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Classifying central nervous system tumors has recently become both more complex and easier. Surgical pathologists now have guidance that helps them work through the whys, hows, and what-ifs of using molecular studies when making diagnoses. The 2016 WHO classification for CNS tumors, which has been described as a conceptual and practical advance over the previous incarnation, from 2007, should also help them move closer to precision medicine.

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Karen Titus
If MSI testing becomes universal, says Dr. Hamilton, “then it needs to be clear that the results of microsatellite instability status are looked at and correctly interpreted by clinicians.” Even a simple positive or negative result can be problematic, “believe it or not.”

April 2017—Molecular testing for colorectal cancer is not for the faint of heart.

While that’s not news to Stan Hamilton, MD—he’s head, Division of Pathology and Laboratory Medicine, and the Frederick F. Becker distinguished chair in cancer research, University of Texas MD Anderson Cancer Center—he was reminded of this fact recently when a friend looked at the multipage molecular pathology report on his own tumor. “He called and basically said, ‘What are you guys doing?’” recalls Dr. Hamilton, noting that his friend, an engineer, is well versed in reading technical reports. “And he was completely befuddled by what he saw.”

Dr. Stan Hamilton (right) at the University of Texas MD Anderson Cancer Center with George Chang, MD, MS, a professor in the Department of Surgical Oncology and chief of the section of colon and rectal surgery. The guideline on molecular biomarkers for the evaluation of colorectal cancer “has brought the quality control aspect [of testing] front and center,” says Dr. Hamilton.

Dr. Hamilton adds, “He asked, ‘Why can’t you make this easier on us patients?’”

And that’s just the report. Left unsaid, but equally valid, is another question: Why can’t molecular testing be easier for clinicians and pathologists, too?

With colorectal cancer, ease is a distant, likely nonexistent, goal. Molecular testing options are complicated to navigate. Even when a molecular portrait of the tumor has emerged, “We don’t have a lot of active agents to choose from,” says Carmen Allegra, MD, chief of oncology and hematology, University of Florida, Gainesville.

Yet the literature continues to grow, and with it come new approaches to using older tests, as well as added data about promising biomarkers. Trying to make sense of it all is a fresh guideline on molecular biomarkers for evaluating CRC, representing the best and the brightest from the CAP, American Society for Clinical Pathology, Association for Molecular Pathology, and American Society of Clinical Oncology (Sepulveda AR, et al. Arch Pathol Lab Med. Epub ahead of print Feb. 6, 2017. doi: 10.5858/arpa.2016-0554-CP).

Unlike previous guidelines from ASCO and the National Comprehensive Cancer Network, says lead author and AMP co-chair Antonia Sepulveda, MD, PhD, that input from four key societies meant unusually heavy emphasis on laboratory testing as well as the more typical guideline coverage of required testing for targeted and conventional therapies. “This has never really been done with such a global scope,” says Dr. Sepulveda, professor and vice chair for translational research, and director, Division of Gastrointestinal Pathology, Department of Pathology and Cell Biology, Columbia University, New York City.

“If you look at the recommendations,” adds Dr. Hamilton, who was the CAP co-chair, “the vast majority of them deal with how to get the testing done. This is not an inconsequential issue. But this is not simply a lab testing guideline. It includes the clinical utility of the tests, and with expert opinion from the medical oncologists who are ordering the tests.”

Another strength, says Dr. Sepulveda, is that the guideline is based on a systematic literature review (with extensive tables to prove it) and levels of evidence, using National Academy of Medicine (formerly Institute of Medicine) standards for developing clinical practice guidelines. This should chase most bias from the recommendations, says Dr. Hamilton. Moreover, even with its 21 statements—“It’s a large and comprehensive guideline,” Dr. Sepulveda says—updates are likely. By following the academy’s standards, the new guideline should remain relevant for some time, she says.

Reflecting the complicated nature of CRC testing, “There was an enormous amount of literature—thousands of papers that we combed through,” says Dr. Allegra, the ASCO co-chair. The major tests for CRC are not new, but their application is evolving—a fact reflected in the guidelines. And in the meantime, researchers continue to find new puzzles in need of solving.

As with the city of Pittsburgh, there are three main rivers to follow in CRC testing: DNA mismatch repair, or MMR, status; BRAF mutation; and RAS mutation.

Testing for MMR, either by immunohistochemistry for the four MMR proteins (MLH1, MSH2, MSH6, and PMS2) or by microsatellite instability DNA-based testing, has evolved from its use in a small group of patients with an inherited disease to a wide variety of clinical decisions, including whether to give postoperative adjuvant therapy and how to treat patients with advanced disease. Oncologists might order that same test for different reasons, says Dr. Hamilton. “That, in fact, is part of the reason we’ve now recommended universal testing in the guideline.”

The first use to emerge was as a marker for Lynch syndrome. MMR is also used as a prognostic marker.

Most recently, researchers have recognized the value of the MSI-high (i.e. high level of microsatellite instability) in patients with advanced disease (about five to six percent of CRC patients) in predicting response to immunotherapy with immune checkpoint inhibiting drugs, specifically pembrolizumab (Le DT, et al. N Engl J Med. 2015;372[26]:2509–2520).

In patients with colorectal cancer, about 20 percent have defects or mutations in one of the DNA repair genes. In about a quarter of those patients, the mutation is based in their germline, the underlying mechanism of Lynch syndrome. As Dr. Hamilton notes, knowing MMR status is crucial not only for managing these patients but also to encourage earlier screening of at-risk family members. For the other 75 percent of patients with mismatch repair deficiency, the mutation is sporadic.

Dr. Allegra

In both groups, MMR mutations carry prognostic information. Those with a deficiency typically, and counterintuitively, have a better outcome, regardless of the stage of their disease. In the case of a stage II patient with an MMR outcome, for example, “They have an extremely good outcome, to the point where we generally don’t consider those patients for any kind of adjuvant therapy after their primary surgery,” says Dr. Allegra.

With other tests, figuring out the next clinical steps often resembles the search for winning lotto numbers.

BRAF mutation (occurring in about eight percent of patients with advanced colorectal cancer) engendered lively discussion when the guideline creators looked at its role as an adverse predictive marker.

