ORIGINAL ARTICLE
Double-Duct Sign in the Clinical Context Rohit Sinha, MBBS, MRCP, PgDip,* Terri Gardner, MBChb,* Krishnaveni Padala, MBBS,* John Richard Greenaway, MD, MBBS, FRCP,* and Diamond Joy, MD, MSc, MBBS, FRCP† Objectives: Double-duct sign (combined dilatation of the common bile duct and pancreatic duct) is an infrequently encountered finding in crosssectional radiological imaging of the pancreatobiliary system. This sign is commonly deemed to signify on ominous pathology and suggests the presence of pancreatic or biliary malignancy. Methods: We aim to correlate double-duct sign discovered on magnetic resonance cholangiopancreatogram (MRCP) in the clinical context. We retrospectively analyzed MRCP database over a period of 4 years, January 2010 to December 2013. Follow-up information was available for a median of 27 months (range, 12–42 months) Results: The commonest cause of double-duct sign was choledocholithiasis followed closely by pancreatobiliary malignancy. Patients with jaundice in the context of double-duct sign had a higher incidence of malignancy (48%). None of the anicteric patients were found to have malignancy (P = 0.002). Conclusions: In patients with MRCP evidence of double-duct sign, the absence of jaundice makes a malignant etiology unlikely. Conversely, in jaundiced patients, a malignant cause is much more likely. Figures from larger series are needed to support this conclusion.
MATERIALS AND METHODS Study Design and Patient Selection In a large gastroenterology unit of a tertiary center, we retrospectively analyzed all the MRCP reports through our computer database using the picture archiving and communication system (PACS, Agfa Healthcare, Belgium) over a period of 4 years, January 2010 to December 2013 (Fig. 1). The radiological reports with dilated CBD and PD or double-duct sign were included. Common bile duct greater than 8 mm with intact gallbladder and 10 mm postcholecystectomy is considered dilated on magnetic resonance imaging (MRI).5 Similarly, a PD measuring greater than 3 mm in the head, 2 mm in the body, and 1 mm in the tail of the pancreas is considered dilated.6 These were all interpreted and reported by the specialist gastrointestinal radiologists. We purposely chose to interrogate the MRCP database because of its diagnostic accuracy7 and, for the same reason, an investigation of choice in our center.
Data Collection and Statistical Analysis
D
The demographics, liver biochemistry, final diagnosis, and outcome for all included patients with the double-duct sign were accessed using the radiology PACS system, biochemical results through ICE (Sunquest Integrated Clinical Environment, Tuscon, Ariz) correspondence from hospital, operative notes, pathology database in select cases, and medical case notes. Follow-up information was available for a mean of 36 months (range, 12–48 months). Our local clinical governance review board approved this study. Histology that was interpreted as “no evidence of invasive malignancy” was considered as negative for malignancy for purposes of this study. We have described the cases where ampullary lesion had been visualized on the MRCP. Statistical (Fig. 2) and demographic analysis was carried from the data obtained from the study.
From the *Gastroenterology, James Cook University Hospital, Middlesborough, United Kingdom; and †Gastroenterology, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia. Received for publication July 20, 2014; accepted January 13, 2015. Reprints: Rohit Sinha, MBBS, MRCP, PgDip, James Cook University Hospital, Marton Rd, Middlesborough TS4 3BW, United Kingdom (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Two thousand seven hundred forty-one patients underwent MRCP examination over a 4-year period from January 2010 to December 2013. Table 1 summarizes the characteristic findings of our study. Eighty-one patients (2.2%–3.3% annual incidence) had double-duct sign with a mean age of 71 (SD, 17.5) years. In our cohort, there was female predominance (male-to-female ratio, 1:1.2), and the commonest cause of double-duct sign was choledocholithiasis (27.2%) followed by malignancy (20%). Patients with jaundice in the context of double-duct sign had a higher incidence of malignancy. A diagnosis of malignancy was made in 16 of 33 jaundiced study patients (sensitivity, 100%; 95% confidence interval [CI], 79.2%–100%) and 0 for non-jaundiced patient (specificity, 73.8%; 95% CI, 61.4%–83.9%). Positive predictive value of double-duct sign in the presence of jaundice was 48.8% (95% CI, 30.8%–66.4%) for malignancy and negative predictive value of double-duct sign in the absence of jaundice was 100% (95% CI, 92.5%–100%). More than half of the patients (48/81 [59%]) with doubleduct sign were anicteric. None of the anicteric patients were found to have a malignancy. All anicteric patients with double-duct sign had a benign disease, and 71% of those checked had normal tumor
Key Words: common bile duct and pancreatic duct dilatation, double-duct sign, jaundice, MRCP Abbreviations: CT - computed tomography, ERCP - endoscopic retrograde cholangiopancreatogram, EUS - endoscopic ultrasound, MRCP - magnetic resonance cholangiopancreatogram, PD - pancreatic duct (Pancreas 2015;44: 967–970)
ouble-duct sign is a common term used by the radiologist for coexisting dilatation of the common bile duct (CBD) and pancreatic duct (PD), a finding usually encountered on magnetic resonance cholangiopancreatogram (MRCP) and/or computed tomography (CT) of the pancreatobiliary system. Whereas some literatures strongly correlate such findings with malignancy,1,2 others are more pragmatic.3,4 With access and advent of sophisticated cross-sectional imaging, it is important to explore the clinical significance of such findings, which was initially coined for findings on endoscopic retrograde cholangiopancreatograms (ERCPs). We aim to evaluate such finding at our center and relate clinically with longitudinal follow-up.
