Pediatric Hematology and Oncology, Early Online:1–6, 2014 C Informa Healthcare USA, Inc. Copyright  ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2014.981901

ORIGINAL ARTICLE

Pediatr Hematol Oncol Downloaded from informahealthcare.com by Deakin University on 03/14/15 For personal use only.

Percutaneous Transhepatic Biliary Drainage in an Infant with Obstructive Jaundice Caused by Neuroblastoma Francesco Saettini,1 Roberto Agazzi,2 Eugenia Giraldi,3 Carlo Foglia,3 Laura Cavalleri,3 Laura Morali,3 Giorgio Fasolini,2 Angelica Spotti,4 and Massimo Provenzi3 1

Department of Pediatrics, Oncohematology Unit, Ospedale Papa Giovanni XXIII University of Milan-Bicocca, Bergamo, Italy; 2 Department of Radiology, Interventional Radiology Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy; 3 Department of Pediatrics, Oncohematology Unit, Ospedale Papa Giovanni XXII, Bergamo, Italy; 4 Department of Anesthesiology and Critical Care, Ospedale Papa Giovanni XIII, Bergamo, Italy

Neuroblastoma presenting with obstructive jaundice is a rare event. Management of this condition includes surgery, chemotherapy, radiotherapy, temporary cholecystostomy tube, endoscopic retrograde cholangiopancreatography (ERCP), and internal biliary drainage (IBD). We herein describe our experience with one infant affected by neuroblastoma presenting with jaundice, who successfully underwent percutaneous transhepatic biliary drainage (PTBD). This report introduces PTBD as a viable treatment option for neuroblastoma and obstructive jaundice and provides a review of the pertinent literature. Keywords neuroblastoma, pediatric oncology, radiology, solid, tumors

INTRODUCTION Neuroblastoma is the most frequent solid tumor in children and it accounts for 7% of all childhood malignancies [1]. Neuroblastoma displays a variety of clinical manifestations depending on the site of the primary tumor and metastases. Nonetheless obstructive jaundice is a rare symptom (either at diagnosis or at recurrence) and has been reported in very few cases. Management options include surgery, chemotherapy, radiotherapy, temporary cholecystostomy tube, endoscopic retrograde cholangiopancreatography (ERCP), internal biliary drainage (IBD), and percutaneous transhepatic biliary drainage (PTBD) [2–10]. We herein describe our experience with one infant affected by neuroblastoma presenting with jaundice, who successfully underwent PTBD. We review the previous cases reported in the literature and discuss feasibility and possible benefits of the different options.

Received 4 August 2014; accepted 26 October 2014. Address correspondence to Francesco Saettini, Department of Pediatrics, Oncohematology Unit, Ospedale Papa Giovanni XXIII - University of Milan-Bicocca, Bergamo, Italy. E-mail: [email protected]





F. Saettini et al.

Pediatr Hematol Oncol Downloaded from informahealthcare.com by Deakin University on 03/14/15 For personal use only.

