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New guideline spells out IPMN essentials

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Karen Titus

June 2015—It was a call he dreaded making.

It was the late 1990s. Volkan Adsay, MD, was following up on a former patient who had been diagnosed eight years earlier with pancreatic cancer, one related to an intraductal papillary mucinous neoplasm. The patient’s medical record noted that despite chemotherapy, the prognosis was grim.

Lead author Dr. Volkan Adsay (right), with coauthors and Emory pathologists Alyssa Krasinskas, MD (front), and Michelle Reid, MD. The new guideline fills a gap in IPMN pathologic evaluation and reporting, says Dr. Adsay. “A lot of pathologists are being exposed to this entity.”

Lead author Dr. Volkan Adsay (right), with coauthors and Emory pathologists Alyssa Krasinskas, MD (front), and Michelle Reid, MD. The new guideline fills a gap in IPMN pathologic evaluation and reporting, says Dr. Adsay. “A lot of pathologists are being exposed to this entity.”

“Everybody was expecting him to be dead,” recalls Dr. Adsay, professor and vice chair and director of anatomic pathology at Emory University. “So I was preparing a very apologetic phone call: I’m sorry to be bothering you, but your father, or your spouse, had this tumor, and we wanted to find out when he died.”

Such was the nature of IPMNs not so long ago. “These tumors were called ordinary pancreas cancers just 20, 25 years ago,” Dr. Adsay says. “And many patients were sent home to die.”

When Dr. Adsay placed the call, he was in for a shock. “The patient himself picked up the phone,” he recalls, the surprise—and delight —still evident in his voice nearly two decades later.

As it turns out, IPMNs are more complicated than first thought, and patients once consigned to a certain mortality, can—as Dr. Adsay discovered—reappear, so to speak, like a character in a Thomas Hardy novel.

Now, no longer willing to rely on fate and muddled data, experts on IPMNs have written a new guideline on their pathologic evaluation and reporting, which was published online March 13 in the Annals of Surgery (Adsay V, et al. 2015).

The time was ripe. “The tumor type is relatively new and not as well known,” says Dr. Adsay. “There’s been a big learning curve for both pathologists and clinicians. And it’s still a challenging tumor type, both for management and diagnostic purposes.”

Hence the impulse behind a 2013 meeting by the Verona (Italy) Pancreas Group, which brought together a multidisciplinary group of 60 to 70 people (per Dr. Adsay’s estimate), including those from pathology, surgery, and gastroenterology. The main parameters of the guideline came primarily from discussions at the Verona meeting, says Dr. Adsay. But after that he sought input from other pathologists via questionnaires. He compiled that information and ran it by the original committee and organizers of the Verona meeting. All of which is to say, “There were many steps to getting input” before the final manuscript emerged.

The guideline fills an obvious gap. Though they were first recognized in 1982, IPMNs hardly took medicine by storm.

No one quite knew what to call them, for starters. Prior to the use of the term “intraductal papillary mucinous neoplasms” in 1994, their identities were never fully settled, as if they were passing repeatedly through Ellis Island, their names changing each time: duct-ectatic mucinous cystic neoplasms, mucin-producing tumors, intraductal papillary neoplasms, papillary adenocarcinomas, and villous adenomas, among others.

Nor did it seem to matter, at first, what they were called. “They were thought to be relatively rare tumors. Back then it was extremely uncommon to find them, and we didn’t know how to interpret the findings,” says Dr. Adsay.

Dr. Anne Marie Lennon (above), who oversees the Multidisciplinary Pancreatic Cyst Clinic at Johns Hopkins, says colleagues such as Dr. Ralph Hruban (center) and Dr. Christopher Wolfgang (left) “bring huge depths of knowledge” to patient management discussions each week. “We all learn from each other.”

Dr. Anne Marie Lennon (above), who oversees the Multidisciplinary Pancreatic Cyst Clinic at Johns Hopkins, says colleagues such as Dr. Ralph Hruban (center) and Dr. Christopher Wolfgang (left) “bring huge depths of knowledge” to patient management discussions each week. “We all learn from each other.”

All that has changed. “Now we’re discovering them in high frequency,” he says. The rise is due in large part to more widespread use of MRIs and other imaging modalities. As Dr. Adsay points out, endoscopic ultrasound didn’t exist when IPMNs first emerged, and even core needle biopsy of the organ was uncommon. (“Everybody was scared to poke the pancreas,” he says, “because it could lead to pancreatitis.”) The sensitivity of these modalities has also improved.

