The Indeterminate Biliary Stricture

Introduction

Indeterminate biliary stricture (IDBS) remains one of the biggest challenges that pancreaticobiliary endoscopists face. While a strict definition of IDBS is frequently not adhered to in the literature, this term refers to biliary strictures with no overt mass on noninvasive imaging such as computed tomography (CT) or magnetic resonance cholangiopancreatography, and that cannot be distinguished as malignant or benign after standard diagnostic procedures such as endoscopic retrograde cholangiopancreatography (ERCP) with tissue sampling (either brushing alone or in combination with biopsies). Surgical series demonstrate that 15% to 24% of patients who undergo resection for suspected malignant strictures based on preoperative imaging or ERCP will ultimately have a benign diagnosis on pathology. This small but significant cohort of patients with benign strictures highlights the importance of accurate preoperative tissue diagnosis to avoid the morbidity and mortality of hepatobiliary surgery. For example, the two most common causes of malignant strictures are cholangiocarcinoma (CCA) and pancreatic cancer. Diagnosis of these malignancies at an early stage can allow curative surgical resection or even liver transplantation for early stage CCA. Tissue diagnosis of pancreaticobiliary malignancy via endoscopic approaches is well known to be limited due to poor cellular yield and often requires surgical exploration for definite diagnosis. This diagnostic dilemma ultimately serves as the driving force behind advances in biliary imaging, improvements in sampling techniques, and the identification of emerging molecular markers. This section will review the etiologies of biliary strictures, the initial clinical evaluation of IDBSs, the diagnostic yield of ERCP-based sampling methods and recommended methods of improving acquisition and analysis, and the role of newer imaging tools in our approach to evaluating strictures.

Etiologies of Biliary Strictures

The leading causes of malignant biliary obstruction are pancreatic cancer and CCA. CCA is a primary malignancy of the bile duct epithelium, and therefore can affect both intra- and extrahepatic ducts. It is the second most common primary liver malignancy after hepatocellular carcinoma. When diagnosed in early stages, surgical resection can have an excellent prognosis. The challenge, however, is in obtaining a histological diagnosis given the typically inadequate cellular yield from initial sampling methods such as ERCP with brush cytology and/or biopsy. Unfortunately, the differential for CCA includes a host of benign causes of biliary strictures that can radiographically mimic CCA.

Biliary strictures due to pancreatic cancer are most often found at the distal common bile duct and are due to extrinsic compression of the extrahepatic duct from a pancreatic head mass with or without biliary invasion. Diagnosis of biliary stricture in the setting of a pancreatic mass does not technically fall into the category of IDBS; however, early tumors may go undetected on cross-sectional imaging, and thorough evaluation of the pancreatic head in such strictures is a necessary part of the evaluation. This is in contrast to CCA, whose desmoplastic nature results in its growing in an infiltrative pattern along the length of the bile duct, making its early detection particularly difficult due to the lack of a visible growth or tumor on imaging. Other less common malignant causes of biliary strictures include intraductal hepatocellular carcinoma, metastatic lesion, and extrinsic compression of the biliary tree from an associated visible mass or lymphadenopathy ( Table 60.1 ).

The varying forms of malignant biliary obstruction are pathologically distinct and represent special problems when attempting tissue sampling. The first major pathologic factor influencing biopsy or cytologic yield is tumor cellularity. Pancreatic carcinoma, in particular, often stimulates an intense desmoplastic and fibrotic reaction, making the tumor very dense and of low cellularity. Sampling often produces acellular or false-negative specimens. Maximizing yield requires repeated, deep, or large specimen sampling. Occasionally, an immune response or relative ischemia produces ulceration, bleeding, exudate, or debris that can obscure the rare malignant cell recovered in an endoscopic specimen. CCA of the primary type begins in the mucosa of the primary or secondary bile ducts. It is a relatively cellular cancer, and cells are more often shed in bile and can be more readily collected by sampling the superficial epithelium. However, the intrahepatic location of these tumors poses difficult access issues, making endoscopic ultrasound fine-needle aspiration (EUS FNA) yields lower, although the procedure is technically possible in select patients.

Hepatocellular carcinoma can often invade and extend intraductally. Superficial sampling generally obtains diagnostic cells in this setting as well. As with pancreatic cancer, gallbladder cancer and, especially, metastatic cancer, encase or compress the biliary tree, often while preserving intact benign biliary epithelium. Establishing a tissue diagnosis often requires sampling deeper than the surface epithelium. Very well-differentiated tumors represent a significant minority of malignant pancreaticobiliary tumors and prove very difficult to diagnose by cytologic criteria. Large specimens are often necessary to permit the pathologist to examine and compare these tumors to differentiate them from normal tissue. This fact likely explains why no biopsy technique, even open surgical wedge biopsy, has a 100% yield. These pathogenetic factors demand refined techniques and devices if adequate specimens are to be obtained to permit a positive cytologic or histologic diagnosis to be made in most cases.