CASE REPORT A 3-month-old boy was admitted into a regional hospital presenting with jaundice and acholia. Abdominal ultrasonography showed an abdominal solid mass. The patient was thus referred to our hospital for further investigation. On admission, blood tests showed slight anemia with a blood hemoglobin concentration of 9.8 g/dL and elevation of white blood cell count (26,340/mm3 , neuthrophilis 11,430/mm3 ), lactate dehydrogenase (1844 U/L), and C activated protein (1.8 mg/dL). Liver function tests were abnormal with elevation of total and direct bilirubin levels (17 and 14.9 mg/dL, respectively), aspartate aminotransferase (AST, 188 U/L), gamma-glutamil transferase (g-GT, 163 U/L), alkaline aminotransferase (ALT, 235 U/L), and alkaline phosphatase (562 U/L). Neuron-specific enolase level was 282 ng/mL and urinary catecholamines (homovanillic acid and vanillymandeic acid) were normal. Abdominal magnetic resonance showed a median retroperitoneal solid mass (60 × 57 × 58 mm), which incorporated the celiac trunk, superior mesenteric artery, and kidney vessels. The mass displaced the inferior vena cava, duodenum, and pancreatic head. The common biliary duct (3 mm), intrahepatic biliary ducts, and pancreatic duct were mildly dilated. Biopsy was in favor of a neuroblastic tumor. While molecular tests were being run, chemotherapy was started with Carboplatin and Etoposide, according to the European protocol for Infant Neuroblastoma with life-threatening symptoms. MIBG scintigraphy was performed after one cycle of chemotherapy. Focal enhancement at the site of the tumor was compatible with the histological diagnosis. Since cholestatic jaundice was rapidly increasing (total and direct bilirubin levels 38.1 and 37.5 mg/dL, respectively, AST/ALT 641/817 U/L, and g-GT 1.191 U/L), PTBD under ultrasonography guidance was preferred to IBD and ERCP. Considering the peculiarity of the case, IBD could have been burdened by severe related complications (i.e., occlusion due to tumor ingrowth into the endoprostheses and difficulty of withdrawal in case of expandable metallic endoprostheses), while ERCP was precluded based on CT anatomy. Therefore, the left bile-duct branch was punctured using a 19R needle (Cook Endoscopy Inc., Limerick, Ireland) from the epigasgauge Echotip trium, using color-doppler to avoid vessels. Compression of the retropancreatic common bile duct caused a mild expansion of the common hepatic duct and intrahepatic R , ducts (Figure 1). A .018” guide wire passed the stenosis and a 6 F catheter (BARD Karlsruhe, Germany) was placed in the common bile duct. The procedure was well tolerated and no complications occurred. Anesthesia was inducted with propofol (6 mg/kg) and rocuronium (0.6 mg/kg) was administered. The patient was intubated and vital signs monitored all along the procedure. Anesthesia was then maintained with propofol (0.5 mg/kg/hour) and fentanyl (2 μg/kg). Acetaminophen (15 mg/kg every 8 hours) was administered for pain management. Molecular tests showed focal amplification of MYCN (v-myc avian myelocytomatosis viral related oncogene, neuroblastoma derived), which is a crucial gene in childhood neuroblastoma, as evidenced by a large subset of high-risk tumors. The tumor was therefore considered as an intermediate risk and three more cycles of chemotherapy (Carboplatin and Etoposide) were administered according to SIOPEN protocol—European Low and Intermediate Risk Neuroblastoma Protocol. Ten weeks after the PTBD was placed, abdominal ultrasonography showed that the retroperitoneal tumor had reduced (maximum diameter 3 cm) and the previously interested anatomic structures were no longer comprised. It was thus decided to remove the drainage. The mass was deemed inoperable because still incorporated the celiac trunk and the superior mesenteric artery. Four more cycles of chemotherapy (Carboplatin and Doxorubicin) were thus administered. Abdominal magnetic resonance, at the end of the treatment, showed further reduction of the tumor (maximum diameter 20 mm) and no dilatation of the biliary tree. Pediatric Hematology and Oncology

Pediatr Hematol Oncol Downloaded from informahealthcare.com by Deakin University on 03/14/15 For personal use only.

PTBD in an Infant with Neuroblastoma



FIGURE 1 Percutaneous transhepatic biliary drainage. (A) Compression of the retropancreatic common bile duct causing expansion of the common hepatic duct and intrahepatic ducts. (B) Insertion of the catheter in the common bile duct.

