0
Original Article |

Choledochal Cysts in Adults FREE

Chi-Leung Liu, MS, FRCS(Edin); Sheung-Tat Fan, MS, MD, FRCS(Glas & Edin); Chung-Mau Lo, MS, FRACS, FRCS(Edin); Chi-Ming Lam, MS, FRCS(Edin); Ronnie Tung-Ping Poon, MS, FRCS(Edin); John Wong, PhD, FRACS, FRCS(Edin)
[+] Author Affiliations

From the Centre for the Study of Liver Disease, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong.


Arch Surg. 2002;137(4):465-468. doi:10.1001/archsurg.137.4.465.
Text Size: A A A
Published online

Hypothesis  Choledochal cyst is rarely diagnosed in adulthood. When complicated by biliary tract malignancy, the disease has a distinct presentation and carries a dismal prognosis despite radical surgical resection.

Design  Retrospective study.

Setting  Tertiary referral center.

Patients  A retrospective study was performed on 30 adult patients who presented with choledochal cyst from January 1, 1989, to December 31, 2000.

Main Outcome Measures  The clinical presentation, management, and outcome of patients with and without biliary tract malignancy.

Results  Nine patients (30%) had biliary tract malignancy complicating choledochal cyst (group A). Compared with 21 patients without malignancy (group B), group A patients had a significantly higher incidence of previous internal drainage operations for choledochal cyst (P = .049) and presentation with cholangitis (P = .03). Four patients in group A underwent pancreaticoduodenectomy and 3 received a palliative biliary drainage operation. The overall median survival of patients in group A was 12 months. Complete excision of choledochal cyst and Roux-en-Y hepaticojejunostomy were performed for all patients in group B, among whom 2 underwent concomitant hemihepatectomy. The operative morbidity and mortality were 14% and 0%, respectively, and there were no long-term complications with a median follow-up of 66 months.

Conclusions  Biliary tract malignancy complicating choledochal cyst in adults should be suspected in patients with a history of internal drainage of choledochal cyst and presentation with cholangitis. Complete excision of choledochal cyst with Roux-en-Y hepaticojejunostomy is the treatment of choice for patients without malignancy and can be performed with low operative morbidity and absence of long-term complications in adult patients.

THE DIAGNOSIS of choledochal cyst is usually made in the first few years of life, and more than 60% of all cases are diagnosed in the first decade.1,2 Presentation in adulthood is uncommon and is often associated with complication of the cyst. Early reports suggested that drainage operations including cystoduodenostomy or cystojejunostomy without excision of the cyst resulted in satisfactory outcome in the treatment of choledochal cysts.3,4 However, late complications occur on long-term follow-up. These include anastomotic stricture, cholangitis, biliary calculi, and biliary tract malignancy.1,5,6 The aim of the present study was to review the clinical presentation, treatment, and outcome of adult patients who had choledochal cyst with and without the complication of biliary tract malignancy.

A retrospective study was conducted on patients older than 18 years presenting with choledochal cyst during a 12-year period from January 1, 1989, to December 31, 2000. Clinical data were derived from patients' records, and radiologic examination films were reviewed. Cysts were grouped according to the classification of Todani and coworkers.7 Preoperative investigations included blood biochemistry, ultrasonography of the hepatobiliary system, computed tomography, endoscopic retrograde cholangiopancreatography, and magnetic resonance imaging in selected patients. In patients who presented with acute pancreatitis or acute cholangitis, conservative management, including intravenous fluid administration, intravenous antibiotics, and analgesics, was provided. Preoperative investigations were completed after the acute attack subsided. When biliary tract malignancy was diagnosed on preoperative investigations (group A), complete evaluation was performed aiming at radical curative resection. Complete excision of choledochal cyst with Roux-en-Y hepaticojejunostomy was performed for all patients without biliary tract malignancy (group B). In selected patients with intrahepatic extension of choledochal cyst (type IV disease), hemihepatectomy was performed.