“In the report,” Dr. Allegra says, “we said that a BRAF mutation means you don’t do as well with an EGFR inhibitor. But the benefit isn’t zero—that’s what the data showed.” While many clinicians balked at the idea of using EGFR inhibitors in people with BRAF mutations—“They thought it was crazy,” Dr. Allegra says—a hard look at the data suggests some benefit. “So it’s hard to say you shouldn’t use it at all.”

As Dr. Hamilton explains, it’s well known that this gene mutation behaves differently in different subsets of patients. For patients with high levels of microsatellite instability and BRAF mutation, “the BRAF mutation doesn’t seem to matter as much. The outcomes are somewhat worse, but not substantially so.”

In contrast, patients with microsatellite stable or MSI-low tumors and BRAF mutation have a far worse outcome and generally present with more advanced disease, Dr. Hamilton observes. They also seem to be more resistant to chemotherapy. During the guideline discussions, “There was some concern about whether this was related to the fact that the BRAF mutation just conferred a worse prognosis, or whether it really was a predictive marker and could be used to make decisions about therapy.”

Another possible use for BRAF popped up in an abstract presented at ASCO’s 2017 Gastrointestinal Cancers Symposium. Research by Dr. Hamilton’s colleague at MD Anderson, Scott Kopetz, MD, PhD, suggested simultaneous EGFR and BRAF inhibition prolonged progression-free survival in patients with advanced disease. Patients were given a combination of cetuximab and irinotecan, with and without vemurafenib, a BRAF inhibitor. Patients who received the latter drug as part of their regimen “did much, much better than those with the classical chemotherapy,” says Dr. Allegra (median PFS of 4.4 versus 2.2 months; disease control rate of 67 percent versus 22 percent). He considers this a major advance and says, “It was probably the most important paper presented at GI ASCO in January.”

Dr. Hamilton, who has collaborated on a number of papers with Dr. Kopetz, adds, “Scott is an absolutely superb researcher. I think the world of him. And I think he’s right.” But, he adds, it is an abstract.

While that abstract was too newly hatched to influence the guideline, the authors had their hands full trying to assess other possible breakthroughs.

“It took us two years to get this done, because every time we turned around and thought we were getting toward the end, something new, like extended RAS, popped up,” says Dr. Hamilton.

For patients with advanced disease, anti-EGFR drugs such as cetuximab and panitumumab are part of the oncologist’s armamentarium. Less well recognized is that patients who have a KRAS mutation generally will not respond well to those drugs. “There have even been a few studies that have suggested they actually get worse,” says Dr. Hamilton.

In looking at targeting the EGFR pathway, the guideline authors looked for literature for or against BRAF testing. “So far the evidence is insufficient to make a recommendation,” says Dr. Sepulveda. Ditto for markers such as PIK3CA and PTEN. “So while we can test these genes for other reasons, they are not useful at this time for making decisions about anti-EGFR therapy,” says Dr. Sepulveda.

The KRAS discussions thus were relatively tranquil. But while the guideline was being developed, the NRAS story began to be told.

An NRAS mutation should sound an alarm. For these patients, anti-EGFR agents don’t work. “They have zero activity,” says Dr. Allegra. “And they’re toxic. Sparing patients from that therapy is important.”

“This has evolved quickly in the last 18 months to two years,” he continues. Those who had been looking at RAS had mostly confined their search to a couple of hot spots. “But what’s become apparent is that if you have a mutation, probably regardless of where that mutation occurs, it carries with it a negative predictive value.”

About half of patients with colorectal cancer have a KRAS mutation. Another five to eight percent has an NRAS mutation.

“A large meta-analysis, summarizing a number of primary trials, provided additional data that led to recommendation No. 1 in our guideline, for expanded [also called extended] RAS testing,” Dr. Sepulveda says (Sorich MJ, et al. Ann Oncol.2015;26[1]:13–21). Patients being considered for such treatment must receive RAS mutational testing, including analysis of KRAS and NRAS codons 12 and 13 of exon 2; 59 and 61 of exon 3; and 117 and 146 of exon 4.

The authors also had to pause in their discussions about mismatch repair testing.

IHC is relatively easy to do and relatively inexpensive. Turnaround times are rapid, and it can be done with small amounts of tissue. “That’s obviously a terrific screening test,” Dr. Hamilton says.

But it’s now recognized that there are situations where IHC doesn’t work.

One occurs in patients with Lynch syndrome who have a gene mutation that abrogates the function of the gene but doesn’t cause loss of immunoreactivity. In other words, the expression exists in the tumor, but the protein is nonfunctional. “So the patient still has high levels of microsatellite instability and is still generating the phenotype of an MSI-high cancer, but the immunohistochemistry is often not able to pick that up,” says Dr. Hamilton. “There are sometimes subtle differences in the tumors, in the pattern of immunohistochemistry, that can give you a clue that something’s up,” including patchy expression or a peculiarity in the nucleus, where the staining may be less than in a typical case. “It just doesn’t look quite right.”

A more recently identified problem is that in some tumors affected by MSH6 mutations, the IHC will yield an abnormal result—no protein expression—but those cases do not show high levels of MSI. “It’s hard to understand why that occurs, but we see it,” says Dr. Hamilton.

“The other thing now recognized is the biallelic inactivation by somatic mutation,” Dr. Hamilton continues, “where there are point mutations in both copies. One of the mismatch repair genes inactivates them, but again, doesn’t affect the protein.” In this subset of cases, it’s not the methylation mechanism that extinguishes expression; rather, the protein is nonfunctional—the immunoassay sequence is changed by the mutations.

IHC and molecular MSI testing have their pros and cons, clearly. The best choice should reflect patient population and the needs of the ordering physician. “If you’re looking for Lynch syndrome on the basis of a clear-cut family history, it’s probably quite reasonable to start with a molecular test,” says Dr. Hamilton. If that comes back abnormal, “move to one of the family cancer germline mutation panels, and don’t worry about [IHC] in the tumor itself.”

If a patient is older, and methylation of MLH1 is likely, “starting off with the molecular sequencing spends a lot of money and takes up time,” but it may be worth it, Dr. Hamilton says. “The bottom line is, if you want to make certain of what you’re dealing with, you’ve got to do a fair amount of work.”

