'Transformative' Tool for Pancreatic Cysts, Cancer?

Nick Mulcahy

March 20, 2017

A novel light-based technology may be 95% accurate in differentiating between pancreatic cysts that are potentially precancerous and those that are benign, according to the results of a two-phase, double-blind prospective study.

The new research was published online on March 13 in Nature Biomedical Engineering.

Roughly 90% of pancreatic cysts are benign and can be monitored without treatment. But precancerous cysts, although uncommon, may develop into pancreatic cancer, which is associated with a dismal median survival rate of 6 months after diagnosis. About 20% of all pancreatic cancers arise from cysts.

In the United States, pancreatic cysts are being found incidentally in "large" numbers on CT and MRI, said study coauthor Douglas Pleskow, MD, an interventional gastroenterologist at Harvard University and Beth Israel Medical Center in Boston, Massachusetts.

"Scans that look for things like kidney stones or gallstones related to abdominal pain are turning up increasing numbers of pancreatic cysts," he told Medscape Medical News. An estimated 10% to 15% of adults have these cysts, which are associated with aging.

Thus, the need for differentiating potentially cancerous cysts from benign cysts is considerable, from both a clinical and an epidemiologic perspective. The urgency is compounded by the fact that surgery, which is curative when cysts are precancerous or cancerous, is associated with high morbidity and mortality rates and should be untaken with great caution, say the study authors.

Currently, cytology is the primary test for assessing whether cysts are malignant or benign before surgery. However, cytology, which is performed in a laboratory after the removal of cystic fluid via diagnostic endoscopic-ultrasound fine-needle aspiration (EUS-FNA), is accurate only 58% of the time.

"We have some tools for the evaluation of pancreatic cysts, but those tools are not very effective," summarized Dr Pleskow.

In the new two-phase pilot study, a device using experimental light-scattering spectroscopy (LSS) evaluated the malignant potential of 27 cystic lesions from 25 patients in a double-blind comparison with either postoperative histopathology or survival outcomes and achieved 95% accuracy (95% confidence interval, 78% - 99%).

The authors explained that postoperative histopathology is the gold standard for assessment of cysts but is only available for patients who have undergone surgery and for whom excisional tissue is available for analysis. In the new study, five of the patients did not have surgery and were followed for more than a year after being evaluated. There was no evidence of malignancy.

This is one the most exciting things I've ever done. Dr Douglas Pleskow

"This is one the most exciting things I've ever done," said Dr Pleskow. "I was hoping it was going to be half as good as it is. It's just amazing. I believe this is transformative."

The transformation is both in the improved accuracy and the speed with which cysts are characterized by LSS.

The LSS probe, which piggybacks onto the EUS-FNA procedure and goes into the mouth and down into the small intestine to rest next to the pancreas, detects the structural changes that occur in cancerous or precancerous cells by bouncing light off tissues and analyzing the reflected spectrum. The researchers intend to eventually be able to undertake in real time an assessment of cysts while the LSS procedure is being performed. The assessment can be completed in a matter of seconds to minutes. In the study, the assessment was performed post procedure by the team, which assessed the LSS results.

The device was developed by study coauthor Lev Perelman, PhD, a renowned biomedical engineer at Beth Israel and Harvard, who owns the LSS technology and is also experimentally employing it to assess Barrett's esophagus.

Dr Pleskow emphasized that LSS is in need of more research. "We need to do more studies with a bigger selection of patients," he said.

A pair of gastroenterologists who were not involved with the study agreed.

"The results of this pilot study are intriguing but need to be confirmed in larger studies," said gastroenterologists Jeffrey Tokar, MD, and Michael Jan Bartel, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania, in a joint email to Medscape Medical News.

The pair said the study was "cutting-edge research in a complex patient cohort." They explained that there are three types of cyst patients.

There are those with nonneoplastic cysts who are without cancer risk (ie, who have pseudocysts), those with benign neoplasms who are without significant cancer risk (ie, who have serous cystic neoplasms), and those with benign neoplasms at risk for malignant transformation over time (ie, who have intraductal papillary mucinous neoplasms [IPMNs] or mucinous cystic neoplasms [MCNs]).

When a patient is suspected of having an IPMN or an MCN, an additional question needs to be asked: is high-grade dysplasia (HGD) or cancer currently present that would warrant surgical pancreatic resection?

"A test which distinguishes LGD from HGD with a high accuracy is desirable and LSS shows promising results in that field," the Fox Chase experts said.

LSS shows promising results in that field. Dr Jeffrey Tokar and Dr Michael Bartel

This comment refers to the some of the findings from the new two-phase study.

In the first phase, the investigators performed an ex vivo pilot study to evaluate the ability of LSS to differentiate cystic neoplasms with varying grades of malignancy from benign cysts. Patients with the former constituted the surgery group.

The team used 11 freshly resected pancreatic specimens containing 13 cysts, including one pseudocyst, one serous cyst adenoma, and 11 IPMNs, consisting of LGD (n = 4) and HGD (n = 7). Cyst characteristics were measured/established using histopathologic specimens (which is the gold standard, as noted above). LSS demonstrated an accuracy of 100% in distinguishing dysplastic from benign cysts and an accuracy of 92% in differentiating LGD from HGD (one HGD was mistakenly identified as LGD by LSS).

In the second phase, the authors performed an EUS-FNA in 14 consecutive patients with pancreatic cysts and used the EUS-guided access for LSS measurement of cysts in vivo. These patients constituted endoscopy group.

Histopathologic specimens obtained via surgery were available for two of these patients. One specimen was classified by LSS as cancer but was misdiagnosed by cytology as being negative for malignancy (the patient later died of metastatic cancer). One was determined to have an adenocarcinoma cytology. As noted above, five patients have survived for more than a year, with follow-up showing no evidence of malignancy. For five other patients, for whom follow-up was inadequate, the diagnosis was established by two independent expert gastroenterologists, who took into account the clinical history and the results of imaging and cyst sampling. In this cohort, LSS yielded an accuracy of 93% in detecting malignant cysts, including invasive cancer and HDG. There was one case of cystic neuroendocrine tumor.

In the their review of the study, Fox Chase's Dr Takor and Dr Bartel made an additional point about how the new results do not fully illuminate the clinical conundrums generated by cysts.

The natural history and progression of pancreatic cystic neoplasms from LGD to HGD and eventually to invasive cancer are not entirely understood, they point out.

So, if HGD is not suspected but LGD is, another issue comes up. "What are that particular individual's chances of transformation to malignancy over time, and what is the pace of the transformation?" they ask. The question is compelling because curative surgery cannot be undertaken lightly, owing to its complexity and the associated risks.

"We do not know the rate and pace of the neoplastic progression from LGD to HGD and from HGD to invasive cancer. Whether LSS can shed light into that dilemma and whether it can identify patients at highest risk progressing to invasive cancer remains to be elucidated," they say.

The study was supported by the National Institutes of Health and the National Science Foundation. Dr Pleskow, Dr Tokar, and Dr Bartel, have disclosed no relevant financial relationships. Dr Perelman is the inventor and owner of LSS.

Nat Biomed Eng. Published online March 13, 2017. Abstract

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