Statistical analysis was performed with the χ2 test or Fisher exact test, when appropriate, to compare discrete variables. The Mann-Whitney test was used to compare continuous variables. Survival analysis of patients with biliary tract malignancy was estimated by the Kaplan-Meier survival method. All P values <.05 were considered to indicate statistical significance. Statistical analyses were made with the help of SPSS for Windows computer software (SPSS Inc, Chicago, Ill).

The study comprised 30 adult patients presenting with choledochal cysts during the study period. There were 9 men (30%) and 21 women (70%), with a median age of 39 years (range, 18-64 years). The choledochal cysts were classified as Todani and coworkers' type I in 20 patients, type II in 2 patients, and type IV in 8 patients.7 Nine patients (30%) were diagnosed as having biliary tract malignancy complicating choledochal cyst (group A), including adenocarcinoma arising from the cyst wall (7 patients) and gallbladder (2 patients). Cholechodal cyst was not complicated by biliary tract malignancy in the remaining 21 patients (70%) (group B). The clinical data of both groups of patients are listed in Table 1. Five patients (56%) in group A presented with acute cholangitis, and the incidence was significantly higher than that of 14% (3 patients) in group B (P = .03). Four patients (44%) in group A and 2 patients (10%) in group B had previous internal drainage operations for choledochal cyst 5 to 21 years before presentation (P = .049) (Table 2).

Table Graphic Jump LocationTable 1. Clinical Data of 30 Adult Patients Who Had Choledochal Cyst With (Group A) and Without (Group B) Biliary Tract Malignancy
Table Graphic Jump LocationTable 2. Previous Surgery for Choledochal Cyst in Patients With (Group A) and Without (Group B) Biliary Tract Malignancy

After evaluation, 8 patients with biliary tract malignancy (group A) underwent laparotomy. The disease was found to be too advanced for curative resection in 4 patients, and 3 of them underwent palliative biliary drainage operation (Table 3). Four patients with adenocarcinoma arising from the cyst wall underwent pancreaticoduodenectomy, but all of them died of recurrent disease 5 to 38 months after the operation. The overall median survival of patients in group A was 12 months.

Table Graphic Jump LocationTable 3. Operations Performed for 9 Adult Patients With Biliary Tract Malignancy Complicating Choledochal Cyst (Group A)

Complete excision of choledochal cyst with Roux-en-Y hepaticojejunostomy was performed for all patients in group A. One patient underwent concomitant left hemihepatectomy and another patient had a right hemihepatectomy for intrahepatic extension of the choledochal cyst (type IV). Operative morbidity in group B was 14%, and there were no operative mortalities. Postoperative complications included leakage from hepaticojejunostomy anastomosis that required laparotomy (1 patient), subhepatic collection that required percutaneous drainage (1 patient), and wound infection (1 patient). Median postoperative hospital stay was 11 days (range, 6-49 days). With a median follow-up of 66 months, all patients in group B were well and none of them developed symptoms suggestive of hepatobiliary disease, such as anastomotic stricture, acute cholangitis, acute pancreatitis, and biliary tract malignancy.

Choledochal cyst is an uncommon anomaly and is estimated to occur in 1 in 13 000 to 1 in 2 million live births.8,9 It is reported to be more common in Asian populations and in females.10,11 In neonates or children, it usually presents with an abdominal mass or abdominal pain.12 Initial manifestation in adulthood is rare, and the presentation is usually nonspecific right-upper-quadrant abdominal pain, jaundice, acute pancreatitis, or acute cholangitis.13 A palpable mass is rare.14,15 It was the chief presenting symptom in only 1 of the 30 patients in the present series. While presentation with acute cholangitis is rare in the pediatric age group,16 it is more common in adult patients with choledochal cysts.17,18 Acute cholangitis was the chief presenting symptom in 27% of our patients and was found to be significantly more common in patients with biliary tract malignancy.

The etiology of choledochal cyst is still controversial. The "common channel theory" proposed by Babbitt et al19 is the most commonly accepted theory. The presence of an abnormally long common channel and ineffective sphincter of Oddi around the union of the common bile duct and the pancreatic duct has been demonstrated by a number of investigators in many patients with choledochal cysts.11,2023 However, this theory cannot satisfactorily explain the cause of diverticular choledochal cyst, choledochocele, or intrahepatic cyst formation.

