laberge J-M. 25 years’ experience with lymphangiomas in children. J Pediatr Surg. 1999;34:1164e1168. 12. Okazaki T, Iwatani S, Yanai T, et al. Treatment of lymphangioma in children: our experience of 128 cases. J Pediatr Surg. 2007;42:386e389. 13. Ogita S, Tsuto T, Nakamura K, Deguchi E, Iwai N. OK-432 therapy in 64 patients with lymphangioma. J Pediatr Surg. 1994;29:784e785. 14. Kosir MA, Sonnino RE, Gauderer MWL. Pediatric abdominal lymphangiomas: a plea for early recognition. J Pediatr Surg. 1991;26:1309e1313. 15. de Perrot M, Rostan O, Morel P, Le Coultre C. Abdominal lymphangioma in adults and children. Br J Surg. 1998;85:395e397. 16. Nehra D, Jacobson L, Barnes P, Mallory B, Albanese CT, Sylvester KG. Doxycycline sclerotherapy as primary treatment of head and neck lymphatic malformations in children. J Pediatr Surg. 2008;43:451e460. 17. Martinot V, Descamps S, Fe´vrier P, et al. Evaluation of the treatment of cystic lymphangioma by percutaneous injection of Ethibloc in 20 patients. Arch Pediatr. 1997;4:8e14.
madsen et al sclerotherapy for lymphatic malformation
18. Chaudry G, Burrows PE, Padua HM, Dillon BJ, Fishman SJ, Alomari AI. Sclerotherapy of abdominal lymphatic malformations with doxycycline. J Vasc Interv Radiol. 2011;22:1431e1435. 19. Russell KW, Rollins MD, Feola GP, Arnold R, Barnhart DC, Scaife ER, et al. Sclerotherapy for intra-abdominal lymphatic malformations in children. Eur J Pediatr Surg. 2014;24:317e321. 20. Uchida K, Inoue M, Araki T, Miki C, Kusunoki M. Huge scrotal, flank, and retroperitoneal lymphangioma successfully treated by OK-432 sclerotherapy. Urology. 2002;60:1112. 21. Shankar KR, Roche CJ, Carty HML, Turnock RR. Cystic retroperitoneal lymphangioma: treatment by image-guided percutaneous catheter drainage and sclerotherapy. Eur Radiol. 2001;11:1021e1023. 22. Molitch HI, Witte CL, vanSonnenberg E. Percutaneous sclerotherapy of lymphangiomas. Radiology. 1995;194:343e347. 23. Shergill A, John P, Amaral JG. Doxycycline sclerotherapy in children with lymphatic malformations: outcomes, complications and clinical efficacy. Pediatr Radiol. 2012;42:1080e1088.
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24. Smith MC, Zimmerman MB, Burke DK, et al. Efficacy and safety of OK-432 immunotherapy of lymphatic malformations. Laryngoscope. 2009;119:107e115. 25. Gigue`re CM, Bauman NM, Smith RJH. New treatment options for lymphangioma in infants and children. Ann Otol Rhinol Laryngol. 2002;111:1066e1075. 26. Aalami OO, Allen DB, Organ Jr CH. Chylous ascites: a collective review. Surgery. 2000;128:761e778. 27. Alomari AI, Karian VE, Lord DJ, Padua HM, Burrows PE. Percutaneous sclerotherapy for lymphatic malformations: a retrospective analysis of patient-evaluated improvement. J Vasc Interv Radiol. 2006;17:1639e1648. 28. Burrows PE, Mitri RK, Alomari A, et al. Percutaneous sclerotherapy of lymphatic malformations with doxycycline. Lymphat Res Biol. 2008;6:209e216. 29. Churchill P, Otal D, Pemberton J, Ali A, Flageole H, Walton JM. Sclerotherapy for lymphatic malformations in children: a scoping review. J Pediatr Surg. 2011;46:912e922. 30. Amodeo I, Cavallaro G, Raffaeli G, et al. Abdominal cystic lymphangioma in a term newborn: a case report and update of new treatments. Medicine. 2017;96:e5984.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Association for Academic Surgery
Symptom resolution and volumetric reduction of abdominal lymphatic malformations with sclerotherapy Helen J. Madsen, MD,a,b,c,* Aparna Annam, DO,b,c,d Roger Harned, MD,b,c,d Taizo A. Nakano, MD, LO,b,c,e Lauren O. Larroque, RN, BSN, CPN,a,b and Ann M. Kulungowski, MDa,b,c a
Division of Pediatric Surgery, Children’s Hospital Colorado, Aurora, Colorado Division of Pediatric Surgery, Children’s Hospital Colorado, Vascular Anomalies Center, Aurora, Colorado c Division of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado d Department of Radiology, Children’s Hospital Colorado, Interventional Radiology, Aurora, Colorado e Department of Oncology, Children’s Hospital Colorado, Center for Cancer and Blood Disorders, Aurora, Colorado b
article info
abstract
Article history:
Background: Lymphatic malformations (LMs) are congenital and arise from errors in
Received 2 March 2018
vascular embryogenesis. LMs are categorized by cyst size as microcystic, macrocystic, or
Received in revised form
combined. Abdominal LMs are rare. Surgical resection of abdominal LMs has been the
20 June 2018
mainstay of therapy, but recurrence and morbidity are high. We sought to determine the
Accepted 11 July 2018
effectiveness of sclerotherapy treatment for abdominal LM.