Imaging performed 5 months after stopping therapy showed an enlargement of the tumor. Second line chemotherapy is currently ongoing. DISCUSSION Obstructive jaundice may be a presenting feature in various diseases in the pediatric population. The differential diagnosis includes retroperitoneal neuroblastic tumors as well as liver and pancreatic tumors, which are both rare in childhood. There have been few cases of obstructive jaundice caused by neuroblastoma in previous reports, either as an initial symptom, recurrence, or metastatic tumors. The treatment options to date have included surgery, chemotherapy, ERCP, IBD, biliary-enteric bypass, and insertion of cholecystostomy tube [2–10]. PTBD may serve as a viable alternative if first-line options, such as ERCP with IBD, are not possible or fail. Surgical resection may be curative, particularly in neonatal neuroblastoma [6, 11, 12], on account of high rates of favorable histology and no amplification of MYCN [13]. On the other hand, neuroblastoma is known to have the highest rate of regression among malignant tumors: thus some authors suggest an observation period in case of neonatal diagnosis [14]. It seems reasonable to schedule a close follow-up in cases of small neuroblastoma (less than 3 cm) with no MYCN amplification and no sign of increasing jaundice. However, there are no conclusive data regarding focal amplification of MYCN and it is indeed a matter of concern for long-term prognosis. Minimally invasive options such as cholecystostomy, IBD, or PTBD may bridge the gap to surgical resection, serve a palliative role in unresectable cases, or serve as the definitive treatment in cases such as ours, in which regression occurs after medical management. In case of obstructive jaundice, ERCP is widely used in adults and has recently been introduced with high rates of technical success as a means of investigation and therapy in the pediatric age group. It has been demonstrated that pediatric ERCP can be effectively used in therapeutic interventions similar to those performed on adults [15]. Overall efficacy and safety are strictly dependent on the experience of the endoscopists employing specialized pediatric duodenoscopes. Even among infants and newborns it has been reported that ERCP can be performed with satisfactory results [16, 17]. Considering these results, ERCP may be performed as a first-line treatment, when anatomy does not limit the efficacy of the procedure. IBD has been introduced as a second-line treatment when ERCP fails. IBD is frequently placed at the same time ERCP and endoscopic sphincterotomy are performed. C Informa Healthcare USA, Inc. Copyright 

Pediatr Hematol Oncol Downloaded from informahealthcare.com by Deakin University on 03/14/15 For personal use only.



F. Saettini et al.

Overall IBD is divided into plastic or metal stent devices. Plastic stents have some advantages, including: cost-effectiveness, ease of insertion, and relatively easy removal and replacement upon stent occlusion or malfunctions. IBD contributes to improving the patients’ quality of life (no need for care of external drainage tube and shortened hospitalization). Compared to PTBD, IBD shows catheter stability in infants and newborns, no electrolyte and mineral deficits and the re-establishment of the physiological bile flow, which is related to nutritional issues. PTBD should be preferred to IBD when it is difficult to cross the obstruction with a guidewire, because prolonging the manipulation may lead to septic complications. Other complications associated with IBD can be occlusion due to tumor ingrowth into the endoprostheses and difficulty of withdrawal (in case of expandable metallic endosprotheses), or slippage, migration, pancreatitis and duodenal perforation in case of plastic tube stent [5]. The use of biliary-enteric bypass has been reported in three pediatric cases (one embryonal rhabdomyosarcoma of the ampulla of Vater [18], one fibrosarcoma, and one type IV glycogen storage disease) [19]. The use of this procedure to palliate obstructive jaundice and to reconstruct the biliary tree after resection should be decided only as an extreme measure when access to the extrahepatic biliary tree is precluded. Cholecystostomy tube has been reported as a safe, fast, and secure method of draining the biliary system and allows easy postoperative cholangiogram study. Few reports describe the use of cholecystostomy tube in pediatric age, particularly in neuroblastoma [4, 7]. Gow et al. suggest that the ideal treatment for patients with obstructive jaundice secondary to neuroblastoma is the insertion of a cholecystostomy tube before chemotherapy [7]. This has also been described in the management of children with severe acute or acalculous cholecystitis, reporting successful outcomes and normal biliary tracts at the time of follow-up. [20]. PTBD is a technique involving cannulation of the biliary ducts under radiological guidance. Although the use of PTBD in children is infrequent, there are some reports regarding this type of management [21–23]. PTBD-related adverse event rates of 9–33% (i.e., cholangitis, sepsis, leakage, bleeding, and tube obstruction) and mortality rates of 2–15% have been reported. In patients undergoing radiotherapy and chemotherapy for malignancies, such complications—especially sepsis—should be contemplated carefully. Even if PTBD is a widely accepted procedure, it has been reported that nondilated bile duct is related to lower success rate, varying from 50% to 100%. Further studies are thus needed to clarify if this condition may represent a limitation [24]. In one infant with gastroschisis and obstructive jaundice, PTBD revealed occlusion of the common bile duct; subsequently a catheter for percutaneous biliary drainage was inserted with successful relief [20]. Sauer et al. described the use of long-term PTBD in an infant with jaundice caused by hemangioendothelioma; biliary drainage was continued for 22 months until reduction of the mass after steroid therapy [23]. Our case is quite different from Sauer’s. Hemangioendothelioma may also be managed with medical treatment as a first-line therapy, but an extrinsic compression on the biliary tract caused by neuroblastoma requires a prompt intervention. In fact certain chemotherapeutics agents, i.e., anthracyclines, which are widely used in the treatment of this condition, are excreted in the bile and the presence of biliary obstruction may cause dose re-scheduling. To our knowledge, there have been only 10 cases of obstructive jaundice caused by neuroblastoma in the literature; in six of these, including the case herein discussed, it was reported as an initial symptom (Table 1). In the subgroup of patients who presented with obstructive jaundice at diagnosis, all but two were deemed inoperable. All the procedures here presented have been reported to be useful techniques. To our knowledge, there are no reports regarding the use of PTBD in infants presenting with neuroblastoma. This procedure let us manage a rapidly increasing cholestatic jaundice Pediatric Hematology and Oncology