It was once thought that internal drainage of choledochal cysts was an appropriate and adequate treatment. However, it has become evident that 30% to 50% of patients with cystoduodenostomy have late complications, such as acute cholangitis, secondary biliary cirrhosis, and development of cholangiocarcinoma.1,24,25 Although Roux-en-Y cystojejunostomy was developed to avoid reflux of the duodenal contents into the biliary tree, acute cholangitis and other problems still commonly occur. While cystenterostomy is technically easier, cyst excision with Roux-en-Y hepaticojejunostomy can be performed with low morbidity and mortality,26 being 14% and 0%, respectively, in the present study.

Biliary tract malignancy has been reported to occur in 2.5% to 28% of patients with choledochal cyst, representing a risk at least 20 times greater than that of the normal population.17,25,2729 The risk is age related and has been reported to be 14.5% in patients older than 20 years.30 Possible factors for carcinogenesis in choledochal cysts include chronic inflammation, bile stagnation with possible development of carcinogens, and a spare distribution of the protective mucin-secreting glands of the bile duct.31,32 The incidence of biliary tract malignancy complicating choledochal cyst in the present series was 30%, which was the highest among the reported series.27 This could be explained by the pattern of referral to the tertiary surgical center. Patients with previous bile duct surgery and evidence suggestive of biliary tract malignancy were more likely to be referred for care to this center.

Biliary tract malignancy complicating choledochal cyst has been reported to be enhanced by cystenterostomy. It is postulated that pancreatic juice easily regurgitates into the bile duct through an anomalous junction of the pancreatobiliary ductal system in patients with choledochal cyst, and enteric drainage causes pancreatic juice in the cyst to become activated because of the influx of enteric content. Therefore, inflammatory changes of the cysts are accelerated and result in carcinoma.25 In the present study, 4 of the 9 patients with biliary tract malignancy had history of a previous drainage operation for choledochal cyst. The incidence was significantly higher than for patients without malignancy (P = .049). The mean age at detection of malignancy complicating choledochal cyst is influenced by previous internal drainage operations. The age at detection of biliary tract malignancy in patients with internal drainage was found to be 15 years less than the age in those without a previous drainage procedure, and most cases of malignant degeneration were detected, on average, 10 years after an internal drainage procedure.25 Since carcinoma developed from choledochal cyst has a very dismal prognosis even after radical surgical excision, and most patients die within 2 years of diagnosis,26,33 excision and biliary reconstruction rather than internal drainage is recommended as the treatment of choice for choledochal cyst.26

The operative morbidity of patients without biliary tract malignancy in the present series was 14% and appeared to be higher than that of patients in the pediatric age group.12 Complete excision of choledochal cyst in adults can be technically difficult, since pericystic inflammatory adhesion is common with repeated attacks of cholangitis and pancreatitis.26 Some researchers recommended leaving part or all of the cystic wall behind and performing cystenterostomy.15 With substantial risk of biliary tract malignancy after cystenterostomy, this should not be taken as an alternative to complete excision of choledochal cyst and hepaticojejunostomy. With a median follow-up of 66 months, no long-term complications were detected in our patients after complete excision of choledochal cyst and hepaticojejunostomy. However, there is evidence that patients who have undergone complete excision of choledochal cyst have an increased risk of developing carcinoma of the intrahepatic bile duct. Long-term close follow-up of these patients for early detection of malignancy is required.34

In summary, biliary tract malignancy complicating choledochal cyst in adults occurred in 30% of the patients in our study. The condition should be suspected in patients who have a history of internal drainage of choledochal cysts and present with cholangitis. The prognosis is still dismal, even after radical resection with pancreaticoduodenectomy. Complete excision of choledochal cyst with Roux-en-Y hepaticojejunostomy is the treatment of choice for patients without malignancy and can be performed with low operative morbidity and absence of long-term complications in adult patients.