Pancreas • Volume 44, Number 6, August 2015
RESULTS
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FIGURE 1. Study design and patient selection flowchart.
markers. Of the anicteric patients, 25% (12/48) had completely normal liver test, and the remaining 75% (36/48) had some abnormality of the liver enzymes (raised γ-glutamyl transferase and/or alkaline phosphatase). Carcinoma of the head of the pancreas was the commonest malignant cause for double-duct sign; none were anicteric. More than a half, 54%, were at early stages (stage I-IIA) of the carcinoma of the head of the pancreas (Fig. 3). Four patients in the anicteric group had benign tumors (1 case of benign intraductal papillary mucinous neoplasm and 3 cases of benign ampullary tumor, histology confirming low- and highgrade dysplasia without evidence of invasive malignancy on resection specimens). The benign nature was confirmed on clinical, pathological, and radiological follow-up. No surgical intervention was deemed appropriate for any of these patients. All 3 remained anicteric over the period of follow-up (mean, 24 months and unrelated death at 18 months). Follow-up information was available for a mean of 36 months (range, 24–48 months). The cases of benign ampullary lesions have been described as follows: A 70-year-old woman with a background of neurofibromatosis type 1 had MRCP for deranged liver tests in the absence of jaundice (raised alkaline phosphatase and γ-glutamyl transferase). She had significant dilatation of the extrahepatic biliary ducts, mild PD dilatation, and an ampullary lesion. Biopsies from the lesion on microscopic examination revealed irregularly distributed glandular structures and focal solid nests formed by mediumsized cells with a pale granular, lightly eosinophilic cytoplasm and oval nuclei with a homogenous chromatin. No mitosis or psammoma bodies were observed. Immunohistochemistry were positive for AE1/AE3 and diffusely positive for synaptophysin
and somatostatin but negative for chromogranin and gastrin. Ki67 index was estimated as approximately 1%, concluding well-differentiated endocrine tumor of the ampulla with somatostatin expression with no evidence of lymphovascular or perineural invasion, World Health Organization classification 2010 of NET G1. The second patient was an 80-year-old woman investigated for double-duct sign in the presence of abnormal liver tests without jaundice. Endoscopic ultrasound (confirmed ampullary mass without metastasis or local invasion). Biopsy of the ampullary lesion was consistent with high-grade adenoma. Regional multi-disciplinary team discussion favored pancreaticoduodenectomy, and ampullary adenoma with high-grade dysplasia was concluded on examination of the resected specimen. The general practitioner referred the third patient with a dilated CBD on ultrasound following an abnormal liver function test (isolated elevated γ-glutamyl transferase with normal alkaline phosphatase and bilirubin). Magnetic resonance cholangiopancreatogram raised the possibility of an ampullary lesion with double-duct sign. Pancreatic protocol CT did not add any further information, and he underwent a duodenoscopy. It revealed a large periampullary diverticulum with normal ampulla. The patient was kept under regular reviews and was finally discharged after 18 months of follow-up. The fourth patient was of a 92-year-old woman known to the hematologists for having non-Hodgkin lymphoma, follicular type, grade I/II, stage IVB disease, who previously received treatment with chlorambucil. Four years later as a part of her disease monitoring, CT scan and subsequently MRCP revealed double-duct sign with prominence of the ampulla. Duodenoscopy confirmed ampullary tumor, which on histology showed ampullary adenoma
FIGURE 2. Statistical analysis.
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Pancreas • Volume 44, Number 6, August 2015
Double-Duct Sign
TABLE 1. Double-Duct Findings (n = 81) Patients With Double-Duct Signs
n
%
Malignancy Carcinoma of the head of the pancreas Cholangiocarcinoma Metastatic external compression IPMN Benign Choledocholithiasis Chronic pancreatitis Pancreatic cyst Common channel fibrotic stricture Anatomical variation Ampullary lesion (NET/LGD/HGD/diverticulum) Idiopathic IPMN
16 12 1 1 2 65 22 10 6 17 2 4 3 1
20 75 6 6 13 80 34 15 9 26 4 6 5 1
CaHOP indicates carcinoma of the head of the pancreas; HGD, highgrade dysplasia; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; NET, neuroendocrine tumor.
with low-grade dysplasia. There was no evidence of malignancy. Her case was discussed at the cancer multidisciplinary meeting, and the plan was to provide supportive care with biliary stent if she became jaundiced. Throughout her follow-up of 12 months, she remained anicteric with mildly cholestatic liver tests (alkaline phosphatase of 184 IU/L [40–125 IU/L]) and γ-glutamyl transferase of 76 IU/L (reference, 1–80 IU/L). Our results show that double-duct sign in the absence of jaundice makes a malignant etiology unlikely (P < 0.005). In presence of jaundice, a double-duct sign on MRCP is strongly associated with pancreatobiliary malignancy. These finding seem to correlate with other studies.1,3,4,8,9
DISCUSSION Freeney et al1,2 coined the term double-duct sign in 1976 on diagnostic ERCP. More widely, this term is now adopted by the radiologists reporting cross-sectional imaging and on abdominal ultrasound, where the body habitus allows visualization of CBD and PD.