PTBD in an Infant with Neuroblastoma



TABLE 1 Management of Neuroblastoma Presenting with Jaundice Author

Patient

Procedure

Complication

Device removal

Followup

Saettini et al., this paper

Infant

CT, PTBD

None

10 w

AED 11 m

Newborn

Surgery

None

–

NED 102 m

Garc´ıa de Andoin Barandiaran et al. [3]

4y

CT

None

–

NED 1 y

Kreeftenberg et al. [6]

Newborn

Surgery

None

–

NED 2 y

2y5m

Cholecystostomy tube

Infection

39 d

Not declared

3y

CT

None

–

Not declared

Pediatr Hematol Oncol Downloaded from informahealthcare.com by Deakin University on 03/14/15 For personal use only.

Nam et al. [2]

Gow et al. [7] Walsh and Shah [8]

Note. CT = chemotherapy. PTBD = percutaneous transhepatic biliary drainage. w = weeks. AED = alive with evidence of disease. m = months. NED = no evidence of disease. y = years. IBD = internal biliary drainage. RT = radiotherapy. d = days. ERCP = endoscopic retrograde cholangiopancreatography.

and subsequently administer full dose chemotherapy. Comparing all the alternatives here presented, PTBD may represent a safe and effective procedure even in infants, if performed by experienced radiologists. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. REFERENCES [1] Park JR, Bagatell R, London WB, et al. Children’s oncology group’s 2013 blueprint for research: Neuroblastoma. Pediatr Blood Cancer. 2013;60:985–993. DOI 10.1002/pbc.24433. [2] Nam SH, Kim DY, Kim SC, Seo JJ. Neonatal neuroblastoma needs the aggressive treatment? World J Surg. 2012;36:2102–2107. DOI 10.1007/s00268-012-1632-y. [3] Garc´ıa de Andoin Barandiaran N, Lassaletta Atienza A, et al. Neuroblastoma presenting as obstructive jaundice. An Pediatr (Barc). 2006;64(1):85–88. [4] Ito A, Uno T, Gunji Y, et al. Obstructive jaundice as a presentation of ganglioneuroblastoma. J Pediatr Hematol Oncol. 2005;27(2):112–114. [5] Okada T, Yoshida H, Matsunaga T, et al. Endoscopic internal biliary drainage in a child with malignant obstructive jaundice caused by neuroblastoma. Pediatr Radiol. 2003;33(2):133–135. [6] Kreeftenberg HG Jr, Zeebregts CJ, Tamminga RY, et al. Scrotal hematoma, anemia, and jaundice as manifestations of adrenal neuroblastoma in a newborn. J Pediatr Surg. 1999;34(12):1856–1857. [7] Gow KW, Blair GK, Phillips R, et al. Obstructive jaundice caused by neuroblastoma managed with temporary cholecystostomy tube. J Pediatr Surg. 1995;30(6):878–882. [8] Walsh MT, Shah KJ. Neuroblastoma presenting with obstructive jaundice. Br J Radiol. 1989;62:626–634. [9] Guelrud M, Mendoza S, Zager A, et al. Biliary stenting in an infant with malignant obstructive jaundice. Gastrointest Endosc. 1989;35:259–261. [10] Chen B, Chang MH, Lin OT, et al. Extrahepatic biliary obstruction caused by cancer of non-liver origin in children: Report of 5 cases. J Formos Med Assoc. 1989;88:819–823. [11] Granata C, Fagnani AM, Gambini C, et al. Features and outcome of neuroblastoma detected before birth. J Pediatr Surg. 2000;35:88–91. [12] Ho PT, Estroff JA, Kozakewich H, et al. Prenatal detection of neuroblastoma: A ten-year experience from the Dana-Farber Cancer Institute and Children’s Hospital. Pediatrics 1993;92:358–364. C Informa Healthcare USA, Inc. Copyright 

