Abstract

INTRODUCTION

Biliary duct strictures are most often caused by neoplastic or inflammatory processes involving the biliary tree, pancreas, gallbladder, or ampulla. The use of endobiliary brush cytology to definitively diagnose malignant biliary strictures has been shown to be useful during endoscopic retrograde cholangiography (ERC). However, the diagnostic yield of this technique remains low, ranging from 30% to 80%[1–14] depending on the literature reviewed. Conservative management with biliary drainage is used in many patients with malignant tumors, most of whom are not candidates for curative resection due to locally advanced or metastatic disease. In such patients, an accurate tissue diagnosis may help in developing a concept for further management[3,4,15,16].

Cytological techniques have become the initial diagnostic modality in many cases since biliary lesions are not always readily accessible to biopsy[4,6,7,17]. Percutaneous radiologically guided fine needle aspiration (FNA), although a very accurate technique, is operator dependent and requires a sufficiently distinct mass lesion for targeting. Additionally, in patients who are surgical candidates ‘seeding’ of the needle tract has been a concern. Brush cytology performed at ERC, in contrast, has a low complication rate and allows sampling from most sites within the biliary duct systems[4,6,7,17].

The objective of this study was to assess the accuracy of brush cytology in biliary strictures and to assess the factors influencing results over a 3.7 years period from January 2002 to September 2005.

MATERIALS AND METHODS

From a total of 2500 endoscopic retrograde cholangi-opancreatography performed between January 2002 and September 2005 at our center (St. Paul’s Hospital, Vancouver), all biliary brush cytology findings were reviewed. This hospital serves as a tertiary referral center for the management of biliary diseases, and clinicians obtained follow up on all their patients. Two hundred and ninety nine specimens were received, from one hundred and ninety nine patients in the review period. For inclusion in the study, patients had to have a definite final benign or malignant diagnosis based either on histological or cytological sampling or by clinical outcome. The latter was obtained by case record review. A total of ten patients (3.3%) were excluded from performance characteristics of endoscopic retrograde cholangiopancreatography (ERCP) brush cytology due to lack of gold standard for diagnosis.

Ethics approval for the chart review was performed through St. Paul’s Hospital, University of British Columbia, Vancouver, Canada.

The specimens were obtained at ERCP with a Cytomax2, single use, 8 french, 2.5 cm long double lumen Wilson-Cook cytology brush (#4900 Benthania, Station Road, Winston-Salem, NC 27105). Fluoroscopic guidance ensured that the brush was within the stricture. Between ten and fifteen “in and out” passes with the brush was routinely used to ensure an adequate sample, and then the entire brush excised into formalin or saline and sent to the laboratory. Routine cytospin preparations were prepared and stained according to Papanicolaou’s method. Samples were classified cytologically as follows: Class 1: Benign; Class 2: Reactive; Class 3: Suspicious for malignancy; Class 4: Cells with cancer morphology recommend biopsy (likely malignant but rarely can be reactive); Class 5: Malignant (equal to tissue diagnosis).

In our study definitively positive biliary brush cytology is defined as class 3 or higher.

Biliary duct stricture location was classified according to one thirds of total biliary duct length and was analyzed via two methods (apriori decided), once combining middle and lower common duct and once dividing the duct system to three equal parts. Other factors evaluated include length of stricture, mass size in CT scan/ultrasound, stricture dilation before brushing, age, and gender.

RESULTS

DISCUSSION

The examination of brush cytology is an established diagnostic technique in the investigation of patients with biliary strictures with suspected pancreatic, bile duct, ampullary, and gallbladder cancers. Acquisition of malignant cells by endoscopic brush cytology during initial ERCP is valuable in planning appropriate therapy and may be important for avoiding additional invasive procedures for tissue diagnosis. We have reviewed brush samples from 199 patients during a time period of almost 4 years for yield, sensitivity, and specificity. This is one of the largest series of biliary brush cytology specimens reported and the largest and broadest study looking at factors associated with positive brush result.

The diagnostic sensitivity of biliary brushing has been relatively modest in most studies to date. Stewart and colleagues reviewed 406 patients and found the overall sensitivity to be 59.8%[13]. Similarly, Kurzawinski and colleagues[7,17] reviewed six early series and found the mean sensitivity to be 59%. However, two other large studies on brush cytology have recorded sensitivities of 35%-48% in the patients with pancreatico-biliary malignancy[5,8].