There are no set criteria for ducts dilatation to qualify for double duct; however, a CBD greater than 8 mm with intact gallbladder and 10-mm postcholecystectomy is considered dilated on CT and MRI. Similarly, a PD measuring greater than 3 mm in the head, 2 mm in the body, and 1 mm in the tail of the pancreas is considered dilated.6 Most of the description of double-duct sign arises from ERCP data and is extrapolated onto cross-sectional imaging. On the ERCP data, sensitivity and specificity of the double-duct sign for malignancy were 38% to 76%8,10 and 60% to 93%,10,11 respectively, and the positive predictive value was 21% to 80%.8,10 Univariate predictors of malignancy included stricture location in the pancreatic head/neck, jaundice, and patient age, whereas history of pancreatitis, multiple strictures, PD stones, pseudocyst, pancreas divisum anatomy, irregular side branches, and irregular PD morphology are predictors of benign process.8 Based on our finding, we recommend use of further investigations, such as pancreatic protocol CT and/or EUS ± fine-needle aspiration, if the index cross-sectional imaging fails to show any malignancy in the presence of double-duct sign and jaundice. The latter has high accuracy for diagnosing pancreatobiliary malignancy.12 Clinical adjuncts such as weight loss and lymphadenopathy are subtle signs that help risk stratify and persuade to investigate further. On further literature searches, we did not find any pancreatobiliary malignancy described in case reports (Table 2) of double-duct sign in anicteric individuals.
CONCLUSIONS Double duct does not unequivocally mean malignancy. It is a term first described in ERCP and carried over to present day in cross-sectional imaging. Several studies have compared diagnostic yield of ERCP with MRCP,12 none validating the predictive power of MRCP.19 Menges et al3,4 observed, in the presence of pancreatic mass or obstructive jaundice, that the discovery of double duct on ERCP has 85% malignancy yield. The prevalence of malignancy is lower on double-duct cases on cross-sectional imaging compared with ERCP data as above (Table 3) and in our experience. It is not a routine practice to cannulate PD unless clinically indicated. This may result in missed cases on ERCP and thus introducing bias favoring high sensitivities. Magnetic resonance cholangiopancreatogram, being a noninvasive imaging modality and risk-free of radiation and contrast hazard, tends to pick up incidental PD dilatation. In such scenarios, clinical context of jaundice provides robust risk stratification. While ERCP provides tissue diagnosis with variable yield, its role should be reserved to obtain tissue diagnosis and/or interventional approach for palliative reasons. TABLE 2. Case Reports on Double Ducts Duct Size, mm Double-Duct Sign 13
Gallstone Helminth (Strongyloides stercolis)14 Serous cystadenoma15 Opiate-induced SOD16 GIST17 Helmith (dead Ascaris)18
FIGURE 3. Carcinoma of the head of the pancreas. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Jaundice Index Imaging
PD/CBD
Absent Absent
AUSS MRCP
4/16 —
Absent Present Present Present
MRCP AUSS CT AUSS
5/10 — 8/13 3/10.8
AUSS indicates abdominal ultrasound; GIST, gastrointestinal stromal tumor; SOD, sphincter of Oddi.
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carcinoma: the ‘double duct’ and other signs. Radiology. 1976;119: 271–274.
TABLE 3. Comparative Study and Analysis No. Patients 43 52 11 26 21 49 234 55 82 38
Double Duct on Imaging
Jaundice, n (%)
Malignancy, n (%)
ERCP3 ERCP4 ERCP1 CT19 ERCP11 ERCP10 CT or MRI9 ERCP20 EUS21 CT or MRI or EUS22
— — — 15 (58) — — 166 (71) — 0 (0) 0 (0)
35 (81) 30 (58) 11 (100) 17 (65) 8 (38) 4 (8.2) 146 (62) 10 (18.2) 6 (7.3) 0 (0)
Our study concludes that malignancy is higher in the context of jaundice with double-duct sign on cross-sectional imaging than the latter on its own. In cases, where further mass is demonstrated on imaging in conjunction with double-duct sign, it is prudent to investigate with further invasive or noninvasive modalities even in the absence of jaundice. In the absence of jaundice, double duct has lower yield of malignancy; however, malignancy has been described in 5.9% to 7.3% (P < 0.005).9,21 There are limitations to this retrospective study such as possible missed cases, especially those who may have had a CT instead of MRCP for various absolute or relative contraindications. We also recognize that we did not investigate cases of double-ducts signs further with EUS as demonstrated by Cohen et al.21 The EUS study of Mitra et al22 demonstrates a causative diagnosis of 13% in the setting of normal biochemical liver tests and dilated ducts; none were malignant. We recognize that EUS may not be a universally available investigation, certainly not in a district general hospital setting. With access to more cross-sectional imaging, incidental findings such as double ducts and pancreatic cysts are growing. There is a growing need to rationalize and risk-stratify the patients who are in greater need for investigations, which are not widely available. Equally, onus should be laid upon as to how far patients would like to be examined through an honest and evidence-based discussion. Informed patient’s choice based on the above incidence of 7.3%,21 age comorbidity, and other factors should be taken in account through a multidisciplinary approach before pursuing an EUS. Our study showed that 4 of 65 patients without jaundice had ampullary lesion. None of these lesions were malignant; all these patients are alive on follow-up. Only 1 required surgery, but on histology, this patient was not reported as having a malignant lesion. It seems we would need to perform EUS in 16 patients with double-duct sign who are not jaundiced to find out one with ampullary lesion, which is benign. We need to make an informed decision based on the clinical context. There is paucity of strong evidence, and ambiguity in clinical practise prevails. Hence, there seems to be a need for larger prospective studies to establish guidance and risk stratification into further investigating double-duct sign both in the presence and absence of jaundice. REFERENCES 1. Freeney P, Bilbao M, Katon R. “Blind” evaluation of endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis of pancreatic
