Methods

Written informed consent was obtained from all patients before ERCP, IDUS, and biopsy. Approval for the study from our institutional review board was not required as biopsy and IDUS are considered standard care for these patients.

ERCP was performed using a conventional duodenoscope (JF-200 or JF-230; Olympus Optical Co., Tokyo, Japan). The stenotic area was cannulated using a 0.025 inch diameter polymer coated guidewire (Radifocus; Terumo Co., Tokyo, Japan). After exchanging the polymer coated guidewire for a stiff Zebra guidewire (Microvasive Co., Watertown, Massachusetts, USA), a 2.0 mm diameter ultrasonic probe with a frequency of 20 MHz (MP-PN20-06L; Aloka Co., Tokyo, Japan) was inserted into the bile duct along the guidewire. Endoscopic sphincterotomy was not performed. The tip of the probe had a side slit for the guidewire. The catheter generated high resolution, real time, cross sectional images with an axial resolution of 0.1 mm and a maximum penetration of approximately 20 mm. The IDUS images were recorded on S-VHS videotapes and individual still frames. After the ultrasonic probe was removed, an endobiliary biopsy was performed under fluoroscopic guidance using a clamshell-type needleless biopsy forceps (FB-39Q; Olympus Optical) with a Teflon sheath (outer diameter 1.8 mm). While maintaining the guidewire over the stricture, the biopsy forceps were inserted into the orifice of the papilla along the upper side of the placed guidewire without endoscopic sphincterotomy (n=35). When the forceps could not be smoothly inserted into the orifice of the papilla, an Olbert 5 French balloon tipped biliary catheter (Microvasive) with a length of 180 cm and a balloon length of 3 cm (maximum diameter 8 mm) was passed over the guidewire and endoscopic papillary balloon dilation (balloon sphincteroplasty) was performed using previously reported techniques.^37–39 During and after the biopsy, the guidewire remained in that position. Three or more specimens were obtained from each patient. After biopsy, an endoscopic nasobiliary drainage (ENBD) tube was introduced along the guidewire when the bile duct was obstructed. During the initial study period, the biopsy was performed following withdrawal of the guidewire as we mistakenly considered that the guidewire would interfere with insertion of the forceps into the papilla (n=14). In the last cases (n=13), a new ropeway-type 1.8 mm diameter clamshell-type needleless biopsy forceps (prototype, Olympus) were used. The tip of the ropeway-type forceps had a side slit for a guidewire⁴⁰ and therefore the guidewire was left in place during the biopsy.

Biopsy specimens were fixed in 1% formalin, embedded in paraffin, and stained with haematoxylin and eosin. When the histological examination of the biopsy specimen showed only atypical cells, the results were judged negative for malignancy.

Relationship between IDUS and histology

The results are summarised in tables 1–3 .

Table 1

Morphology on intraductal ultrasonography (IDUS) findings and final diagnosis

	*Final diagnosis
Malignant
Morphology on IDUS	Biopsy positive	Biopsy negative	Benign	Total
Without sessile tumour
No apparent lesion	0	0	2	2
Localised wall thickening	1	1	6a	8
Polypoid lesion	8	2b	9	19
Sessile tumour
Intraductal sessile tumour	12	1	0	13
Sessile tumour outside of the bile duct	10	9c	1d	20
Total	31	13	18	62

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^aTwo with bile duct stone, one with post out mobile injury, one with chronic pancreatitis, one with primary sclerosing cholangitis, and one with Mirizzi's syndrome; ^btwo with bile duct thrombi by hepatocellular carcinoma; ^csix with pancreatic cancer, two with peripheral cholangiocarcinoma, and one with gall bladder cancer; and ^done with tumour forming pancreatitis.

*The process of final diagnosis is shown in table 4 .

Table 2

Bile duct wall structure on intraductal ultrasonography (IDUS) findings and final diagnosis

	*Final diagnosis
Morphology on IDUS	Malignant	Benign	Total
Wall structure
Preserved	11	17	28
Interrupted	33	1a	34

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^aOne with tumour forming pancreatitis.

*The process of final diagnosis is shown in table 4 .

Table 3

Maximum tumour size on intraductal ultrasonography (IDUS) findings and final diagnosis

*Final diagnosis
Maximum tumour size on IDUS	Malignant	Benign	Total
Maximum tumour diameter or maximum wall thickening
<10.0 mm	7	15	22
≥10.0 mm	37	3a	40

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^aOne with inflammatory polyp, one with polypoid lesion located at the distal end of the bile duct, and one with tumour forming pancreatitis.

*The process of final diagnosis is shown in table 4 .

When IDUS showed a polypoid lesion, the biopsy was sensitive in diagnosing malignancy in 80% (8/10) of patients. It was sensitive in all patients who had polypoid lesions with cholangiocarcinoma (n=8). The two patients with false negative biopsy results had tumour thrombi from hepatocellular carcinomas (HCC). In the intrapancreatic bile duct, only two of nine patients with polypoid lesions had malignancy. On the other hand, in the extrapancreatic bile duct, eight of nine patients with polypoid lesions had malignancy.

