Taking measure of cholangiocarcinoma

Karen Titus

January 2019—Ten years ago, says Manhal Izzy, MD, the approach might have seemed quixotic: performing liver transplants in patients with early intrahepatic cholangiocarcinoma. Even today, it’s hardly standard of care. Nevertheless, it has moved well beyond the impossible dream category.

Medicine advances, and practices change. There’s nothing unusual about that. But Dr. Izzy, assistant professor of medicine, Vanderbilt University School of Medicine, and transplant hepatologist, Vanderbilt University Medical Center, goes out of his way to credit the wisdom and work of those in hepatology and oncology who have been pushing forward curative approaches for cholangiocarcinoma. Given the exceptionally poor prognosis, he says, physician-scientists were open to heading in new directions. “It’s a very aggressive tumor,” Dr. Izzy says. By the time patients exhibit symptoms, “things are often already late.” And when they seek medical care, “it’s almost over.”

The five-year survival rate without any treatment is dismal—less than 10 percent. “That has not changed over time,” says Sumera Rizvi, MBBS, assistant professor of medicine, College of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic. Moreover, the overall incidence of cholangiocarcinoma has increased over the past few decades.

Seen from other angles, however, the numbers are more cheering. Take liver transplantation. The latest approach uses neoadjuvant chemoradiation prior to transplant. A 12-center study (Darwish Murad S, et al. Gastroenterology. 2012;143[1]:88–98.e3) that looked at patients with perihilar cholangiocarcinoma showed recurrence-free survival rates of 78 percent and 65 percent at two and five years, respectively, post-transplant. (Survival following liver transplant alone, without neoadjuvant therapy, is about 20 percent, says Dr. Rizvi, citing data from the 1990s.)

“Everybody sees the prognosis for this tumor,” Dr. Izzy says, “so everybody is eager to try to find something new,” both diagnostically and therapeutically. When the challenge is large, it’s often best to get everyone kicking in the same direction, like the Rockettes.

The first step is to master the basics of cholangio-carcinoma. Although it’s the most common biliary malignancy and the second most common hepatic malignancy, the numbers are still low enough for it to be considered rare. It’s hard to gain mastery over a problem that’s rarely encountered, says Rondell Graham, MBBS, GI molecular pathologist, Mayo Clinic, noting there are about 3,000 new cases total in the United States annually.

That number alone doesn’t tell the entire story. The need for diagnostic testing—including laboratory-based modalities—is high for certain subsets of patients, who will need more intensive monitoring, including multiple FISH assays. “So even though incidence is low, the number of patients being tested is significantly higher,” says Benjamin Kipp, PhD, section head, genomics laboratory, solid tumor testing, Mayo Clinic.

The low incidence is one reason cholangiocarcinoma remains somewhat misunderstood. In fact, “The genetic profile of these are so different,” says Dr. Kipp, “that it really represents three different diseases.”

To review:

• Perihilar cholangiocarcinoma arises between the second-order bile duct and the insertion of the cystic duct. These account for approximately half of cholangiocarcinomas. These are often de novo, but they can also be associated with primary sclerosing cholangitis, or PSC, a chronic inflammatory condition of the biliary tree. Perihilar cholangiocarcinoma occurs in about 10 percent of PSC patients at some point in their lifetime.
• Distal cholangiocarcinoma arises below the insertion of the cystic duct and accounts for about 30 percent of cases.
• Intrahepatic cholangiocarcinoma arises above the second-order bile duct. This is usually found incidentally, in patients who may have underlying chronic liver disease or cirrhosis and undergo a routine surveillance CAT scan or ultrasound, which reveals an intrahepatic mass lesion. These account for 20 percent of cholangiocarcinomas.

The first two types are the focus of laboratory-based diagnostic modalities, including biliary cytology and FISH. Diagnosis can be a challenge, says Dr. Graham, “because there is no specific affirmative marker for cholangiocarcinoma. We rely heavily on morphology.”

Very high levels of CA 19-9 are associated with metastatic cholangiocarcinoma, Dr. Izzy says. “So it gives an impression, a clue, about the extent of the disease when it’s very high.” But some cancers—the subset called Lewis antigen-negative—don’t secrete the marker, so normal levels can’t be used to rule out disease, he cautions.