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2. Baillie J, Paulson EK, Vitellas KM. Biliary Imaging: a review. Gastroenterology. 2003;125:1565. 3. Menges M, Lerch MM, Zeitz M. The double duct sign in patients with malignant and benign pancreatic lesions. Gastrointest Endosc. 2000; 52:74–77. 4. Plumley TF, Rohrmann CA, Freeny PC, et al. Double duct sign: reassessed significance in ERCP. Am J Roentgenol. 1982;138:31–35. 5. Soto JA, Barish MA, Ferrucci JT. Magnetic resonance imaging of the bile ducts. Semin Roentgenol. 1997;32:188–201. 6. Ladas SD, Tassios PS, Giorgiotis K, et al. Pancreatic duct width: its significance as a diagnostic criterion for pancreatic disease. Hepatogastroenterology. 1993;40:52–55. 7. Singh A, Mann HS, Thukral CL, et al. Diagnostic accuracy of MRCP as compared to ultrasound/CT in patients with obstructive jaundice. J Clin Diagn Res. 2014;8:103–107. 8. Kalady MF, Peterson B, Baillie J, et al. Pancreatic duct strictures: identifying risk of malignancy. Ann Surg Oncol. 2004;11:581–588. 9. Krishna N, Tummala P, Reddy A, et al. Dilation of both pancreatic duct and the common bile duct on computed tomography and magnetic resonance imaging scans in patients with or without obstructive jaundice. Pancreas. 2012;41:767–772. 10. Ralls PW, Halls J, Renner I, et al. Endoscopic retrograde cholangiopancreatography (ERCP) in pancreatic disease. Radiology. 1980;134:347–352. 11. Inoue K, Ohuchida J, Ohtsuka T, et al. Severe localized stenosis and marked dilatation of the main pancreatic duct are indicators of pancreatic cancer instead of chronic pancreatitis on endoscopic retrograde balloon pancreatography. Gastrointest Endosc. 2003;58:510–515. 12. Georgopoulos SK, Schwartz LH, Jarnagin WR, et al. Comparison of magnetic resonance and endoscopic retrograde cholangiopancreatography in malignant pancreaticobiliary obstruction. Arch Surg. 1999;134: 1002–1007. 13. Oterdoom L, Weyenberg S, Boer N. Double-duct sign: do not forget gallstones. J Gastrointestin Liver Dis. 2013;22:447–450. 14. Dearden JC, Ayaru L, Wong V, et al. The double duct sign. Lancet. 2004; 364:302. 15. Khalpey Z, Rajab TK, Ashley SW, et al. Serous cystadenoma causing the double duct sign. J Gastrointest Surg. 2012;16:1282–1283. 16. Sharma M, Balakrishnan M. An unusual cause of double duct sign. Type I sphincter of Oddi dysfunction due to chronic opium addiction. Gastroenterology. 2011;40:e1–e2. 17. Kalman R, Bresnick M, Huang C. Now you see it, now you don’t: an unusual cause of the “double duct sign”. Gastroenterology. 2014;146: 348–592. 18. Sharma M, Mookiah B, Hari RS, et al. Double duct sign in a 3-year-old child. Gastroenterology. 2014;146:e6–e7. 19. Edge M, Hoteit M, Patel A, et al. Clinical significance of main pancreatic duct dilation on computed tomography: single and double duct dilation. World J Gastroenterol. 2007;13:1701–1705. 20. Shemesh E, Czerniak A, Nass S, et al. Role of endoscopic retrograde cholangiopancreatography in differentiating pancreatic cancer coexisting with chronic pancreatitis. Cancer. 1990;65:893–896. 21. Cohen J, Sawhney MS, Pleskow DK, et al. Double-Duct sign in the era of endoscopic ultrasound: the prevalence of occult pancreaticobiliary malignancy. Dig Dis Sci. 2014;59:2280–2285. 22. Mitra V, Nayar M, Bonninton S, et al. Yield of endoscopic ultrasound (EUS) in patients with dilated common bile duct (CBD) and or pancreatic duct (PD) with normal liver function tests (LFTs) and cross sectional imaging. Gut. 2013;62:A238.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Double-Duct Sign in the Clinical Context Rohit Sinha, MBBS, MRCP, PgDip,* Terri Gardner, MBChb,* Krishnaveni Padala, MBBS,* John Richard Greenaway, MD, MBBS, FRCP,* and Diamond Joy, MD, MSc, MBBS, FRCP† Objectives: Double-duct sign (combined dilatation of the common bile duct and pancreatic duct) is an infrequently encountered finding in crosssectional radiological imaging of the pancreatobiliary system. This sign is commonly deemed to signify on ominous pathology and suggests the presence of pancreatic or biliary malignancy. Methods: We aim to correlate double-duct sign discovered on magnetic resonance cholangiopancreatogram (MRCP) in the clinical context. We retrospectively analyzed MRCP database over a period of 4 years, January 2010 to December 2013. Follow-up information was available for a median of 27 months (range, 12–42 months) Results: The commonest cause of double-duct sign was choledocholithiasis followed closely by pancreatobiliary malignancy. Patients with jaundice in the context of double-duct sign had a higher incidence of malignancy (48%). None of the anicteric patients were found to have malignancy (P = 0.002). Conclusions: In patients with MRCP evidence of double-duct sign, the absence of jaundice makes a malignant etiology unlikely. Conversely, in jaundiced patients, a malignant cause is much more likely. Figures from larger series are needed to support this conclusion.