IHC will tell physicians which genes are involved. If BRAF is mutated, then Lynch syndrome is highly unlikely. “But that’s not perfect,” Dr. Hamilton says. It’s also important to test MLH1 to determine if methylation is present. “But that’s not perfect, either, because methylation does occur in patients who have Lynch syndrome as the underlying cause.” And don’t forget the aforementioned biallelic somatic gene mutations that can lead to abnormal protein—and the need for gene sequencing. “Finally, we now recognize a hypermutable—some refer to it as ultramutated—group with high mutational burden due to abnormalities in the polymerase epsilon and delta genes. Those do not have MSI at all.”

“Fortunately,” says Dr. Hamilton, “we’re beginning to understand much better what we’re dealing with. But unfortunately, it turns out to be very complicated to do the whole workup to get the answer in these individual patients when you get these unusual results.”

Dr. Hamilton pauses, then plunges ahead with a rueful laugh. “I’m still not done. To make things even worse,” he says, studies of germline testing have shown that looking at the phenotype in families has a significant error rate in identifying which genes are abnormal. “Cases that look like Lynch syndrome turn out to be something like PTEN deficiency.”

The guideline can help with even these most complicated cases. Genes are fickle—a fact not always reflected in other guidelines, says Dr. Hamilton. “Frankly, most of the other guidelines looking at results of assays, particularly panel sequencing, are not looking at how you got those results,” Dr. Hamilton says. “This guideline has brought the quality control aspect front and center. I’m not casting aspersions. It’s simply a matter of how they think about that.”

In colorectal cancer, there are few straight lines through the testing process. Even KRAS testing—ostensibly one of the least complicated steps—has its hiccups. Given the exceptions that may turn out to be unexceptional, and the growth of targeted therapies, stepping precisely through CRC testing, with close attention to the quality control directives in the guidelines, becomes even more crucial, says Dr. Hamilton.

Dr. Sepulveda

Dr. Sepulveda drives home that point when she highlights the predominance of statements devoted to lab-specific issues, such as types of tissue and fixative to use and the benchmarks for choosing them, turnaround times, analytical sensitivity, reporting clarity, quality improvement measures, and the like. “There’s a lot there,” she says. “It’s all important.”

“We tried to cover the waterfront,” Dr. Hamilton adds.

The guideline could add another level of clarification to the MMR discussion as well. Calling for its universal testing should nudge third-party payers. “That’s one of the goals of a national guideline,” says Dr. Allegra. “If you say something ought to be tested, it’s harder for third parties to say no.”

Despite the high stakes, molecular testing results can sometimes fall through the cracks, even when delivered promptly. How can pathologists make sure the results are seen by the right pair of eyes, understood, then acted on?

In the current National Cancer Institute-MATCH trial, for example (a precision medicine trial in which specimens are evaluated for a series of markers to qualify patients for one of 24—soon to be 30—arms), two of the MSI genes are used for determining access to one of the arms. Pathologists are clear on the drill: If a result is positive, that means the gene retains expression; a negative result means loss of expression. And a loss of the protein (i.e. a negative result) is a positive for receiving therapy.

“You would have thought that would have been fairly clear to everyone, but almost on a weekly basis we got a contact from a site: ‘Does that positive [result] mean my patient’s eligible for immunotherapy?’” says Dr. Hamilton.

Counterintuitive reasoning is one problem. Electronic medical records, oddly, are another.

Dr. Hamilton explains: Pathology reports have actually become quite clear. “The CAP has been working on that for years, and the biomarker guidelines are out there [he served on the biomarker reporting committee], and most pathology departments have taken them to heart,” he says. The guidelines, when followed, ensure results are clearly presented—typically in tabular form and thus highlighted in the text.

So far, so good. But when the results become part of the EMR, data from the laboratory information system get converted. Depending on the EMR being used, “You lose that nice visibility when the clinician looks at it,” Dr. Hamilton says.

Dr. Hamilton didn’t recognize the problem until he became involved in the NCI-MATCH trial and saw what happened with certain EMRs. “It can be really tough to find the results in these reports.” The problem extends to reports from the major reference labs. “Their reports are very well laid out,” Dr. Hamilton says. “It’s very easy to get the information at a glance.” When the information hits the EMR, however, all bets are off. The difference, in some cases, “is night and day.”

It’s more than frustrating. “Frankly, it’s a patient safety and quality of care issue,” says Dr. Hamilton. Targeted therapies and immunotherapeutic agents associated with these assays yield good results in a significant proportion of patients, he says. “It’s a real issue that needs to be addressed,” especially given the pressures on already-busy clinicians to see more patients.

Dr. Allegra agrees about the busy part. Even if the results are clear in the EMR (which seems to be the case at his institution), he voices frustration at how test answers often come to him piecemeal. “As docs get busier and busier, it may not get acted on.”

The guideline’s authors—experts all—breezily admit to not following them to the letter in their own practices. It’s to be expected, given their patient populations, which often include those with advanced disease who’ve run out of options elsewhere. As Dr. Allegra puts it, “You go to the university, and for those patients, if they’re lucky enough to have a certain kind of genetic defect, the magic does happen.”

Dr. Hamilton is involved in a large phase one program that is testing tumors in an attempt to develop biomarkers in tandem with identifying toxicity. “We’re requesting testing on a very high percentage of patients with advanced disease with a panel of genes related to that approach. We’re looking at pathways that may be important, not only as targets but also as modifiers of the response and resistance to therapy.”

Dr. Kopetz’s work fits in with those efforts to identify resistance to mutation. Work like this will, it’s hoped, help explain why BRAF inhibitors that work spectacularly in melanomas with a BRAF mutation don’t translate to CRC. “Colon didn’t respond at all,” says Dr. Hamilton. “There were resistant pathways that developed in EGFR and C-meth. When the drug blocked the BRAF pathway, these other pathways were activated, and the tumors kept growing.”

While this deeper understanding is starting to become part of general usage, “We’re not there yet,” says Dr. Hamilton. “In particular, the understanding of which pathways and how many of them can be inhibited without introducing horrible toxicities needs to be answered.” The other problem is that combinations of co-mutations are variable, he says. “So we’re trying to figure out in advance what the most common co-mutations are that you might want to try to inhibit.”