Corresponding author: Chi-Leung Liu, MS, FRCS(Edin), Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong. (e-mail: clliu@hkucc.hku.hk).

Powell  CSSawyers  JLReynolds  VH Management of adult choledochal cysts. Ann Surg. 1981;193666- 676
Sela-Herman  SScharschmidt  BF Choledochal cyst, a disease for all ages. Lancet. 1996;347779
Fonkalsrud  EWBoles  ET  Jr Choledochal cysts in infancy and childhood. Surg Gynecol Obstet. 1965;121733- 742
O'Neill  JA  JrClatworthy  HW  Jr Management of choledochal cysts: a fourteen-year follow-up. Am Surg. 1971;37230- 237
Ishida  MTsuchida  YSaito  SHori  T Primary excision of choledochal cysts. Surgery. 1970;68884- 888
Deziel  DJRossi  RLMunson  JLBraasch  JWSilverman  ML Management of bile duct cysts in adults. Arch Surg. 1986;121410- 415
Todani  TWatanabe  YNarusue  MTabuchi  KOkajima  K Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg. 1977;134263- 269
Kasai  MAsakura  YTaira  Y Surgical treatment of choledochal cyst. Ann Surg. 1970;172844- 851
Howell  CGTempleton  JMWeiner  SGlassman  MBetts  JMWitzleben  CL Antenatal diagnosis and early surgery for choledochal cyst. J Pediatr Surg. 1983;18387- 393
O'Neill  JA  JrTempleton  JM  JrSchnaufer  LBishop  HCZiegler  MMRoss  AJ  III Recent experience with choledochal cyst. Ann Surg. 1987;205533- 540
Nagata  ESakai  KKinoshita  HHirohashi  K Choledochal cyst: complications of anomalous connection between the choledochus and pancreatic duct and carcinoma of the biliary tract. World J Surg. 1986;10102- 110
Stringer  MDDhawan  ADavenport  MMieli-Vergani  GMowat  APHoward  ER Choledochal cysts: lessons from a 20 year experience. Arch Dis Child. 1995;73528- 531
Lipsett  PAPitt  HAColombani  PMBoitnott  JKCameron  JL Choledochal cyst disease: a changing pattern of presentation. Ann Surg. 1994;220644- 652
O'Neill  JA  Jr Choledochal cyst. Curr Probl Surg. 1992;29361- 410
Kabra  VAgarwal  MAdukai  TKDixit  VKAgrawal  AKShukla  VK Choledochal cyst: a changing pattern of presentation. ANZ J Surg. 2001;71159- 161
Postema  RRHazebroek  FW Choledochal cysts in children: a review of 28 years of treatment in a Dutch children's hospital. Eur J Surg. 1999;1651159- 1161
Jan  YYChen  HMChen  MF Malignancy in choledochal cysts. Hepatogastroenterology. 2000;47337- 340
Chaudhary  ADhar  PSachdev  A  et al.  Choledochal cysts—differences in children and adults. Br J Surg. 1996;83186- 188
Babbitt  DPStarshak  RJClemett  AR Choledochal cyst: a concept of etiology. Am J Roentgenol Radium Ther Nucl Med. 1973;11957- 62
Iwai  NYanagihara  JTokiwa  KShimotake  TNakamura  K Congenital choledochal dilatation with emphasis on pathophysiology of the biliary tract. Ann Surg. 1992;21527- 30
Ono  JSakoda  KAkita  H Surgical aspect ot cystic dilatation of the bile duct: an anomalous junction of the pancreaticobiliary tract in adults. Ann Surg. 1982;195203- 208
Oguchi  YOkada  ANakamura  T  et al.  Histopathologic studies of congenital dilatation of the bile duct as related to an anomalous junction of the pancreaticobiliary ductal system: clinical and experimental studies. Surgery. 1988;103168- 173
Okada  ANakamura  THigaki  JOkumura  KKamata  SOguchi  Y Congenital dilatation of the bile duct in 100 instances and its relationship with anomalous junction. Surg Gynecol Obstet. 1990;171291- 298
Flanigan  DP Biliary carcinoma associated with biliary cysts. Cancer. 1977;40880- 883
Todani  TWatanabe  YToki  AUrushihara  N Carcinoma related to choledochal cysts with internal drainage operations. Surg Gynecol Obstet. 1987;16461- 64
Stain  SCGuthrie  CRYellin  AEDonovan  AJ Choledochal cyst in the adult. Ann Surg. 1995;222128- 133
Bloustein  PA Association of carcinoma with congenital cystic conditions of the liver and bile ducts. Am J Gastroenterol. 1977;6740- 46
Nagorney  DMMcIlrath  DCAdson  MA Choledochal cysts in adults: clinical management. Surgery. 1984;96656- 663
Rossi  RLSilverman  MLBraasch  JWMunson  JLReMine  SG Carcinomas arising in cystic conditions of the bile ducts: a clinical and pathologic study. Ann Surg. 1987;205377- 384
Voyles  CRSmadja  CShands  WCBlumgart  LH Carcinoma in choledochal cysts: age-related incidence. Arch Surg. 1983;118986- 988
Spitz  LPetropoulos  A The development of the glands of the common bile duct. J Pathol. 1979;128213- 220
Reveille  RMVan Stiegmann  GEverson  GT Increased secondary bile acids in a choledochal cyst: possible role in biliary metaplasia and carcinoma. Gastroenterology. 1990;99525- 527
Weyant  MJMaluccio  MABertagnolli  MMDaly  JM Choledochal cysts in adults: a report of two cases and review of the literature. Am J Gastroenterol. 1998;932580- 2583
Todani  TWatanabe  YToki  AUrushihara  NSato  Y Reoperation for congenital choledochal cyst. Ann Surg. 1988;207142- 147