MATERIALS AND METHODS Study Design and Patient Selection In a large gastroenterology unit of a tertiary center, we retrospectively analyzed all the MRCP reports through our computer database using the picture archiving and communication system (PACS, Agfa Healthcare, Belgium) over a period of 4 years, January 2010 to December 2013 (Fig. 1). The radiological reports with dilated CBD and PD or double-duct sign were included. Common bile duct greater than 8 mm with intact gallbladder and 10 mm postcholecystectomy is considered dilated on magnetic resonance imaging (MRI).5 Similarly, a PD measuring greater than 3 mm in the head, 2 mm in the body, and 1 mm in the tail of the pancreas is considered dilated.6 These were all interpreted and reported by the specialist gastrointestinal radiologists. We purposely chose to interrogate the MRCP database because of its diagnostic accuracy7 and, for the same reason, an investigation of choice in our center.
Data Collection and Statistical Analysis
D
The demographics, liver biochemistry, final diagnosis, and outcome for all included patients with the double-duct sign were accessed using the radiology PACS system, biochemical results through ICE (Sunquest Integrated Clinical Environment, Tuscon, Ariz) correspondence from hospital, operative notes, pathology database in select cases, and medical case notes. Follow-up information was available for a mean of 36 months (range, 12–48 months). Our local clinical governance review board approved this study. Histology that was interpreted as “no evidence of invasive malignancy” was considered as negative for malignancy for purposes of this study. We have described the cases where ampullary lesion had been visualized on the MRCP. Statistical (Fig. 2) and demographic analysis was carried from the data obtained from the study.
From the *Gastroenterology, James Cook University Hospital, Middlesborough, United Kingdom; and †Gastroenterology, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia. Received for publication July 20, 2014; accepted January 13, 2015. Reprints: Rohit Sinha, MBBS, MRCP, PgDip, James Cook University Hospital, Marton Rd, Middlesborough TS4 3BW, United Kingdom (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Two thousand seven hundred forty-one patients underwent MRCP examination over a 4-year period from January 2010 to December 2013. Table 1 summarizes the characteristic findings of our study. Eighty-one patients (2.2%–3.3% annual incidence) had double-duct sign with a mean age of 71 (SD, 17.5) years. In our cohort, there was female predominance (male-to-female ratio, 1:1.2), and the commonest cause of double-duct sign was choledocholithiasis (27.2%) followed by malignancy (20%). Patients with jaundice in the context of double-duct sign had a higher incidence of malignancy. A diagnosis of malignancy was made in 16 of 33 jaundiced study patients (sensitivity, 100%; 95% confidence interval [CI], 79.2%–100%) and 0 for non-jaundiced patient (specificity, 73.8%; 95% CI, 61.4%–83.9%). Positive predictive value of double-duct sign in the presence of jaundice was 48.8% (95% CI, 30.8%–66.4%) for malignancy and negative predictive value of double-duct sign in the absence of jaundice was 100% (95% CI, 92.5%–100%). More than half of the patients (48/81 [59%]) with doubleduct sign were anicteric. None of the anicteric patients were found to have a malignancy. All anicteric patients with double-duct sign had a benign disease, and 71% of those checked had normal tumor
Key Words: common bile duct and pancreatic duct dilatation, double-duct sign, jaundice, MRCP Abbreviations: CT - computed tomography, ERCP - endoscopic retrograde cholangiopancreatogram, EUS - endoscopic ultrasound, MRCP - magnetic resonance cholangiopancreatogram, PD - pancreatic duct (Pancreas 2015;44: 967–970)
ouble-duct sign is a common term used by the radiologist for coexisting dilatation of the common bile duct (CBD) and pancreatic duct (PD), a finding usually encountered on magnetic resonance cholangiopancreatogram (MRCP) and/or computed tomography (CT) of the pancreatobiliary system. Whereas some literatures strongly correlate such findings with malignancy,1,2 others are more pragmatic.3,4 With access and advent of sophisticated cross-sectional imaging, it is important to explore the clinical significance of such findings, which was initially coined for findings on endoscopic retrograde cholangiopancreatograms (ERCPs). We aim to evaluate such finding at our center and relate clinically with longitudinal follow-up.