Pediatr Hematol Oncol Downloaded from informahealthcare.com by Deakin University on 03/14/15 For personal use only.



F. Saettini et al.

[13] Isaacs H Jr. Fetal and neonatal neuroblastoma: Retrospective review of 271 cases. Fetal Pediatr Pathol. 2007;26:177–184. [14] Hero B, Simon T, Spitz R, et al. Localized infant neuroblastomas often show spontaneous regression: Results of the prospective trials NB95-S and NB97. J Clin Oncol. 2008;26:1504–1510. [15] Enestvedt BK, Tofani C, Lee D. Endoscopic retrograde cholangiopancreatography in the pediatric population is safe and efficacious. J Pediatr Gastroenterol Nutr. 2013;57(5):649–654. DOI: 10.1097/MPG.0b013e31829e0bb6. [16] Saito T, Terui K, Mitsunaga T. Role of pediatric endoscopic retrograde cholangiopancreatography in an era stressing less-invasive imaging modalities. J Pediatr Gastroenterol Nutr. 2014;59(2):204–209. [17] Yasushi I, Rintaro N, Makoto I. The role of endoscopic retrograde cholangiopancreatography in infants with cholestasis. J Pediatr Surg. 2000;35:545–549. [18] Caty MG, Oldham KT, Prochownik EV. Embryonal rhabdomyosarcoma of the ampulla of Vater with long-term survival following pancreaticoduodenectomy. J Pediatr Surg. 1990;12:1256–1258. [19] Blanchard H, St-WI D, Youssef S, et al. Intrahepatic biliary-enteric bypass for complete extrahepatic biliary obstruction in children. J Ped Surg. 1997;32(6):902–904. [20] Pieretti R, Auldist AW, Stephens CA. Acute cholecystitis in children. Surg Gynecol Obstet. 1975;140:16–18. [21] Kullendorff CM, Arnbj¨ornsson E, Cwikiel W. Stenting of the biliary tract in children. Eur J Pediatr Surg. 2002;12(3):199–202. [22] Hancock BJ, Wiseman NE, Rusnak BW. Bile duct stricture in an infant with gastroschisis treated by percutaneous transhepatic drainage, biliary stenting, and balloon dilation. J Pediatr Surg. 1989;24:1071–1073. [23] Sauer L, Harrison MR, Bond SJ, et al. Long-term percutaneous biliary drainage in an infant with hemangioendothelioma. J Pediatr Surg. 1987;22:606–608. [24] Kuhn JP, Busemann A, Lerch MM, et al. Percutaneous biliary drainage in patients with nondilated intrahepatic bile ducts compared with patients with dilated intrahepatic bile ducts. AJR Am J Roentgenol. 2010;195(4):851 –857.

Pediatric Hematology and Oncology