Figures

Tables

Table Graphic Jump LocationTable 1. Clinical Data of 30 Adult Patients Who Had Choledochal Cyst With (Group A) and Without (Group B) Biliary Tract Malignancy
Table Graphic Jump LocationTable 2. Previous Surgery for Choledochal Cyst in Patients With (Group A) and Without (Group B) Biliary Tract Malignancy
Table Graphic Jump LocationTable 3. Operations Performed for 9 Adult Patients With Biliary Tract Malignancy Complicating Choledochal Cyst (Group A)

References

Powell  CSSawyers  JLReynolds  VH Management of adult choledochal cysts. Ann Surg. 1981;193666- 676
Sela-Herman  SScharschmidt  BF Choledochal cyst, a disease for all ages. Lancet. 1996;347779
Fonkalsrud  EWBoles  ET  Jr Choledochal cysts in infancy and childhood. Surg Gynecol Obstet. 1965;121733- 742
O'Neill  JA  JrClatworthy  HW  Jr Management of choledochal cysts: a fourteen-year follow-up. Am Surg. 1971;37230- 237
Ishida  MTsuchida  YSaito  SHori  T Primary excision of choledochal cysts. Surgery. 1970;68884- 888
Deziel  DJRossi  RLMunson  JLBraasch  JWSilverman  ML Management of bile duct cysts in adults. Arch Surg. 1986;121410- 415
Todani  TWatanabe  YNarusue  MTabuchi  KOkajima  K Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg. 1977;134263- 269
Kasai  MAsakura  YTaira  Y Surgical treatment of choledochal cyst. Ann Surg. 1970;172844- 851
Howell  CGTempleton  JMWeiner  SGlassman  MBetts  JMWitzleben  CL Antenatal diagnosis and early surgery for choledochal cyst. J Pediatr Surg. 1983;18387- 393
O'Neill  JA  JrTempleton  JM  JrSchnaufer  LBishop  HCZiegler  MMRoss  AJ  III Recent experience with choledochal cyst. Ann Surg. 1987;205533- 540
Nagata  ESakai  KKinoshita  HHirohashi  K Choledochal cyst: complications of anomalous connection between the choledochus and pancreatic duct and carcinoma of the biliary tract. World J Surg. 1986;10102- 110
Stringer  MDDhawan  ADavenport  MMieli-Vergani  GMowat  APHoward  ER Choledochal cysts: lessons from a 20 year experience. Arch Dis Child. 1995;73528- 531
Lipsett  PAPitt  HAColombani  PMBoitnott  JKCameron  JL Choledochal cyst disease: a changing pattern of presentation. Ann Surg. 1994;220644- 652
O'Neill  JA  Jr Choledochal cyst. Curr Probl Surg. 1992;29361- 410
Kabra  VAgarwal  MAdukai  TKDixit  VKAgrawal  AKShukla  VK Choledochal cyst: a changing pattern of presentation. ANZ J Surg. 2001;71159- 161
Postema  RRHazebroek  FW Choledochal cysts in children: a review of 28 years of treatment in a Dutch children's hospital. Eur J Surg. 1999;1651159- 1161
Jan  YYChen  HMChen  MF Malignancy in choledochal cysts. Hepatogastroenterology. 2000;47337- 340