Pancreas • Volume 44, Number 6, August 2015
RESULTS
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967
Pancreas • Volume 44, Number 6, August 2015
Sinha et al
FIGURE 1. Study design and patient selection flowchart.
markers. Of the anicteric patients, 25% (12/48) had completely normal liver test, and the remaining 75% (36/48) had some abnormality of the liver enzymes (raised γ-glutamyl transferase and/or alkaline phosphatase). Carcinoma of the head of the pancreas was the commonest malignant cause for double-duct sign; none were anicteric. More than a half, 54%, were at early stages (stage I-IIA) of the carcinoma of the head of the pancreas (Fig. 3). Four patients in the anicteric group had benign tumors (1 case of benign intraductal papillary mucinous neoplasm and 3 cases of benign ampullary tumor, histology confirming low- and highgrade dysplasia without evidence of invasive malignancy on resection specimens). The benign nature was confirmed on clinical, pathological, and radiological follow-up. No surgical intervention was deemed appropriate for any of these patients. All 3 remained anicteric over the period of follow-up (mean, 24 months and unrelated death at 18 months). Follow-up information was available for a mean of 36 months (range, 24–48 months). The cases of benign ampullary lesions have been described as follows: A 70-year-old woman with a background of neurofibromatosis type 1 had MRCP for deranged liver tests in the absence of jaundice (raised alkaline phosphatase and γ-glutamyl transferase). She had significant dilatation of the extrahepatic biliary ducts, mild PD dilatation, and an ampullary lesion. Biopsies from the lesion on microscopic examination revealed irregularly distributed glandular structures and focal solid nests formed by mediumsized cells with a pale granular, lightly eosinophilic cytoplasm and oval nuclei with a homogenous chromatin. No mitosis or psammoma bodies were observed. Immunohistochemistry were positive for AE1/AE3 and diffusely positive for synaptophysin
and somatostatin but negative for chromogranin and gastrin. Ki67 index was estimated as approximately 1%, concluding well-differentiated endocrine tumor of the ampulla with somatostatin expression with no evidence of lymphovascular or perineural invasion, World Health Organization classification 2010 of NET G1. The second patient was an 80-year-old woman investigated for double-duct sign in the presence of abnormal liver tests without jaundice. Endoscopic ultrasound (confirmed ampullary mass without metastasis or local invasion). Biopsy of the ampullary lesion was consistent with high-grade adenoma. Regional multi-disciplinary team discussion favored pancreaticoduodenectomy, and ampullary adenoma with high-grade dysplasia was concluded on examination of the resected specimen. The general practitioner referred the third patient with a dilated CBD on ultrasound following an abnormal liver function test (isolated elevated γ-glutamyl transferase with normal alkaline phosphatase and bilirubin). Magnetic resonance cholangiopancreatogram raised the possibility of an ampullary lesion with double-duct sign. Pancreatic protocol CT did not add any further information, and he underwent a duodenoscopy. It revealed a large periampullary diverticulum with normal ampulla. The patient was kept under regular reviews and was finally discharged after 18 months of follow-up. The fourth patient was of a 92-year-old woman known to the hematologists for having non-Hodgkin lymphoma, follicular type, grade I/II, stage IVB disease, who previously received treatment with chlorambucil. Four years later as a part of her disease monitoring, CT scan and subsequently MRCP revealed double-duct sign with prominence of the ampulla. Duodenoscopy confirmed ampullary tumor, which on histology showed ampullary adenoma
FIGURE 2. Statistical analysis.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 6, August 2015
Double-Duct Sign
TABLE 1. Double-Duct Findings (n = 81) Patients With Double-Duct Signs
n
%
Malignancy Carcinoma of the head of the pancreas Cholangiocarcinoma Metastatic external compression IPMN Benign Choledocholithiasis Chronic pancreatitis Pancreatic cyst Common channel fibrotic stricture Anatomical variation Ampullary lesion (NET/LGD/HGD/diverticulum) Idiopathic IPMN
16 12 1 1 2 65 22 10 6 17 2 4 3 1
20 75 6 6 13 80 34 15 9 26 4 6 5 1
CaHOP indicates carcinoma of the head of the pancreas; HGD, highgrade dysplasia; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; NET, neuroendocrine tumor.
with low-grade dysplasia. There was no evidence of malignancy. Her case was discussed at the cancer multidisciplinary meeting, and the plan was to provide supportive care with biliary stent if she became jaundiced. Throughout her follow-up of 12 months, she remained anicteric with mildly cholestatic liver tests (alkaline phosphatase of 184 IU/L [40–125 IU/L]) and γ-glutamyl transferase of 76 IU/L (reference, 1–80 IU/L). Our results show that double-duct sign in the absence of jaundice makes a malignant etiology unlikely (P < 0.005). In presence of jaundice, a double-duct sign on MRCP is strongly associated with pancreatobiliary malignancy. These finding seem to correlate with other studies.1,3,4,8,9
DISCUSSION Freeney et al1,2 coined the term double-duct sign in 1976 on diagnostic ERCP. More widely, this term is now adopted by the radiologists reporting cross-sectional imaging and on abdominal ultrasound, where the body habitus allows visualization of CBD and PD.