At Columbia, Dr. Sepulveda says, every case of primary CRC undergoes IHC testing for the four MMR proteins, as well as MSI testing. “Some of the immunotherapy clinical trials ask for MSI status of the tumor, so we want that information up front.” They also use a commercial next-generation sequencing panel, do extended RAS testing, and routinely test for BRAF and PIK3CA. Though the guideline does not recommend PIK3CA, compelling retrospective data show that it might be a useful biomarker for patients postsurgically, as well as to qualify patients for a clinical trial. “Because we are an academic center, we decided to go ahead and include this on our reports,” she says.

Dr. Hamilton blithely says there was almost no controversy during the guideline discussions—until he’s asked about turnaround times. The memory of that, like childbirth, was something he managed to forget. “I guess that was a Freudian thing on my part,” he says.

Oncologists, naturally, want test results delivered as if borne by the wing-footed Mercury.

Dr. Hamilton is sympathetic. “Think of it from the patient perspective,” he says. Those with advanced disease understand the gravity of their situation. “Sitting and waiting for lab results to come back is awful. We have a duty to patients to do this as rapidly as possible.”

But real limitations weigh on laboratories as well, such as having sufficient staff to pull a case and review it, in the case of a resection, or sending out a biopsy specimen when that’s the only tissue available from that patient. “These are practical, day-to-day issues that confront us all,” says Dr. Hamilton. “If we had unlimited resources and a guarantee that specimens we’re going to send out are going to be sent back, that obviously would make things much easier.”

Hence, the intense back and forth among physicians. “Some of the pathologists took issue with how fast we were recommending tests and reports got returned,” says Dr. Allegra. Initial suggestions were deemed impractical, he says, given that pathologists can’t always control how quickly they receive tissue for testing.

“There were some areas where there was consternation and handwringing,” says Dr. Allegra. In the end, the guideline says things like, “Laboratories must provide clinically appropriate turnaround times,” “molecular biomarker results should be made available as promptly as feasible,” and “It is suggested that a benchmark of 90 percent of reports be available within 10 working days of tissue receipt in the molecular diagnostics laboratory.”

Says Dr. Allegra: “There was some hesitancy to make things very strict—everyone wanted a little flexibility.”

Apart from some spirited TAT discussions, there was good concordance between the pathologists and oncologists. “That’s a tribute to Antonia Sepulveda as she led the group,” Dr. Hamilton says. What few differences did emerge often had to do with practice styles, he says. “It’s not unexpected. There are some of us who are early adopters, and there are other people who look for a much more advanced level of evidence before they’ll start to take a new approach.”

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

Anne Paxton

April 2017—Quarantine, antisepsis, sanitation, vaccination. Over more than a century and a half, as these staples of public health have evolved, they have proved that stunning improvements in general health status can result from adopting broad public policies based on data and statistical analysis.

But just in the past few years, the concept of “population health” has been grabbing attention as a framework for strategizing more tailored improvements in patient care—with laboratory data as one of the linchpins of those strategies. Large health care systems and diagnostics companies, among others, are increasingly seeing the value of a population health approach to process improvement.

As experts in the field explain it, population health is similar to public health but addresses more finely sliced subsets of people receiving health care. Keri Donaldson, MD, founder and chief executive officer of Prescient Medicine, prefers the term “population health management” because it connotes action. Population health management is more targeted than traditional descriptive public health policies, he says, because it “provides for a comprehensive way to classify conditions and stratify risks or underlying health trends across multiple data sources into one analytic stream so we can determine which ones are influencing public health.”

Dr. Donaldson

After identifying populations at risk through laboratory and demographic data analysis, population health management makes it possible to focus resources on that subset at risk, he explains. “You’re really drilling down on interrelated conditions that influence health over the course of a life, and what systemic variations may influence those conditions.”

For example, a simple proactive public health approach might say women should be offered or receive age-appropriate breast cancer screening consisting of self-exams, annual physicals, and mammograms. “But the general idea of a population health management approach is recognizing that we are in a capitated environment with limited resources, so let’s focus on where the current system is failing. By determining gaps in the current system, identifying the patients who have a high likelihood of benefiting from additional re-sources—the ones who are at highest risk—we can design interventions that can help change the outcome before it occurs or progresses.”

“A good population health approach really tries to answer the question: ‘So what?’” says Dr. Donaldson, who is also medical director of Penn State Hershey Institute of Personalized Medicine. “You can see you have genetic variation that places you at higher risk for cancer, or you have under-reported diabetes, or you have 50 percent of the population that is not on statin but should be. But those are just facts or statistics. Population health allows us to address these questions, ‘What are you going to do about it? How do you change that?’”

Prescient Medicine is a predictive medicine organization that offers predictive intelligence, Dr. Donaldson says. “We believe that earlier identification of risk and earlier detection of disease leads to more informed decisions.” Early at-risk patient identification and surveillance, reduction in unnecessary procedures, early identification of changes in prescribing practice, and custom, multifactorial decision support are among the services Prescient provides.

A collaborative blood services module, which can overlay or be built within any LIS or EMR, is an early success, he says. “It’s been able to reduce the red cell utilization rate significantly—by 17 to 20 percent just in nonsecular trend analysis. If you take into account secular trends, the number is 30 to 40 percent. In a midsize institution, that’s millions of dollars per year.”

Haemonetics is a competitor of Prescient in blood utilization, but in other areas of population health management, “Prescient has no defined competitors,” Dr. Donaldson says. “We’re sort of a trailblazing kind of organization. If you look at comprehensive opioid solutions or pain management or pain control, not a lot of people are playing in that space. In addition, many people are dropping out of personalized genomics because they can’t figure out how to make it make money. I think 14 or 15 PGx labs closed last year.”

One way pathologists can improve disease outcomes is by looking for opportunities within the hospital or system to implement a rule in the electronic health record to better identify a patient population, Dr. Donaldson says. With its oral anticoagulation module, for instance, his group found that some patients at zero risk who should not have been on an oral anticoagulant were receiving it, while only about 80 percent of those at high risk were receiving it.

“So you ask, should we change how providers are interacting with patients? Send them a letter? Post flags?” The project leaders realized there was an opportunity to improve care. “So we’ve gone through and conditioned decision support on this idea. Providers receive a letter saying: ‘Is this a purposeful action? Are you purposely not giving that patient an oral anticoagulant even though you know they have an overall risk-of-stroke score of six?’”