Available online xxx
Methods: A single-center, retrospective review from 2014 to 2018 was conducted evaluating pediatric patients with abdominal LM.
Keywords:
Results: Ten patients were included, n ¼ 9 had macrocystic LM and one patient had combined
Abdominal
disease. The average age at first treatment was 6.8 y. The most common presenting symptoms
Lymphatic malformation
were abdominal distention, pain, infection, and anemia. Preprocedural imaging was per-
Lymphangioma
formed for all patients; median pretreatment volume was 1572.9 cm3 (range, 67.2-13,226.4).
Sclerotherapy
LMs were accessed using ultrasound guidance and injected with opacified doxycycline. Pa-
Doxycycline
tients received a mean of 7.1 sclerotherapy injections. Complications included intraperitoneal
Pediatric
doxycycline extravasation (n ¼ 1), managed conservatively, and LM infection (n ¼ 1), treated with intravenous antibiotics and drainage. One patient went on to surgical resection due to inability gain stable intracystic access; follow-up ultrasonography showed no recurrence. Postprocedural imaging was available in n ¼ 8. Volume decreased by 96.7% after sclerotherapy. The median remaining volume was 0 cm3 (range, 0-599.7) (P ¼ 0.016). Postsclerotherapy magnetic resonance imaging was obtained in n ¼ 6, with complete resolution in 83.3%. All patients had resolution of presenting symptoms. Follow-up duration was 12.3 mo. Conclusions: Initial results demonstrate that sclerotherapy is an effective and durable treatment for symptom resolution and volume reduction of abdominal LM. ª 2018 Elsevier Inc. All rights reserved.
* Corresponding author. University of Colorado School of Medicine, 13001 E 17th Place, Aurora, CO 80045, USA. Tel.: þ1720 979 5779; fax: þ1 303 724 2761. E-mail address: [email protected] (H.J. Madsen). 0022-4804/$ e see front matter ª 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2018.07.031
madsen et al sclerotherapy for lymphatic malformation
Introduction Pediatric lymphatic malformations (LMs) are congenital vascular anomalies that arise due to errors during vascular embryogenesis.1-4 LMs are rare with a prevalence of 1 in 20,000 children.5 The most common location for an LM is the head and neck, with only 10% occurring in the abdomen.2,5 Cystic LMs are categorized by the size of their lymphatic channels as either macrocystic, microcystic, or combined. In general, macrocystic LMs are those which can be accessed by a hypodermic needle and undergo visible decompression; however, the microcystic form comprises numerous small cysts that are difficult to enter with a needle. Combined LMs contain both macrocysts and microcysts.2 LMs can spontaneously regress, but this is the exception as most persist and can enlarge over time.1,2 Abdominal LMs typically present with vague abdominal complaints of pain and distention. They can also present acutely with vomiting, peritonitis, intestinal obstruction, or intestinal necrosis.6,7 Additional complications of intraabdominal LMs include anemia due to intracystic bleeding, sepsis due to bacterial translocation, and/or inability to empty dilated lymphatic channels, and chylous ascites.2 Historically, the first-line treatment for problematic LMs has been surgical resection.3,6,8-12 Regardless of location, LMs tend to be infiltrative, involve vital structures, and are poorly demarcated.3,13 Complete excision is difficult and can require staged interventions. Surgical principals for LM include limiting the resection to a defined anatomic area, performing as complete a resection as possible, preserving vital structures, and minimizing blood loss. Prolonged closed suction drainage is often needed for large resections involving soft tissues. Resection of intra-abdominal or mesenteric LM can require segmental bowel resection; consideration of postsurgical enteral length is essential.8,14,15 Expectant management of an abdominal LM is a viable option in some instances in an effort to avoid anesthesia in very young infants; however, treatment is preferred over observation to avoid the aforementioned complications.1,5 Sclerotherapy has become an important mainstay and alternative to surgical resection for the treatment of macrocystic lymphatic malformation.2,13,16-21 Sclerotherapy involves aspiration and subsequent injection of a sclerosant that causes scarring of cyst walls to one another. We sought to add to the collective experience for the treatment of abdominal lymphatic malformation with doxycycline, as the body of literature supporting this treatment remains sparse.11,15,18,19,22,23