Causes of benign biliary strictures include a variety of diseases ranging from recurrent cholangitis, postsurgical causes (most commonly after cholecystectomy or liver transplantation) to cholangiopathy from autoimmune disease, HIV, and primary sclerosing cholangitis (PSC). A long-standing yet poorly understood impersonator of a malignant stricture is autoimmune or Ig4-associated sclerosing cholangitis (IgG4-SC). The prevalence and pathogenesis of this disease remains largely unknown, but more than 80% of patients will have elevations of serum IgG4 above the upper limit of normal, and a similar percentage of patients will have an associated autoimmune pancreatitis. On cholangiogram, hilar IgG4-SC strictures can be indistinguishable from CCA. Histologic sampling, which can be diagnostic, may demonstrate diffuse infiltration of IgG4-positive plasma cells with fibroinflammatory involvement of the submucosa of the bile duct wall.

Laboratory Evaluation

The most common laboratory abnormality seen in patients with malignant biliary stricture is obstructive cholestasis. Direct hyperbilirubinemia is seen more commonly in patients with malignant obstruction than those with a benign etiology such as choledocholithiasis. Hyperbilirubinemia also has a higher likelihood of being associated with malignancy than elevations in alkaline phosphatase.

The most frequently used serologic markers for CCA are CA19-9 and possibly carcinoembryonic antigen (CEA). CEA has sensitivities and specificities that range from 33% to 84% and 50% to 87.8%, respectively. Unfortunately, CA19-9 also has a wide range of sensitivity and specificity: 38% to 93% and 67% to 98%. Furthermore, it can be undetectable in 7% of the general population due to absence of the Lewis antigen. The variable diagnostic accuracies of CA19-9, therefore, limit its role in screening, and its greatest value may be in the surveillance of patients with PSC.

In response to this poor reliability of CA19-9, other serum tumor markers have been recently evaluated. For example, cytokeratin-19 fragments (CYFRA 21-1) get released into the bloodstream by malignant epithelial cells. Several studies have demonstrated elevated CYFRA 21-1 expression in CCA, albeit with variable sensitivities depending on the cut-off value. Specificities also vary given that elevation of CYFRA 21-1 expression has been reported in multiple other gastrointestinal (GI) and non-GI epithelial malignancies such as gastric, breast, and cervical. Similarly, high matrix metalloproteinase-7 (MMP-7) expression has been found to be associated with cancer invasion in esophageal, colon, and pancreatic cancers. Given the lack of specificity for these individual markers, use of combinations of the markers may be the most useful, such as in multimarker panels. For example, a panel with the combination of these markers with CEA and CA19-9 demonstrated the highest diagnostic accuracy of 93.9%.

Another serum marker, interleukin-6 (IL-6), which has been shown to be a biliary epithelial growth factor, has demonstrated sensitivity as high as 100% in diagnosing CCA. Like the other markers mentioned earlier, however, the specificities are limited due to its elevation in patients with hepatocellular carcinoma, benign biliary disease, and metastatic lesions. Sperm-specific protein 411 (SSP411) is a protein that shows some promise in serving as a single serum-based biomarker given its elevation in the bile of CCA patients and use in distinguishing CCA from choledocholithiasis.

Recent work has been performed evaluating the utility of measuring microRNAs (miRNAs) that are shed into the circulation in a free form when dysregulated in the setting of malignancies, compared to their stable protein-bound form. The value of miRNAs lies in their tissue-specific patterns of expression. MicroRNAs that are commonly upregulated in other epithelial cancers such as miR-192, 194, and 215 in colon, liver, pancreas, and stomach cancers, are not altered in CCA. Conversely, CCA-specific miRNA expression profiles do exist, such as downregulation of miR-125a, -31, or, alternatively, upregulation of some miRNA's such as miR-21. The specificity is limited, however, given its upregulation in other cancers (gastric, breast, and colon ). As with tumor markers discussed earlier, perhaps the evaluation for miRNAs are best performed as part of a multimarker panels specific for CCA.

ERCP

Tissue Acquisition During ERCP

The goals of ERCP for a suspected malignant biliary stricture are to first obtain definite tissue diagnosis to obviate the need for exploratory surgery, and second, to provide palliation of biliary obstruction with stent placement. In fact, the constant quest for improved methods of tissue acquisition remains the focus of innovation in biliary technology. Initial efforts were limited to simple aspiration of bile and occasionally pancreatic juice when deep cannulation was achieved. While specificity in early reports was uniformly 100%, low sensitivities of only 6% to 32% in six published studies have caused this technique to fall from practice.

Aspirating bile after brush cytology has occasionally been reported to increase yield using standard cell block preparation. Combined methods of tissue sampling will be presented later in this chapter.