There are no set criteria for ducts dilatation to qualify for double duct; however, a CBD greater than 8 mm with intact gallbladder and 10-mm postcholecystectomy is considered dilated on CT and MRI. Similarly, a PD measuring greater than 3 mm in the head, 2 mm in the body, and 1 mm in the tail of the pancreas is considered dilated.6 Most of the description of double-duct sign arises from ERCP data and is extrapolated onto cross-sectional imaging. On the ERCP data, sensitivity and specificity of the double-duct sign for malignancy were 38% to 76%8,10 and 60% to 93%,10,11 respectively, and the positive predictive value was 21% to 80%.8,10 Univariate predictors of malignancy included stricture location in the pancreatic head/neck, jaundice, and patient age, whereas history of pancreatitis, multiple strictures, PD stones, pseudocyst, pancreas divisum anatomy, irregular side branches, and irregular PD morphology are predictors of benign process.8 Based on our finding, we recommend use of further investigations, such as pancreatic protocol CT and/or EUS ± fine-needle aspiration, if the index cross-sectional imaging fails to show any malignancy in the presence of double-duct sign and jaundice. The latter has high accuracy for diagnosing pancreatobiliary malignancy.12 Clinical adjuncts such as weight loss and lymphadenopathy are subtle signs that help risk stratify and persuade to investigate further. On further literature searches, we did not find any pancreatobiliary malignancy described in case reports (Table 2) of double-duct sign in anicteric individuals.
CONCLUSIONS Double duct does not unequivocally mean malignancy. It is a term first described in ERCP and carried over to present day in cross-sectional imaging. Several studies have compared diagnostic yield of ERCP with MRCP,12 none validating the predictive power of MRCP.19 Menges et al3,4 observed, in the presence of pancreatic mass or obstructive jaundice, that the discovery of double duct on ERCP has 85% malignancy yield. The prevalence of malignancy is lower on double-duct cases on cross-sectional imaging compared with ERCP data as above (Table 3) and in our experience. It is not a routine practice to cannulate PD unless clinically indicated. This may result in missed cases on ERCP and thus introducing bias favoring high sensitivities. Magnetic resonance cholangiopancreatogram, being a noninvasive imaging modality and risk-free of radiation and contrast hazard, tends to pick up incidental PD dilatation. In such scenarios, clinical context of jaundice provides robust risk stratification. While ERCP provides tissue diagnosis with variable yield, its role should be reserved to obtain tissue diagnosis and/or interventional approach for palliative reasons. TABLE 2. Case Reports on Double Ducts Duct Size, mm Double-Duct Sign 13
Gallstone Helminth (Strongyloides stercolis)14 Serous cystadenoma15 Opiate-induced SOD16 GIST17 Helmith (dead Ascaris)18
FIGURE 3. Carcinoma of the head of the pancreas. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Jaundice Index Imaging
PD/CBD
Absent Absent
AUSS MRCP
4/16 —
Absent Present Present Present
MRCP AUSS CT AUSS
5/10 — 8/13 3/10.8
AUSS indicates abdominal ultrasound; GIST, gastrointestinal stromal tumor; SOD, sphincter of Oddi.
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carcinoma: the ‘double duct’ and other signs. Radiology. 1976;119: 271–274.
TABLE 3. Comparative Study and Analysis No. Patients 43 52 11 26 21 49 234 55 82 38
Double Duct on Imaging
Jaundice, n (%)
Malignancy, n (%)
ERCP3 ERCP4 ERCP1 CT19 ERCP11 ERCP10 CT or MRI9 ERCP20 EUS21 CT or MRI or EUS22
— — — 15 (58) — — 166 (71) — 0 (0) 0 (0)
35 (81) 30 (58) 11 (100) 17 (65) 8 (38) 4 (8.2) 146 (62) 10 (18.2) 6 (7.3) 0 (0)
Our study concludes that malignancy is higher in the context of jaundice with double-duct sign on cross-sectional imaging than the latter on its own. In cases, where further mass is demonstrated on imaging in conjunction with double-duct sign, it is prudent to investigate with further invasive or noninvasive modalities even in the absence of jaundice. In the absence of jaundice, double duct has lower yield of malignancy; however, malignancy has been described in 5.9% to 7.3% (P < 0.005).9,21 There are limitations to this retrospective study such as possible missed cases, especially those who may have had a CT instead of MRCP for various absolute or relative contraindications. We also recognize that we did not investigate cases of double-ducts signs further with EUS as demonstrated by Cohen et al.21 The EUS study of Mitra et al22 demonstrates a causative diagnosis of 13% in the setting of normal biochemical liver tests and dilated ducts; none were malignant. We recognize that EUS may not be a universally available investigation, certainly not in a district general hospital setting. With access to more cross-sectional imaging, incidental findings such as double ducts and