Some areas in which Prescient has programs, such as the comprehensive metabolic panel, are contained within the lab. At one time, in a more basic laboratory information system, built-in rules would put a hard stop on repetitive ordering of the panel and halt testing at the point of receipt, Dr. Donaldson points out. “The lab would see that the order was for a test with a previously normal result within 24 hours. That violated the rule, and they would throw it out.”

The real source of expense is not in performing extra tests that waste only pennies, however. It’s when one of the tests is abnormal and is followed up with unnecessary workups, he says. In its study at a 1,200-bed hospital system, Prescient moved beyond the old LIS model to cumulative probability analysis. “If I have one normal calcium, how likely is it that the second calcium in a single admission is going to be normal? What about after two normals or three normals?” The algorithm set a time limit on how many comprehensive metabolic panels can be ordered within a day.

The result was a more than 50 percent reduction in the number of glucose and chloride tests ordered, 40 to 50 percent reduction for magnesium, 60 percent for phosphate, and 30 percent for albumin. Prescient is now implementing the next version of this algorithm (linking it to ICD, location, point of order, or indication) in its logic engine. Eliminating standing orders was another application of this same algorithm.

But population health can also relate to an evolution of lab information outside the laboratory, to the systems-based enterprise level, Dr. Donaldson says. “Our original work on areas like urine microanalysis was done at a 550-bed hospital. We modeled it using lab-stored specific data as well as some demographic data, but you don’t have control of decision support within an LIS or at the EHR level.”

“Our type of decision support lives at a data universe that allows application programming interfaces, and those APIs overlay any input or output. So the data may come from the LIS or the EHR, but [for some areas], you’re at a level outside the LIS.” For instance, for drugs of abuse and pain management—an expanding area for Prescient, which has active programs in Pennsylvania, New Jersey, Florida, and Missouri, with Illinois on deck—the customer base tends to be broad with diverse applications.

Closing the quality gap is the key for hospitals as well as insurers, and simply not performing a test is one way to reduce health care dollar outlays, he says. “For example, a lot of people close the quality gap on catheter-associated urinary tract infections [CAUTIs] by just not culturing these patients. We actually prevent CAUTIs from occurring by using high-sensitivity multi-parameter urinalysis. That gives you an opportunity to increase return directly with the insurer, or through partnering with Prescient customers, whether they are small mom-and-pop shops or a very large enterprise. If you chew through their data, you can increase return and decrease costs.” Depending on the desired outcome, that could be identification of diabetic patients, increased compliance with a statin regimen, or decreased length of stay for hysterectomy patients.

Prescient’s ability to address risk factors through population health management connects directly to its business model. One example: “One of the things that’s hot right now in psychiatric hospitals is if they define and treat comorbidities appropriately, they get a higher reimbursement. If they are treating a person for psychiatric illness but the patient also has renal disease, hypermetabolic syndrome, or an infectious disease, they receive more if the comorbidity is classified and treated appropriately. So as an analytics firm, if we help you define testing for that population or to classify disease better with the testing you’re already doing, Prescient’s value to the client can be directly measured with the increase in recoveries.”

As a long-time public health specialist, James Halloran, MSN, RN, CNS, FAAN, deputy chief consultant for strategy and planning in Population Health Services at the U.S. Department of Veterans Affairs, confesses he might be a bit biased. He does see “public health” and “population health” as very similar. “There are certainly tools in the public health armamentarium that we use in population health, especially surveillance and epidemiologic procedures.”

But no one has a copyright on the term, and the VA’s model emphasizes that population health involves attention to nonclinical social determinations.

Halloran

“Those of us who wear white coats and are very egocentric think that everything that matters is clinical: If it’s not on my chart or not in a field on my computer screen, then it doesn’t matter,” Halloran says. “But population health says there are a lot of [nonclinical] things that do matter.” Socioeconomic status, occupational exposures, geography, access to water, and access to food are examples. The VA measures, monitors, and identifies trends that affect veterans’ health and tries to find patterns that can “turn numbers into knowledge” that will help improve the health of veterans and their families.

Population health is an evolving science, Halloran says, “and the specific models and metrics have been discussed for years,” beginning as classic public health and strongly influenced by disease management models popular in the 1990s. A 2013 Institute of Medicine (now National Academy of Medicine) report proposed a framework for quality measures in population health and used the term “social determinants of health.” At the VA, Halloran says, “Population health goes beyond the model of sickness care to understanding as many of the variables as possible that contribute to the health status of veterans.” Laboratory and pathology data are important, but they’re not the only part of getting to an understanding of veterans’ health. “So they’re necessary, but not sufficient.” Electronic data resources have been key, he adds.

Pamela S. Belperio, PharmD, has been working with the hepatitis C program in the VA for about six years. As a clinical pharmacy specialist for patient care services/population health, Dr. Belperio helps the VA roll out education for national initiatives and policy and works with the pharmacy benefits management group to make the medications available across the VA system. Her responsibilities relating to population health include national reporting on numbers treated and untreated, numbers tested, and numbers cured after treatment, all using the VA’s national clinical case registry and corporate data warehouse, or CDW.

Recently, each of the VA’s 18 VISNs (Veterans Integrated Service Networks, regions of roughly eight to 10 VA facilities each) put together innovation teams to map out a system redesign process, developing processes to improve the current state of care. One of these teams led by Ron B. Schifman, MD, chief of pathology and laboratory medicine at the VA facility in Tucson, Ariz., demonstrated what can be done with population health by reaching out to veteran patients who would benefit from HCV screening.

A patient registry was developed that included all VA-enrolled patients born between 1945 and 1965 who had no record of ever having been tested for HCV infection. This is the high-risk “birth cohort” population that the CDC and VA recommend for targeted screening. Dr. Schifman and his team, in collaboration with the medical staff, developed a patient notification system using letters that could be automatically created and mailed from a central printing facility in Sacramento, Calif.

“Based on the patient registry, a letter is triggered to the appropriate patients explaining why it’s important for them to be screened, and that if they have any questions they can call a certain phone number and talk to a primary care physician. Or if they want to go ahead, the letter can be brought into the various phlebotomy stations we have and they can use it as a requisition form to have their HCV testing performed,” Dr. Schifman explains. The population health team also uses letters because “not all of our patients have information systems where they can get secure messages. Many do, but we can’t count on all of them receiving emails, so we find that old-fashioned mailing system seems to be effective, and it also serves as a lab requisition.”

