Taking measure of cholangiocarcinoma

Mayo Clinic has been at the forefront of developing and using FISH to diagnose cholangiocarcinoma, including a specific pancreatobiliary FISH probe set (Barr Fritcher EG, et al. Gastroenterology. 2015;149[7]:1813–1824.e1) that Dr. Rizvi and her colleagues use. Cytology and FISH are done simultaneously, after an MRI/MRCP to look for a mass lesion or dominant stricture. Dr. Rizvi says that Mayo is one of the few institutions in the country that offers FISH analysis on biliary brushings. “That has been essential in our ability to diagnose these patients,” she says.

It has four locus-specific probes (1q21, 7p12, 8q24, and 9p21) against loci that are known to be abnormal in cholangiocarcinoma. A normal finding is two copies of a chromosome. FISH polysomy is the abnormal finding. Sensitivity with this set is about 65 percent. Neither trisomy nor disomy indicates cholangiocarcinoma.

This approach “has proven very useful and valuable, especially in those challenging, difficult-to-diagnose cases,” Dr. Rizvi says. Because PSC is a chronic inflammatory condition, however, “We have to be very careful if we notice FISH polysomy.” In these patients, FISH polysomy alone would not confirm cholangiocarcinoma. “We have to be careful not to overdiagnose.”

Although Mayo obviously sees its fair share of referrals, it also performs its FISH analysis as a sendout test for other centers. “I do think if there’s any lack of clarity in terms of the diagnosis, it’s beneficial to send the patient to a tertiary referral center, just because it’s such a challenging malignancy to diagnose,” Dr. Rizvi says.

A good management protocol is essential, she continues, and she credits Mayo’s for helping colleagues sidestep the field’s many knowledge gaps (Rizvi S, et al. Clin Gastroenterol Hepatol. 2015;13[12]:​2152–2165). If a patient—particularly one with PSC—has a first-time FISH polysomy result, with nothing else to indicate possible cholangiocarcinoma, a repeat ERCP is done in three to four months to ensure the finding is true. If a patient has serial polysomy FISH, “we keep them under intensive surveillance,” she says.

Should a repeat ERCP show positive cytology, that, coupled with serial FISH polysomy, would result in a diagnosis of cholangiocarcinoma. “We’re done,” says Dr. Rizvi. But if a repeat ERCP shows normal cytology, and if the FISH result is now also normal, “then we would probably just do an MRI/MRCP in about six months to make sure if anything’s evolving, we can capture it.”

Though PSC clouds the diagnostic process, it offers one advantage: These patients are being followed closely, increasing the odds of earlier detection. Cases of de novo perihilar cholangiocarcinoma are difficult to catch early.

Says Dr. Kipp of Mayo’s genomics laboratory: “The best way to cure this disease is to detect it earlier.” But laboratorians also need to keep an eye on the literature, “so we can assure ourselves, when there is a companion diagnostic or a new targeted therapy, that we have the assays in-house to predict whether patients will respond.”

A correct diagnosis of perihilar cholangiocarcinoma can offer hope to some patients. If the tumor is less than 3 cm and is unresectable, otherwise healthy patients might qualify for neoadjuvant chemoradiation and liver transplantation. Mayo has done more than 200 transplants for this indication, Dr. Rizvi says.

Patients with PSC will qualify for this treatment even if their tumor is resectable, assuming they meet the other criteria. “PSC patients have what we call a field defect,” Dr. Rizvi says, placing them at risk for developing cholangiocarcinoma—a risk that would remain even if half the liver were removed.

She urges caution on one more point. With the emphasis on making the correct diagnosis, some providers might be tempted to perform a confirming biopsy on a mass lesion present on MRI/MRCP. But Dr. Rizvi and colleagues have found that for patients who’ve undergone a liver transplantation who first underwent a percutaneous biopsy—in other words, not an endoscopic biliary biopsy—“the risk of seeding along that needle track was incredibly high,” Dr. Rizvi says, “and the vast majority of patients developed recurrent or metastatic disease after liver transplantation.” Even biopsying via endoscopic ultrasound is a contraindication for liver transplant. “We have had instances where patients who otherwise qualified for liver transplant were, unfortunately, not candidates because the mass had been biopsied percutaneously.”

For intrahepatic and distal cholangiocarcinoma, patients might be candidates for surgical resection, which is the current standard of care in early disease. Emerging data show a potential benefit for transplanting in very early cases of intrahepatic cholangiocarcinoma. “It’s still under investigation,” cautions Dr. Izzy.

If surgery is not an option in these types of cases, the treatment is systemic therapy. In some cases of intrahepatic cholangiocarcinoma, Dr. Izzy adds, locoregional therapy can be considered, which involves transarterial embolization or radiotherapy; a combination of locoregional therapy and chemotherapy might also be an option. Dr. Izzy pronounces himself “hopeful” that future approaches will offer better survival and outcome.

The incidence of cholangiocarcinoma overall is rising, in part due to improved diagnostic modalities. A recent study looking at tumor of unknown primary in the liver showed that a good percentage were, in fact, cholangiocarcinoma (Hainsworth JD, et al. J Clin Oncol. 2013;31[2]:217–223). In addition, some risk factors that contribute to the development of cholangiocarcinoma, such as obesity and alcoholic liver disease, are on the rise.

Many, including Dr. Izzy, are holding out hope for cell-free DNA or circulating tumor DNA. One study involving cases of predominantly perihilar cholangiocarcinoma has shown that circulating cfDNA with certain differentially methylated regions can detect the presence of cholangiocarcinoma. The sensitivity exceeded 80 percent in the same study, presented in 2017 at Digestive Disease Week, Dr. Izzy says, though he hastens to add that more studies are needed.

Dr. Rizvi and her colleagues recently reviewed emerging technologies for diagnosing perihilar cholangiocarcinoma (Rizvi S, et al. Semin Liver Dis. 2018;38[2]:160–169). Next-generation sequencing is being compared to FISH, and is in the looks-promising-but . . . category.

Some groups have looked at extracellular vesicles, which are membrane-bound vesicles that are intimately involved in cell-to-cell communication, carrying possibly cancer-promoting proteins such as microRNAs. Looking at the cargo carried by extracellular vesicles, and comparing the difference between patients with and without cholangiocarcinoma, might be a future diagnostic modality, Dr. Rizvi says.

Another possible diagnostic: proteomic analysis by mass cytometry, which has been used to look at a variety of specimens from bile duct cancer patients, including urine, serum, bile, and stool. Different peptide panels have been reported on, with variable sensitivity and specificity.

Of all the options Dr. Rizvi has seen so far, circulating tumor cells and cell-free DNA look to be the most promising, she says. All are novel biomarkers and could aid in earlier diagnosis.

Progress continues at a polite pace, but no one is sounding discouraged. As Dr. Izzy notes, the obstinate nature of the tumor, and not of physicians, is the real challenge, and what seems to draw many to this field. Like singing “Bohemian Rhapsody” at a karaoke bar, tackling cholangiocarcinoma is not for the shy.

“As a transplant hepatologist, you see that this is one of the most difficult topics we deal with in our specialty,” says Dr. Izzy. “Difficult topics are stimulating topics—and you want to help patients.”

Dr. Graham likewise enjoys the twists and turns in the road, especially with molecular genetics and biomarkers. “There’s been so much to explore. We are just getting started.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.