Chaudhary  ADhar  PSachdev  A  et al.  Choledochal cysts—differences in children and adults. Br J Surg. 1996;83186- 188
Babbitt  DPStarshak  RJClemett  AR Choledochal cyst: a concept of etiology. Am J Roentgenol Radium Ther Nucl Med. 1973;11957- 62
Iwai  NYanagihara  JTokiwa  KShimotake  TNakamura  K Congenital choledochal dilatation with emphasis on pathophysiology of the biliary tract. Ann Surg. 1992;21527- 30
Ono  JSakoda  KAkita  H Surgical aspect ot cystic dilatation of the bile duct: an anomalous junction of the pancreaticobiliary tract in adults. Ann Surg. 1982;195203- 208
Oguchi  YOkada  ANakamura  T  et al.  Histopathologic studies of congenital dilatation of the bile duct as related to an anomalous junction of the pancreaticobiliary ductal system: clinical and experimental studies. Surgery. 1988;103168- 173
Okada  ANakamura  THigaki  JOkumura  KKamata  SOguchi  Y Congenital dilatation of the bile duct in 100 instances and its relationship with anomalous junction. Surg Gynecol Obstet. 1990;171291- 298
Flanigan  DP Biliary carcinoma associated with biliary cysts. Cancer. 1977;40880- 883
Todani  TWatanabe  YToki  AUrushihara  N Carcinoma related to choledochal cysts with internal drainage operations. Surg Gynecol Obstet. 1987;16461- 64
Stain  SCGuthrie  CRYellin  AEDonovan  AJ Choledochal cyst in the adult. Ann Surg. 1995;222128- 133
Bloustein  PA Association of carcinoma with congenital cystic conditions of the liver and bile ducts. Am J Gastroenterol. 1977;6740- 46
Nagorney  DMMcIlrath  DCAdson  MA Choledochal cysts in adults: clinical management. Surgery. 1984;96656- 663
Rossi  RLSilverman  MLBraasch  JWMunson  JLReMine  SG Carcinomas arising in cystic conditions of the bile ducts: a clinical and pathologic study. Ann Surg. 1987;205377- 384
Voyles  CRSmadja  CShands  WCBlumgart  LH Carcinoma in choledochal cysts: age-related incidence. Arch Surg. 1983;118986- 988
Spitz  LPetropoulos  A The development of the glands of the common bile duct. J Pathol. 1979;128213- 220
Reveille  RMVan Stiegmann  GEverson  GT Increased secondary bile acids in a choledochal cyst: possible role in biliary metaplasia and carcinoma. Gastroenterology. 1990;99525- 527
Weyant  MJMaluccio  MABertagnolli  MMDaly  JM Choledochal cysts in adults: a report of two cases and review of the literature. Am J Gastroenterol. 1998;932580- 2583
Todani  TWatanabe  YToki  AUrushihara  NSato  Y Reoperation for congenital choledochal cyst. Ann Surg. 1988;207142- 147

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 46

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Topics
PubMed Articles