Methods Study population After approval by the institutional review board with a waiver of consent, a retrospective review was conducted evaluating patients with macrocystic lymphatic malformation treated with doxycycline sclerotherapy from 2012 to 2018. The clinical records and imaging for presclerotherapy and postsclerotherapy treatment were reviewed for age, gender,
257
radiographic imaging, sclerotherapy intervention, hospital admissions, and follow-up information. Diagnosis of LM and classification of cyst size was based on magnetic resonance imaging (MRI) characteristics. Dimensions were calculated using width, height, and length at time of diagnosis. Follow-up data included imaging to determine presence and size of the LMs. Subjective data regarding symptom resolution was obtained from patients and families.
Technique Preprocedural MRI was used to plan the sclerotherapy intervention. Sclerotherapy was performed by an experienced interventional radiologist. General anesthesia was administered in all cases. For the initial treatment, ultrasound guidance was used to access the macrocysts with a needle. Under fluoroscopic guidance the needle was exchanged for a pigtail catheter. Cysts were aspirated and opacified doxycycline was injected via the pigtail catheters at a concentration of 10 mg/ mL. Volume injected was equal to the aspirated volume of each macrocyst, up to a typical maximum of 1000 mg per treatment. Each catheter was clamped for 8 h and left to gravity drainage after this 8 h period. The patients returned to interventional radiology for subsequent injections of sclerosant through the existing catheter during the same cycle. After a median of three sclerotherapy injections, the catheter was removed. The next cycle was initiated after 4-8 wk if imaging demonstrated the presence of continued macrocysts, or if the patient experienced a complication or increase in symptoms.
Statistical analysis Wilcoxon matched pairs signed-rank test was used to determine if the difference between pre- and post-treatment volume was significant. The difference was considered significant when P < 0.05. Calculations were performed in GraphPad Prism 7.0 (GraphPad Software Inc, La Jolla, California).
Results Ten patients underwent sclerotherapy as the primary treatment of their abdominal LM. Diagnosis for all patients was based on pretreatment imaging, MRI was used in n ¼ 9 and CT was used in n ¼ 1. One patient was diagnosed prenatally with ultrasonography and confirmed with postnatal MRI. Average age at diagnosis was 6.8 y (range, 0-17 y). Nine patients were male. Common presenting symptoms were abdominal distention (n ¼ 5), abdominal pain (n ¼ 5), infection (n ¼ 2), and anemia (n ¼ 1). Macrcocystic LM was identified in nine patients; one patient had a combined LM. Patient characteristics, LM type, and symptoms are presented in (Table 1). Nine patients were treated solely with sclerotherapy. Sclerotherapy was unable to be performed in one patient due to inability to achieve a stable intracystic location after two distinct, failed attempts. This patient underwent resection of the mesenteric LM with a 5 cm segmental small intestinal
258
j o u r n a l o f s u r g i c a l r e s e a r c h j a n u a r y 2 0 1 9 ( 2 3 3 ) 2 5 6 e2 6 1
Table 1 e Patient demographics. Patient
Age (y)
Gender
Presenting symptom(s)
LM classification Macrocystic
1
13
Male
Abdominal pain, nausea/vomiting
2
11
Male
Abdominal pain, infection
Combined
3
3
Male
Abdominal distention
Macrocystic
4
17
Male
Abdominal pain and distention
Macrocystic
5
2
Female
Abdominal pain & distention, constipation, decreased appetite
Macrocystic
6
0
Male
Prenatal imaging
Macrocystic
7
7
Male
Abdominal pain, infection