When IDUS showed a intraductal sessile tumour, all patients had histological evidence of malignancy. All intraductal sessile tumour showed an interruption of wall structures on IDUS findings. Biopsy was sensitive in 92% (12/13) of patients.

When IDUS showed localised wall thickening, 75% (6/8) of patients had benign diseases; of the two patients with malignancy, the biopsy was sensitive in only 50% (1/2). Five of six patients with benign strictures that were described as localised wall thickening by IDUS had some clinical origin of their stenosis (two with bile duct stones, one with outmobile injury, one with chronic pancreatitis, and one with Mirizzi's syndrome). On the other hand, two of three patients without evidence of a clinical origin of the stenosis had malignancy.

When IDUS showed sessile tumour outside of the bile duct, 95% (19/20) of patients had malignant diseases, and biopsy was sensitive in 53% (10/19) of patients. Biopsy was sensitive in 50% (6/12) of patients with pancreatic cancer.

Multiple regression analysis showed that sessile tumour (intraductal or outside of the bile duct: p<0.05), tumour size (p<0.001), and interrupted wall structure (p<0.05) were independent variables that predicted malignancy.

As shown in table 2 , when the IDUS finding of interrupted wall structure was used as the criterion of malignancy, the accuracy, sensitivity, and specificity of IDUS were 81%, 75%, and 94%, respectively. As shown in table 3 , when the IDUS finding of a tumour greater than 10 mm was used as the criterion of malignancy, the accuracy, sensitivity, and specificity of IDUS were 84%, 84%, and 83%, respectively.

Course of the patients

The clinical courses of the patients and the process of final diagnosis are summarised in table 4 . Sixteen patients were judged as having no biliary tract carcinoma and were clinically observed. Two required transient replacement of their biliary endoprosthesis. Seven other patients underwent lithotripsy under endoscopic papillary balloon dilatation. One patient with Mirizzi's syndrome was observed after laparoscopic cholecystectomy. In seven of these 16 patients, a repeat IDUS and biopsy were performed 1–6 months later (mean three months). Improvement in wall thickening or a decrease in the size of the polypoid lesion was seen in five of seven observed patients. The remaining nine of 16 patients rejected a second ERCP as they were asymptomatic. Ultrasonography and laboratory data showed no signs of biliary obstruction in these patients. No signs of malignancy were detected in any of the observed patients during the follow up period of 18–64 months.

Table 4

Course of the patients

Surgical treatment with diagnosis of malignancy (n=31)

Cholangiocarcinoma (n=21)

Polypoid lesion (n=7)

Intraductal sessile tumour (n=12)

Localised wall thickening (n=1)

Sessile tumour outside of the bile duct (n=1)

Gall bladder cancer (n=3)

Sessile tumour outside of the bile duct (n=3)

Pancreatic cancer (n=5)

Sessile tumour outside of the bile duct (n=5)

Inflammatory polyp (n=1)

Polypoid lesion (n=1)

Tumour forming pancreatitis (n=1)

Sessile tumour outside of the bile duct (n=1)

Conservative treatment (stenting) with diagnosis of malignancy (n=15)

Evidence of adenocarcinoma

Transpapillary bile duct biopsy (n=7)

Percutaneous bile duct biopsy (n=1)

Gastric or duodenal biopsy (n=2)

Pancreas aspiration biopsy (n=2)

Bile juice cytology (n=1)

Evidence of hepatocellular carcinoma

Liver aspiration biopsy (n=2)

Follow up by IDUS and biopsy with diagnosis of benign disease (n=7)

Decrease in tumour size on IDUS images (n=5)

No change on IDUS images (n=2)

Follow up with diagnosis of benign disease, second ERC was rejected (n=9)

No symptoms during the period (n=9)

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ERC, endoscopic retrograde cholangiography.

Scoring of intraductal ultrasonographic findings

Based on the results of multiple regression analysis, (1) the presence of sessile tumour (intraductal or outside of the bile duct), (2) tumour size greater than 10.0 mm, and (3) interrupted wall structure were used as positive factors to predict malignancy on IDUS findings, and the relationship between intraductal ultrasonographic findings and final diagnosis was retrospectively analysed. As shown in table 5 , in cases with no evidence of malignancy on histological findings of the biopsy specimen (n=31), if IDUS findings showed two or three positive factors, 92% of patients showed malignancy on the final diagnosis. In contrast, if IDUS showed no positive factor, no patient showed malignancy on the final diagnosis when the biopsy specimen showed no evidence of malignancy.

Table 5

Scoring of intraductal ultrasononographic findings and frequency of malignancy on final diagnosis

No positive factors on IDUS	Frequency of malignancy on final diagnosis*
(1) Total cases (n=62)
0	2/17 (12%)
1	5/7 (71%)
2–3	37/38 (97%)
(2) Cases with no evidence of malignancy on the histological findings of biopsy specimen (n=31)
0	0/15 (0%)
1	2/4 (50%)
2–3	11/12 (92%)

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Positive factors in predicting malignancy on intraductal ultrasonography (IDUS ) findings: (1) presence of sessile tumour (intraductal or outside of the bile duct); (2) tumour size greater than 10.0 mm; and (3) interrupted wall structure.

*The process of final diagnosis is shown in table 4 .