Most of these cystic lesions appear incidentally during workup for other diseases, which creates a major management question, says Dr. Adsay. Should they be resected? Or is it reasonable to follow them closely?

The literature has provided limited guidance, unfortunately. From one study to the next, a slackness crept into the IPMN lexicon. More recently, in his post-Verona, pre-guideline survey of pathologists, Dr. Adsay says he found a fair amount of variation among how pathologists—including experts—reported IPMNs.

One stark example: Not everyone agreed on what the word “malignant” meant.
Some groups reported noninvasive cancers as being malignant or included high-grade dysplasia in that category, others applied the word to invasive cancers, and yet others reserved it for only those tumors that involved recurring metastases. “Those years of research are hard to interpret because of the loose terminology,” says Christopher Wolfgang, MD, PhD, chief of hepatobiliary and pancreatic surgery and the Paul K. Neumann professor of pancreatic cancer research, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine. Some groups also reported that some patients with malignant IPMNs did just fine (which helps explain Dr. Adsay’s surprising phone call), while others found that malignant IPMNs did indeed lead to mortality.

The new guideline tries to impose order on this and other chaos. It couldn’t come at a better moment. “There’s a virtual epidemic of patients being diagnosed with IPMNs,” says another guideline author, Ralph Hruban, MD, professor of pathology and director of the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins. “And there’s controversy clinically as to how they should be managed. This is an exciting time for pathologists who are involved in the care of patients with intraductal papillary mucinous neoplasms.”

That’s quite a few pathologists. Ten, or even five, years ago, IPMNs would have been termed a problem for specialists alone, Dr. Adsay says. Now, “A lot of pathologists are being exposed to this entity.”

That means surgeons are, too. Although Dr. Wolfgang (who is a guideline author) is no stranger to IPMNs, he and his colleagues still struggle at times to unravel their meaning. “The most challenging thing about the IPMN is that the vast majority of these are premalignant lesions, and we don’t know how many will progress to cancer.”

Here’s how the guideline, with its obbligato of precision (not to mention a sample synoptic report), might help.

Tumor size

As Dr. Adsay learned when he queried colleagues both in Verona and afterward, there’s plenty of variation in how pathologists report IPMN tumor size.

The invasive component—the true cancerous component—needs to be reported as a separate item, says Dr. Adsay. But this is not always done. Instead, he says, pathologists were reporting both cancerous and noncancerous components—the entire tumor—together, which clouded assessment of individual patients as well as overall understanding of their biology.

“These tumors can be large—six, seven centimeters—but still be preinvasive,” Dr. Adsay says. But they might have a small invasive focus. “That needs to be acknowledged separately.” Is the whole tumor cancer, or just a small percentage? Failure to distinguish the two components on pathology reports “was probably the biggest problem we encountered,” he says.

That leads to a discussion of size. “It’s not easy,” Dr. Adsay concedes, noting that a similar difficulty occurs with breast cancer, especially if the invasive cancer is multifocal. “Do you measure the largest focus? Do you combine the sizes?” In breast, he notes, the decision has been made to use the largest focus for staging. “The other foci are kind of ignored.” But, he notes, the discussion continues, since there are studies showing that the size in aggregate may correlate better with the cancer’s behavior.

For measuring overall IPMN tumor size, the guideline says that while size becomes less significant in resected specimens, “Regardless, every attempt should be made to accurately determine the size of the lesion in the pathology report.”

Noting that some IPMNs have thin-walled cysts prone to rupturing, the guideline advises pathologists to correlate size with imaging findings, and to document the mode of measurement: “For example, ‘Overall size of IPMN: 3 cm, as measured clinically (cyst ruptured during processing).’”

Measuring size of the invasive carcinoma is just as challenging and even more important. If the invasive carcinoma is unifocal, pathologists should measure the largest diameter of the invasive focus, according to the guideline. For multifocal tumors, pathologists should report both the diameter of the largest one and the overall estimated size of all foci in aggregate.

Persuading pathologists to report the two components separately is, says Dr. Adsay, “I hope, the most important accomplishment of this guideline.”

Terminology

As mentioned, the guideline wrestles the word “malignant” to the mat.

In fact, it recommends eliminating the term “malignant IPMN” and instead clarifying whether the IPMN is invasive.

Then there’s the term “minimally invasive.” Like “malignant,” the guideline would like to move this term to pathology’s no-fly list.

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