The laboratory team and primary care physicians collaborated. “We’ve sent out almost 8,000 letters at this point. Notification is automatically documented in the patient record by triggering a note informing the provider that the letter’s been sent,” Dr. Schifman says. Once tested, another automated letter is created and sent to patients with their results and, if needed, instructions for follow-up care. Patients who test positive are immediately contacted and seen by specialists for further management and treatment. About 35 percent of patients who received the letters have been tested so far. “We’ve had a little over one percent of the patients who have been screened test positive for HCV, and all of those patients have had access to care and treatment.”

The Tucson VA is now remotely managing the program to support HCV screening at other VA health care facilities such as San Diego and Albuquerque, with more on the way.

Interestingly, some of the patients who received the letter knew they had HCV (they were diagnosed outside the VA) but were not aware that a new curative treatment was available. “That letter prompted them to then go back and seek retesting and access to care at our VA facility,” Dr. Schifman says.

The initiation of a VA corporate data warehouse—a national, updated repository of data from the VA’s computerized patient records of all VA facilities—helped bring a change to the care of veterans with HCV, Dr. Belperio says. “Originally, our population health care group had developed and maintained a national HCV clinical case registry of everyone with a confirmed laboratory result or ICD-9 diagnosis. Providers at a VA facility can use the registry to generate customized local reports that could be used to assess and manage their population of HCV-infected patients. It can be set up so that every morning an updated report is waiting.” The registry data are used nationally to report metrics and outcomes that guide clinical care, she says.

Dr. Belperio

But until the warehouse came along, there was no good way nationally to look at a particular patient population at higher risk for HCV that had not yet been tested. “The CDW provided a way for us to look for the 1945 to 1965 birth cohort, a group recommended by the CDC to have HCV testing, and see who in that cohort had not been tested.” The data warehouse also made it easier to generate a list and automate the letter mailing.

Automated letters are not new, but in the past they were used to notify people of test results or appointments. The difference here lay in contacting a certain group of veterans to say, “You’re at risk for this disease. We need you to come in and get tested for it,” Dr. Belperio says. “We have the tests already ordered. You just need to come into your local lab with this letter, you don’t have to see the provider, and we’ll notify you of the results.”

“That’s really important for the patient, because it’s one less appointment they need to come in for. I’m not aware of other programs that have been so impressive in identifying people who are at a very high risk for a particular disease, notifying them to get tested, having orders in place for the testing to occur, and then notifying them of the results.”

The VA has seen the highest testing rates for HCV in that birth cohort of any large health care system in the U.S. by far, she says. “We’re at about 75 percent of that birth cohort being tested, and nothing that I’ve seen in the literature is over 50 percent.”

But the approach is not limited to HCV. “Any other disease state where there might be a need to reach out to people who are unaware they have the disease, this approach could be used for.” For example, Dr. Belperio is involved in a pre-exposure prophylaxis program for HIV that will administer medication to people who are at a high risk of developing HIV.

Having new medications that sharply improved HCV treatment gave impetus to this population health project. “That was the thing that transformed HCV, because we had these new medications available and we wanted to get as many people in and cured as we could,” Dr. Belperio says. “If there were some new diabetic medication that would be life-changing for patients meeting specific criteria, you could use the [data warehouse] to identify the markers of patients who would gain the greatest benefit from the new treatment. Several transforming medications are on the horizon and expected to be quite life-changing compared to what we’ve had, so we’re expecting that in the future, that will affect the VA’s choice of other population health projects.”

Unlike breast cancer, lung cancer, and cervical cancer, “liver cancer is rising and the main reason is HCV. It’s also the leading cause for liver transplants,” Dr. Schifman says. So he thinks of the VA’s HCV testing notification program as not just a screening program to help prevent and cure HCV and chronic liver disease, but also as a cancer prevention screening program.

Dr. Schifman

“This is one example of where pathologists can get involved with patient care with regard to population health,” Dr. Schifman says. Traditionally, utilization management has focused on reducing unnecessary tests or removing obsolete testing. “But a widely quoted study has shown that it’s more common to omit testing that needs to be done than to over-test. So in terms of outcomes, that’s where we’re trying to go.”

Dr. Schifman cites three areas of laboratory testing where pathologists can contribute to population health approaches. “One is screening high-risk populations. Another is chronic disease monitoring such as HbA1c for patients with diabetes. Those are patients who might fall through the cracks but should be getting monitoring.” High-risk medications present a third area: “This would include patients on oral anticoagulants, or high-risk medications like amiodarone that require thyroid testing because of the risk of side effects.”

One of the strategies is to try to improve awareness of clinicians or help them use decision support techniques that are built into the ordering process, he notes. “So there will be a pop-up, for example, that will remind the clinician it is time for the patient’s HbA1c test because they are in a population that requires screening.” As decision support systems, however, pop-up menus have two problems, Dr. Schifman cautions. “One is that clinicians are being inundated by alerts.”

“The second issue is the doctor doesn’t necessarily get an alert if they’re not interacting with the patient’s medical record. So if there hasn’t been a patient encounter, then there may not be an opportunity to get the alert, order the test, or make a decision about that patient’s screening or monitoring.”

If the pathologist has access to a patient registry, and it could include HCV, oral anticoagulation, or other similar patient populations that require lab monitoring, then that pathologist could use that information to determine whether the testing has been done. “If it has been done, then that’s fine—move on to the next patient. But if it hasn’t been done, then develop some type of intervention in partnership with the patient’s provider to provide easier access to needed testing.”

An approach similar to the VA’s HCV program would involve taking a registry of patients with diabetes, “to remind them in a primary care clinic of their HbA1c screening, so we can check on patients who have not had their testing performed within the specified period.”

The pharmacist is an important partner, says Dr. Schifman. He or she might have the most knowledge about what testing might be needed for specific medications. “And then you can tie that list into your LIS to see if the patients have had their testing done for potential drug side effects.”

The VA is poised to launch a new population health screening that addresses patients’ opioid use. “There’s a lot of attention, particularly in the VA system, to making sure that pain management is optimized, and one part of that program for patients receiving pain medication is that they get periodic urine drug screening to check for compliance,” Dr. Schifman says.