There are very few studies evaluating the factors influencing positive results. McGuire and colleagues have documented the association between the yield of enteropancreatic brush cytology and the location of malignancy, such that strictures of the head and body yielded higher rates of positive cytology compared to the strictures of ampulla, pancreatic genu, and tail regions[9]. DeBellis and colleagues have shown that stricture dilation does not improve the sensitivity of brush cytology for the detection of cancer. However, repeated brushing appears to increase the diagnostic yield[1].

We found that brush cytology accurately identified 76 of 124 (61.2%) neoplasms in our series, a similar result to those of earlier studies reviewed by Stewart and colleagues[13], Kurzawinski and colleagues[7,17], and by Foutch et al[3,4,18]. When we consider a second brushing in some patients our sensitivity increases to almost 70%. This is among the highest sensitivity reported in the literature. Other studies such as Lee et al[19,20], Ponchon et al[21], Longo et al[8,22], and Macken et al[23] all had lower sensitivities at 37%, 35%, 48%, and 57%, respectively. The reasons for the varied sensitivity are unclear.

Previous studies have shown that a diagnosis of carcinoma on brush cytology is highly specific. The specificity of biliary brush cytology in previous studies has been reported to be between 90%[17] to 100%[3,16,18,24–28]. There was one false positive diagnosis in our study (specificity 98%) in a patient with primary sclerosing cholangitis. Stewart and colleagues also reported three false positives cytological diagnoses among one hundred and sixty patients (specificity 98.1%)[13]. Sturm and colleagues also reported specificity of 97.2% with two false positive cytological diagnoses among 74 patients with benign strictures[30].

It has been suggested in previous studies that the limited sensitivity of brush cytology may be due to an inadequate cellular yield. Theoretically, stricture manipulation may increase exfoliation of tumor cells, making these cells more available for histopathologic evaluation, but DeBellis and colleagues have shown that stricture dilation does not improve the sensitivity of brush cytology for detection of cancer. In their study, brush cytology had a sensitivity of 34.5% before dilation and 31% after dilation (P = 0.54)[1]. On the other hand, Mohandas et al[31] found that dilation before bile aspiration improved the cancer detection rate of bile cytology. In their series, cytology was positive in 27% of cases without biliary stricture dilation compared to 63% when the stricture was dilated (P < 0.03). Use of scraping brush in the series reviewed by Parasher and Huibregtse[16] achieved a sensitivity of 100%. However, stricture dilation did not improve the diagnostic yield of brush cytology specimen in our series of 31 patients who had dilation prior to brush cytology OR 1.18 (0.48-2.85).

We have not routinely performed biliary aspiration or biopsy technique biopsies of the biliary tree; both of which may enhance diagnostic yield. Using a combination of simple biliary brushings occasionally with a second brushing combined with endoscopic ultrasound staging (and biopsy where required) sensitivity reaches more than 90%. Only a small selected group remains undiagnosed through the above two methods, and thus the benefit of other techniques (i.e. aspiration, endoscopic biopsy at ERCP) in increasing the yield is marginal in our hands.

We also analyzed positive yield for multiple factors including age, gender, location of stricture, mass size in CT scan or ultrasound, and the length of stricture. From all the mentioned variables positive brush result was associated with older age: 1.02 (1.00-1.05), mass size of more than 1 cm: 2.22 (1.01-4.89) and stricture longer than 1 cm: 3.49 (1.18-10.2).

In summary, in this study brush cytology identified 76 of 124 (61.2%) of neoplasms in a series of 199 consecutive patients evaluated during a 3.7 years period in our institution. One false positive cytological diagnosis occurred. From all the variables studied only age, length of stricture, and mass size in CT scan or ultrasound were associated with a higher yield. Gender, dilation of stricture prior to cytological sampling, or location of stricture were not found to be associated with a higher yield. Although the limitations of this technique must be recognized,, brush cytology is useful in investigation of patients with suspected biliary neoplasm. The challenge for future developments in this field is to develop strategies to improve lesion targeting facilitating retrieval of cytology specimens with higher quality.

COMMENTS

References