Macrocystic
8
1.4
Male
Abdominal distention, constipation, anemia, poor feeding
Macrocystic
9
1.25
Male
Abdominal distention
Macrocystic
Male
Incidental finding
Macrocystic
10
12
resection and primary anastomosis. The patient was discharged on postoperative day 3 on a regular diet. A variable number of sclerotherapy injections were performed on each patient, with a range of 2-16 (average, 7.1 injections). The cumulative total dose of doxycycline was on average 5577 mg (range 370-17,900 mg). Details of the sclerotherapy treatment course are presented in (Table 2), (Fig. 1). Successive sclerotherapy injections were performed via existing indwelling pigtail catheters for a median of three injections (range, 1-7) per cycle. Postprocedural imaging was available in 80% (8/10) of patients. All patients (in whom imaging was available posttreatment) experienced LM volume reduction. The LM locations were abdominal (n ¼ 6) and mesenteric (n ¼ 4). The median pretreatment volume was 1572.9 cm3 (range, 67.213,226.4) and the median remaining volume was 0 cm3 (range, 0-599.7), (P ¼ 0.016). Statistical analysis excluded patients 2, 3 (follow-up imaging pending), and patient 6 (surgical resection). Ultrasonography was performed for patient 6 showing complete resolution after surgical resection. Notably, three
patients (patient 3, 4, and 10) have not yet completed their sclerotherapy courses. These patients are doing clinically well but have evidence of residual LM on ultrasound imaging that is amenable to sclerotherapy and will continue to undergo sclerotherapy treatment. Patient 2 has not followed up for postsclerotherapy imaging, so need for further treatment versus resolution of the LM is not able to be determined. Volumetric details are presented in (Table 3), (Fig. 2). Complications during sclerotherapy included intraperitoneal extravasation of doxycycline (n ¼ 1), which was treated conservatively, and infection of the LM (n ¼ 1), treated with intravenous antibiotics successfully. Patients were followed up in clinic for symptom monitoring from the date of first treatment for a median of 376.5 d (range, 38-612). Follow-up imaging was available in 8 of 10 patients and was performed an average of 402 d (range, 71-819) from the first treatment.
Discussion
Table 2 e Details on sclerotherapy treatment course. Patient
Number of sclerotherapy injections
Total dosage of doxycycline (mg)
1
11
2
2
6200 370
3
9*
5900
4
13*
18,400
5
6
4800
6 (surgery)
2y
7
4
2200
8
16
12,100
9
3
0
1700
10
4
*
4000
Average
7.1
5577
*
Sclerotherapy treatment ongoing. y Failed sclerotherapy attempts.
Historically, the treatment of LM was surgical. In recent years, sclerotherapy has become the mainstay of treatment for macrocystic lesions. Sclerotherapy is favored over surgical resection due to greater effectiveness and lower morbidity.16,24 Sclerotherapy preserves vital structures such as intestines, nerves, arteries, and veins. Incomplete surgical resection or debulking procedures result in re-expansion or “recurrence.” The perceived “recurrence” is due to growth and expansion of affected lymphatics in the remaining, seemingly normal appearing tissue.10 Partial resection has “recurrence” rates approaching 100%. Complete surgical excision is difficult as resection is limited to macroscopically visibly affected tissue; recurrence as high as 27% is documented in cases of complete excision.9,25 Surgery also is morbid and complication rates as high as 33% have been reported.9 Common complications include bleeding, infection, and damage to neurovascular structures.2,9,12 Prolonged closed suction drains are often needed in the resection bed due to lymphatic leakage and for seroma prevention, adding to postoperative pain. Surgically resected abdominal LM can result in chylous
madsen et al sclerotherapy for lymphatic malformation
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Fig. 1 e Sclerotherapy technique performed by interventional radiology. (A) Injection of contrast through needle to ensure position in cyst before placement of pigtail catheter. (B) Injection of sclerosant with Isovue through existing catheters.