Ensuring that this occurs will require taking a registry of all patients undergoing pain management, checking to see if they’ve had their periodic urine screen performed, and then sending the same type of letter used for HCV screening, to remind the patients and to provide them with a ready-made requisition for the testing. “So population health goes beyond just screening for chronic disease; it includes compliance with health management programs as well.”

Before the birth-cohort HCV screening program was launched, Tucson had slightly below average compliance on HCV screening. “There was an option in the electronic health care system to remind clinicians about patients who needed HCV testing, and our facility had the auto-alert turned off.” This may have played a role in lowering the compliance level.

The current 75 percent compliance with HCV screening throughout the VA is about twice the national average. In September 2016, a VA database study showed that new drug regimens for HCV have resulted in high cure rates among patients within the VA’s national health care system. Among patients with the most common strain of HCV, 93 percent of veterans receiving treatment were cured.

The VA’s HCV program shows how pathologists can add value to health care by making sure patients have the testing they need, Dr. Schifman believes. “In this particular case, we identified that HCV was a problem, and so we went to GI and our medical staff and said, ‘Here’s a solution that will let us increase our screening by identifying this population that needs screening.’ So this was a pathology-driven process.”

Population health will continue to influence health care systems’ approaches to improving patient care, Dr. Donaldson believes, for two reasons. “No. 1, the complexity of the data within an EHR or patient medical record at this point exceeds the intellectual and analytic capacity of any one person. No. 2, applying that data to determine resource allocation is even more difficult. So when you’re trying to make decisions based on complex data that have an impact on people’s lives, and also reflect a wise use of resources, you’re really out of your depth. You need decision support. Getting people to understand these two points is what population health management is all about.”

Anne Paxton is a writer and attorney in Seattle.

Following our annual reception at the 2015 USCAP meeting in Boston, and withthe generous support of our prospective members, the decision was made to officially register our organization.

After a thorough search by the Executive Committee members for a suitable management company, in May 2016 we signed a contract with Badger Bay. Over the course of summer and fall, we worked closely with the management team to accomplish our goals within our budget and in accordance with our mission. 

Having an interactive website was our first priority.   After much discussion and fine tuning, the website became operational in December 2016.  This website allows members to safely and conveniently pay their dues and donations.  A monthly newsletter and announcement of important news and activities, soon to include members’ publications, are also provided.  Our Facebook page is also maintained.

After implementation, we learned that there are problems for our Canadian members in regards to electronic payment.  The management team has been notified and we will provide updates soon.

At the same time and after detailed analysis of available options for registering our society, the Executive Board decided to register our association as a charitable non-profit organization.   In this manner, the donations of our generous members will be tax-deductible.  A portion of the dues may be tax-deductible as well.  We are in the final stages of official registration.

Again, for our Canadian members, we have learned that IPANA has to register as a charity with the Canadian Revenue Agency in order to allow our Canadian members to benefit from the tax deductible status for their dues and donations.  This is also being pursued by the management company and we will pride updates as soon as available.


Our trainee award program recognizes the scientific presentations of ourpathologists in-training at the USCAP Annual Meeting and is supported by the generous donation of one of our members.  Please join as a “Resident/Trainee” member to participate in this wonderful program, in the spirit of friendly competition.

The Executive Board also wishes to recognize Dr. Nadji as our ultimate “Champion Level” member. He has been the biggest advocate for our success, by his generous financial and moral support.

In the end, we had a very positive year, and we couldn’t have done it without our prospective members’ support.  Now that we clearly have organized our efforts, it is certainly up to all of us to make sure our organization thrives.  Sustainable and enthusiastic member support is the key to the success of any organization.  And as the Executive Board, we thank you and welcome your ideas and your active involvement in the society’s functions.

Congratulations to Dr. Shabnam Zarei (Mayo Clinic, Rochester, MN), recipient of IPANA’s 4th Annual Trainee Award, for her 2017 USCAP platform presentation titled “Ovarian Serous Carcinomas with Mixed Features of High Grade and Low Grade Serous Carcinoma Display Heterogeneous Genome Wide Copy Number Variation Profiles.”

Cory Porteus, DO, and Marilyn M. Bui, MD, PhD

February 2017—“Quality management” is the practice of continually evaluating, identifying, and improving the diagnostic process. It refers not only to retrospective action taken after mistakes have been made but also to evaluating near misses and opportunities for improvement in every facet of practice. Quality management is the purest expression of the desire to offer safe patient care across all specialties and practices. A prompt and accurate diagnosis is only the first step in ensuring patient safety.

The past decade has seen explosive growth in areas of medicine chiefly practiced by pathologists such as molecular testing, all of which need to be validated and continually assessed for safety in practice. As pathology can be viewed as the nexus where the art of medicine meets the science of medicine, quality management has become increasingly important and come to demand greater attention.

The CAP has published quality management guides since 1988, when it published its Surgical Pathology/Cytopathology Quality Assurance Manual. There have since been five iterations that highlight the importance of and need for quality management programs in a variety of pathology settings, and pathologists have considered them valuable resources.

The new version from CAP Press, Quality Management in Anatomic Pathology—Strategies for Assessment, Improvement, and Assurance (edited by Qihui “Jim” Zhai, MD, and Gene P. Siegal, MD, PhD), is organized into four informative sections, each of which is divided into chapters on specific areas. The general approaches to quality management are covered in an introduction and six chapters in the first section. This section encompasses designing a quality management plan, a plan’s components and quality indicators, responding to and preventing errors, and regulatory compliance.

Section two is on the systematic approaches, and it is here that each section of the laboratory has its own forum in which to stress the differences inherent in its setting.

Section three comprises chapters on the implementation of informatics and its importance to the quality management process, ISO 15189, and specimen tracking systems. In an era in which information technology is transforming how we practice medicine, this section is timely and offers practical information on laboratory information systems, digital pathology, synoptic reporting, and more. It introduces the nongovernmental organization, ISO, which sets standards for quality assurance, improvement, and management, and it highlights the various ways in which ISO influences daily practice.

The fourth and final section introduces the legal and regulatory issues that quality management programs face as well as the legal and ethical outcomes after errors occur. This section contains some of the most critical and immediately applicable points of interest and consists of standout chapters.