It’s not unusual, says Dr. Rizvi, for someone to be told they have bile duct cancer based on suspicious cytology. “They’ll come to us, but on a repeat ERCP we don’t see suspicious cytology and/or FISH polysomy, and we can’t confirm it or find other confirmatory criteria. That is a situation we occasionally encounter.”

Perihilar and distal cholangiocarcinomas are the most diagnostically challenging, Dr. Izzy says. “You need multiple modalities in addition to imaging,” including endoscopic biopsy and both cytology and FISH. “Even then, you might not be able to confirm or exclude the diagnosis,” Dr. Izzy says.
It’s also important, he says, to rule out IgG4 cholangiopathy in perihilar and distal biliary strictures. This is a type of autoimmune phenomenon that affects the biliary tree and can be confused with cholan­giocarcinoma.

As noted, intrahepatic cholangiocarcinoma is usually detected during radiologic surveillance in patients with cirrhosis. “When we do every-six-months imaging,” says Dr. Izzy, “we see sometimes atypical lesions—atypical in the sense that they don’t look like hepatocellular carcinoma.” These are the simplest cases to address diagnostically, he says, which can be done with an intralesional biopsy that reveals features of intrahepatic cholangiocarcinoma rather than hepatocellular carcinoma.

Diagnosing perihilar and distal cholangiocarci­nomas requires cumulative evidence from the multiple modalities.

“Let’s start with cytology,” suggests Dr. Izzy. The problem is that cholangiocarcinoma is a desmoplastic tumor—the fibrotic surface can make it difficult to discern any malignant cells that are obtained from the brushings. In other cases, samples can be paucicellular.

The rather subjective nature of cytology can also bedevil clinicians, despite pathologists’ best efforts to classify a sample as normal, atypical, suspicious, or positive.

With all those challenges, cytology becomes a very specific but relatively insensitive test. One study showed cytology sensitivity can be as low as 18 percent, says Dr. Izzy; that same study showed that FISH revealing polysomy was 47 percent sensitive (Moreno Luna LE, et al. Gastroenterology. 2006;131[4]:​1064–1072). Another study showed sensitivity of 15 percent and 34 percent, respectively (Kipp BR, et al. Am J Gastroenterol. 2004;99[9]:1675–1681). “So there’s an increased yield for FISH when it reveals polysomy,” Dr. Izzy says. “With advanced FISH probes, you can improve sensitivity to more than 60 percent” (Barr Fritcher EG, et al. Gastroenterology. 2015;149[7]:1813–1824.e1).

Despite the need for cumulative evidence, clinical practice can fall short of that ideal. “Sometimes all you have is just one of these,” Dr. Izzy says—imaging suggesting a malignant stricture, but nothing else. “There may be no supporting evidence whatsoever, whether histologically or biochemically.” In those cases, physicians are compelled to keep obtaining follow-up specimens to prove or disprove cancer.

Primary sclerosing cholangitis adds to the diagnostic difficulties. Unlike most other cancers, Dr. Rizvi explains, cholangiocarcinoma cells have an affinity for bile, so they tend to grow longitudinally, along the bile ducts. It can be tricky, on imaging, to differentiate between a stricture related to PSC and one that is cancer in a patient who also has PSC.

The first step from a laboratory perspective would be to obtain biliary brushings from endoscopic retrograde cholangiopancreatography, which are sent for cytologic evaluation and FISH.

Biliary cytology can be as high as 95 percent specific. That’s the good news. The bad news: “Sensitivity is terrible,” says Dr. Rizvi. Though estimates vary depending on the study (as Dr. Izzy noted), she puts it at about 30 percent. “Cholangiocarcinomas are, histologically, very dense, desmoplastic tumors. They have an abundant tumor microenvironment, but they’re also paucicellular.”

Adding to the challenge, the biliary specimen can be difficult to access. Nevertheless, because of its specificity, biliary cytology remains the gold standard.

Dr. Rizvi notes that some cytology diagnoses are trickier for clinicians to deal with than others. Atypical cytology is a frequent diagnosis in PSC, and by itself should not raise concern for the presence of cholangiocarcinoma. “When we see it, we consider it in the same way we would consider normal cytology. So we don’t react to it, especially in PSC patients.”

In terms of suspicious cytology, she continues, “That’s more concerning than atypical,” especially if there’s FISH polysomy and perhaps a dominant stricture. About 30 to 40 percent of PSC patients who have a suspicious cytology but don’t have a mass lesion ultimately end up being diagnosed with cholangiocarcinoma down the line.