Finally, advanced molecular diagnostics in bile, including proteomic, lipidomic, and volatile organic compound analysis, may reopen bile aspiration as an accepted modality to determine a malignant diagnosis with sufficient specificity.

Brush Cytology Sampling Methods

Inadequate tissue acquisition at ERCP remains the most common reason for failing to establish an accurate pathologic diagnosis. Technical difficulty, time consideration, patient restlessness, and the need to proceed with the primary goal of biliary drainage all contribute to limit the time and thoroughness of tissue collection for many endoscopists. Because of these factors, brush cytology has been the universally adopted technique in clinical practice. Initially, standard nonwire guided endoscopic brushes were inserted, usually after sphincterotomy; however, negotiation through the stricture was often problematic. This factor and the very superficial nature of this technique of sampling produced disappointing yields, and it never became popular. Thus, a variety of cytology brushes, some of which could be inserted over a guidewire placed through the malignant-appearing stricture before attempted sampling, were developed and are the devices we currently use today. These brushes are housed in catheters with a variety of diameters and stiffnesses, and the brushes themselves range in configuration as well as bristle length ( Fig. 60.1 ). Techniques for performing brushing have subtle varieties but are centered around the idea of advancing the brush and catheter over the guidewire through the stricture, followed by manipulation of the exposed brush through the stricture multiple times. Protection of the acquired cells is paramount and best achieved by withdrawing the brush back into the catheter before leaving the area of the stricture ( Fig. 60.2 ). Some also advocate for simultaneous aspiration of bile immediately after brushing, thereby collecting loose cells in the milieu of the brushing into the catheter before removing the entire device from the duct.

Published yields of ERCP brush cytology devices vary widely for reasons that can only be speculated. Generally, series that have a higher proportion of pancreatic adenocarcinomas and, perhaps, earlier smaller tumors, have a much lower yield of positive results compared with series with more cholangiocarcinomas. Published overall sensitivities using these devices range from 8% to 57%.

A 2013 review of ERCP brush cytology covered 16 studies over 10 years from 2002 to 2012, which included a total of 1586 patients. The combined yield of brush cytology ranged from 6% to 64% with an overall sensitivity of only 41.6% +/− 3.2%, and did not appear to vary across new devices and techniques.

As discussed subsequently, many of these series are also flawed by including patients with “suspicious for malignancy” reports as positive results. A single center study of 142 patients with pancreatic or biliary cancer undergoing ERCP brushing reported in 2016 is such an example. The overall sensitivity was 58%, but actually only 50% in distal and presumably pancreatic cancer strictures. Adding “atypia” as a positive result increased yield to 65.5% but decreased specificity from 100% to 68.6%, clearly an unacceptable result.

A probable pathologic explanation for these varied yields relates to the observation that the interiors of malignant strictures are composed of benign epithelium compressed by surrounding neoplastic tissue, with the exception of CCA of the major bile ducts. This fact explains the low yield of simple bile aspiration for cytology because few, if any, malignant cells are in contact with the bile flow as previously discussed. When the stricture is traumatized by dilation, removing the benign epithelium, the yield of aspirating bile increases.

The yield of brushing is lower with deeper and more remote encasing tumors. One would predict the lowest yield is in metastatic malignancy, followed by pancreatic cancer, with a much higher yield with primary CCA. Generally, this prediction has been confirmed in clinical practice.

The type of brush bristles, the overall brush length, and the amount of time spent brushing all affect yield. Rabinovitz et al (1990) used three separate brushes at each ERCP and repeated the procedure with three new brushes when suspicious strictures were initially negative. Positive yield continued to increase until diagnoses were eventually made by brushing alone in 62% of their patients. Two additional ERCP brushing studies have been performed in an attempt to increase yield. In a large number of patients, a newer long cytology brush with stiff angulated bristles was compared with the standard-length brushes described previously. The true-positive yields were uniformly disappointing—only 27% and 30%—and no advantage was observed with the new brush. The second study compared brushing with a more traumatic technique of inserting a grasping basket through the suspicious stricture. Of 50 malignant strictures, the basket technique had a near doubling of yield to 80% compared with a brush yield of 48% ( p = 0.018). The unexpected high yield of the brushing suggests some selection bias, and this technique requires additional study.

Building on this concept of traumatizing the surface epithelium, a new scraping device was developed and trialed in Japan. In 123 indeterminate stricture cases, 119 were eventually proven to be malignant. This device involves a three-leaf clover–type design of three nitinol loops, rather than bristles, that are compressed in guidewire-compatible catheters. The structure is roughly scraped and bile is aspirated using the device's side angled port. The yield was compared to a transpapillary forceps biopsy, and the device was also used in combination. The yields of forceps biopsy, the new scraping device, and both were 51%, 65%, and 75%, respectively. It is important to consider that 67% of their 119 cases had CCA and only 32% had pancreatic cancer. Furthermore, experience with this device is needed.

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