pancreatic cysts are growing. There is a growing need to rationalize and risk-stratify the patients who are in greater need for investigations, which are not widely available. Equally, onus should be laid upon as to how far patients would like to be examined through an honest and evidence-based discussion. Informed patient’s choice based on the above incidence of 7.3%,21 age comorbidity, and other factors should be taken in account through a multidisciplinary approach before pursuing an EUS. Our study showed that 4 of 65 patients without jaundice had ampullary lesion. None of these lesions were malignant; all these patients are alive on follow-up. Only 1 required surgery, but on histology, this patient was not reported as having a malignant lesion. It seems we would need to perform EUS in 16 patients with double-duct sign who are not jaundiced to find out one with ampullary lesion, which is benign. We need to make an informed decision based on the clinical context. There is paucity of strong evidence, and ambiguity in clinical practise prevails. Hence, there seems to be a need for larger prospective studies to establish guidance and risk stratification into further investigating double-duct sign both in the presence and absence of jaundice. REFERENCES 1. Freeney P, Bilbao M, Katon R. “Blind” evaluation of endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis of pancreatic
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2. Baillie J, Paulson EK, Vitellas KM. Biliary Imaging: a review. Gastroenterology. 2003;125:1565. 3. Menges M, Lerch MM, Zeitz M. The double duct sign in patients with malignant and benign pancreatic lesions. Gastrointest Endosc. 2000; 52:74–77. 4. Plumley TF, Rohrmann CA, Freeny PC, et al. Double duct sign: reassessed significance in ERCP. Am J Roentgenol. 1982;138:31–35. 5. Soto JA, Barish MA, Ferrucci JT. Magnetic resonance imaging of the bile ducts. Semin Roentgenol. 1997;32:188–201. 6. Ladas SD, Tassios PS, Giorgiotis K, et al. Pancreatic duct width: its significance as a diagnostic criterion for pancreatic disease. Hepatogastroenterology. 1993;40:52–55. 7. Singh A, Mann HS, Thukral CL, et al. Diagnostic accuracy of MRCP as compared to ultrasound/CT in patients with obstructive jaundice. J Clin Diagn Res. 2014;8:103–107. 8. Kalady MF, Peterson B, Baillie J, et al. Pancreatic duct strictures: identifying risk of malignancy. Ann Surg Oncol. 2004;11:581–588. 9. Krishna N, Tummala P, Reddy A, et al. Dilation of both pancreatic duct and the common bile duct on computed tomography and magnetic resonance imaging scans in patients with or without obstructive jaundice. Pancreas. 2012;41:767–772. 10. Ralls PW, Halls J, Renner I, et al. Endoscopic retrograde cholangiopancreatography (ERCP) in pancreatic disease. Radiology. 1980;134:347–352. 11. Inoue K, Ohuchida J, Ohtsuka T, et al. Severe localized stenosis and marked dilatation of the main pancreatic duct are indicators of pancreatic cancer instead of chronic pancreatitis on endoscopic retrograde balloon pancreatography. Gastrointest Endosc. 2003;58:510–515. 12. Georgopoulos SK, Schwartz LH, Jarnagin WR, et al. Comparison of magnetic resonance and endoscopic retrograde cholangiopancreatography in malignant pancreaticobiliary obstruction. Arch Surg. 1999;134: 1002–1007. 13. Oterdoom L, Weyenberg S, Boer N. Double-duct sign: do not forget gallstones. J Gastrointestin Liver Dis. 2013;22:447–450. 14. Dearden JC, Ayaru L, Wong V, et al. The double duct sign. Lancet. 2004; 364:302. 15. Khalpey Z, Rajab TK, Ashley SW, et al. Serous cystadenoma causing the double duct sign. J Gastrointest Surg. 2012;16:1282–1283. 16. Sharma M, Balakrishnan M. An unusual cause of double duct sign. Type I sphincter of Oddi dysfunction due to chronic opium addiction. Gastroenterology. 2011;40:e1–e2. 17. Kalman R, Bresnick M, Huang C. Now you see it, now you don’t: an unusual cause of the “double duct sign”. Gastroenterology. 2014;146: 348–592. 18. Sharma M, Mookiah B, Hari RS, et al. Double duct sign in a 3-year-old child. Gastroenterology. 2014;146:e6–e7. 19. Edge M, Hoteit M, Patel A, et al. Clinical significance of main pancreatic duct dilation on computed tomography: single and double duct dilation. World J Gastroenterol. 2007;13:1701–1705. 20. Shemesh E, Czerniak A, Nass S, et al. Role of endoscopic retrograde cholangiopancreatography in differentiating pancreatic cancer coexisting with chronic pancreatitis. Cancer. 1990;65:893–896. 21. Cohen J, Sawhney MS, Pleskow DK, et al. Double-Duct sign in the era of endoscopic ultrasound: the prevalence of occult pancreaticobiliary malignancy. Dig Dis Sci. 2014;59:2280–2285. 22. Mitra V, Nayar M, Bonninton S, et al. Yield of endoscopic ultrasound (EUS) in patients with dilated common bile duct (CBD) and or pancreatic duct (PD) with normal liver function tests (LFTs) and cross sectional imaging. Gut. 2013;62:A238.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