ascites due to transected lymphatics, resulting in patient morbidity and mortality.26 The success of sclerotherapy for LM in the literature is largely based on case report studies conducted on craniofacial LM, necessitating extrapolation of data for abdominal LMs.16,24,27-29 This study adds to a sparse body of literature, as just two other studies have focused on abdominal LM treated with doxycycline sclerotherapy.18,19 Our study finds sclerotherapy to be effective, with significant LM volume reduction. We report complete resolution rate of the macrocystic LM in 83% of cases. The symptom resolution was observed in 100% of our patient with durability of about a year. To date, we have had no recurrence of the LMs. Prior studies reported most recurrences in the first year, with some up to 10 y.9,25 Our cohort continues to be followed for recurrence to ensure durability of effect. A critical factor for sclerotherapy success is the classification of the LM. Macrocystic malformations are more effectively treated by sclerotherapy than combined or microcystic
Table 3 e Volume of LM before and after sclerotherapy treatment. Patient
Pre-treatment volume (cm3)
Post-treatment volume (cm3)
1
1338.1
0
2
388.5
Not available
3
2443.9
Not available*
4
13,226.4
5
2517.1
6 (surgery)
599.7* 0
67.2
0
7
1807.6
0
8
1952.5
0
9
1271.6
0
10
963.1
151.3*
Average *
2597.6 (3820.1)
Sclerotherapy treatment ongoing.
107.3 (224.3)
LM.1,16,24,27 In this study, one combined LM underwent successful sclerotherapy for the macrocysts. Follow-up imaging is pending in this case, but patient’s symptoms have decreased considerably. One patient failed sclerotherapy and required surgery. Interestingly, the sclerotherapy failure was not predicted by the classification of the LM (macrocystic) or mesenteric location.18 Mobility of the cyst, not discernible on cross-sectional imaging, was cited as the reason for failure, as no stable intracystic access could be established for sclerotherapy. Cyst mobility was not observed in the other cases. Prior studies do not indicate the size or volume of the LMs undergoing treatment. Compared with prior investigations, our patients underwent more sclerotherapy injections19 and received a higher mean dose of doxycycline.18 We theorize the discrepancies are either technical, related to our patients having larger LM, or a combination. Similar to other studies, sclerosant extravasation occurred in one patient, which was managed expectantly without any adverse effects.2,18 Another patient experienced infection of the LM midway through their treatment. We were not able to rule out sclerotherapy as a cause; however, infection of LM is a common complication.1,2 Skin ulceration, the most common complication of doxycycline sclerotherapy, was not observed in our series.2 Doxycycline, a tetracycline antibiotic, was our agent of choice due to its safety profile.2,3,16,18,22,23,30 Doxycycline is the agent of choice for sclerotherapy of macrocystic LM in our institution. The mechanism of action of doxycycline is unclear. Theories include inhibition of matrix metalloproteinases and suppression of factors associated with lymphangiogenesis.1,23 There is no standard dose for doxycycline and the total dosage for sclerotherapy is related to a patient’s intracystic LM volume. Our study has several limitations. The sample size is small and retrospective in nature. In addition, not all patient followup or sclerotherapy treatment courses have been completed leading to some gaps in the data. Sclerotherapy treatment is considered complete when there is total resolution of the LM on imaging; residual LM that is amenable to sclerotherapy requires further treatment to prevent re-expansion of the LM. In conclusion, our results indicate that doxycycline
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j o u r n a l o f s u r g i c a l r e s e a r c h j a n u a r y 2 0 1 9 ( 2 3 3 ) 2 5 6 e2 6 1
Fig. 2 e Abdominal lymphatic malformation treated with sclerotherapy. (A) T2-weighted magnetic resonance imaging (MRI) showing large abdominal, macrocystic lymphatic malformation (stars). (B) Postsclerotherapy MRI showing resolution.
sclerotherapy is effective for volume reduction and durable symptom resolution in abdominal LM. Many patients have no residual or visible LM after treatment. Doxycycline sclerotherapy should be considered first-line treatment for macrocystic abdominal LM.
Acknowledgment Authors’ contributions: H.J.M. participated in study design and performed acquisition and analysis/interpretation of data and drafted the article. A.M.K. participated in study conception and design, analysis and interpretation of the data, and critical revisions of the article. A.A., R.H., T.A.N., and L.O.L. performed critical revisions of the article.
Disclosures The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. The authors have no conflicts of interest to report. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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