All of the chapters are easy to read and will appeal to a wide range of expertise on the subject matter. The section introductions are brief and set the stage for the chapters to supply the detail. The format is quickly searchable, with the chapters structured such that it is easy to find a section pertaining to a specific area of a laboratory or step of the process. Tables and figures are well laid out and clearly illustrate the desired point.

Designed for pathologists who have limited time to decipher texts, this is a well-organized resource with easy-to-digest points. For those new to the practice of quality management and looking to apply it to their own practice, this text provides a useful and comprehensive step-by-step outline that can enable implementation in minimal time. It is a strategy guide that can bring a reader of any skill level up to speed.

This text also serves as a primary resource for any resident studying for board examinations. The percentage of questions involving quality assurance/improvement has been increasing steadily in recent years. This text is an excellent resource that covers all necessary review material in one easy-to-absorb format. Recently graduated residents and fellows complain of feeling unprepared for the task of being in charge of a lab, which is increasingly expected of recent graduates, and quality management is a key component of successfully managing a laboratory.

In summary, this is a superb resource for quality management that every practicing pathologist should use. It surpassed expectations as to what a general resource guide should provide. It is thoroughly researched, is well written, and will appeal to those with casual interest and to those well schooled in the material. Furthermore, it should be regarded as a primary study text for residents who want to boost board scores and cement their understanding of this complex topic. As of now, it should be the resource book of choice for quality management.

Dr. Porteus is chief resident, Department of Pathology and Cell Biology, University of South Florida Morsani College of Medicine, Tampa. Dr. Bui, a member of the CAP Publications Committee, is a senior member, Departments of Anatomic Pathology and Sarcoma, scientific director of analytic microscopy core, and section head of bone and soft tissue pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa. She is a professor in the Departments of Oncological Sciences and Cell Biology and Pathology, USF Morsani College of Medicine.

Source: Cap TODAY Online

Thomas McDonald, MD, MSc
Frank Kuo, MD, PhD

CAP TODAY and the Association for Molecular Pathology have teamed up to bring molecular case reports to CAP TODAY readers. AMP members write the reports using clinical cases from their own practices that show molecular testing’s important role in diagnosis, prognosis, and treatment. The following report comes from Brigham and Women’s Hospital. If you would like to submit a case report, please send an email to the AMP at amp@amp.org. For more information about the AMP and all previously published case reports, visit amp@amp.org.

February 2017—An activating BRAF mutation is found in 40 to 60 percent of melanoma patients.¹ BRAF (B-Raf proto-oncogene) encodes a protein-kinase that activates the MAP kinase/ERK signaling pathway, a pathway that regulates cell differentiation, growth, and survival. Another protein, NRAS, normally activates BRAF. A mutated BRAF, however, can act independently of NRAS and skew cell activity toward growth and survival and away from differentiation.²

Fig. 1. The pyrosequencing peak pattern for the patient sample does not match the wild type or the V600E controls. The sizes of the first two C peaks are unusual (blue arrows), and the first G peak is not consistent with V600E (red arrow).

In melanoma patients, approximately 90 percent of the activating BRAF mutations are V600E (a change from valine to glutamic acid at amino acid 600 in exon 15).¹ A number of BRAF inhibitors have been developed that specifically target the V600E mutation. Generally, patients with metastatic melanoma are tested for BRAF mutations to determine if they might be candidates for BRAF inhibitor therapy.

Case presentation. A 57-year-old Caucasian woman with a history of metastatic melanoma (with metastases to the liver and brain) presented with five weeks of pleural congestion and one to two weeks of worsening shortness of breath. She reported decreased energy and appetite, but denied fever, chills, hemoptysis, night sweats, and weight loss.

A computed tomography scan of the chest showed a right-sided pleural effusion and a right-sided collapsed lung. A thoracentesis was performed, and tissue was sent to pathology for BRAF mutation testing.

A pyrosequencing BRAF test was performed on formalin-fixed, paraffin-embedded tumor tissue. A pattern consistent with V600E was present, but this could not explain all of the peaks (Fig. 1). It appeared that more than one alteration may have been present. A satisfactory interpretation consisting of one or two alterations was not identified, even with the aid of a computational peak prediction program. Therefore, the test was interpreted as inconclusive after it was repeated with the same result.

Given that the V600E alteration may have been present, a V600E immunohistochemical stain was performed. This new stain is a mutation specific monoclonal mouse antibody raised against a synthetic peptide representing the V600E sequence from amino acids 596–606.³ In this case, the V600E stain was negative (Figs. 2–4). Next-generation sequencing was then performed. (The NGS method used employs hybrid capture with an Agilent SureSelect custom probe set and massively parallel sequencing on an Illumina HiSeq 2500.⁴) It showed that two alterations were present: V600R and S602T (Fig. 5). The allele frequency was 44 percent. For all of the reads, both alterations were either present or absent; no reads had only one of the alterations.

In light of the BRAF test results, the patient was enrolled in a translational study of ipilimumab and nivolumab. Progression of disease was noted, however, and so the patient was then switched to dabrafenib and trametinib. To date, she has responded well to this regimen.

Fig. 5. The next-generation sequencing results for the patient showed two alterations: CAC to TCC at position 600 (for which the wild type is valine [V]) and AGA to TGA at position 602 (for which the wild type is serine [S]). Note: the amino acid numbering is from right to left in the figure.

Discussion. Pyrosequencing is the preferred method for BRAF testing in many institutions because of its rapid turnaround time (approximately one day) and because it is highly sensitive and specific (the sensitivity is greater than 99 percent and the specificity is greater than 90 percent for allele frequencies greater than five percent).

In this case, the pyrosequencing was inconclusive because it was not possible to interpret the peaks in a satisfactory way. It would have been a mistake to report a V600E alteration even though the peaks appeared to be consistent with a V600E along with a second alteration. Additional studies were warranted.

After the next-generation sequencing identified two alterations, one possible explanation for the peak pattern is that the S602T alteration occurred under the pyrosequencing primer, and thus may have caused a delayed start to primer elongation because of a mismatch in the primer binding site. If this hypothesis is correct, the pattern of the peaks is plausible (Fig. 6).

Fig. 6. The S602T alteration was under the pyrosequencing primer sequence. This may have caused the primer to bind inefficiently. A delayed start to elongation may account for the second C peak (position 5 in the strip). Thus, the first C may or may not have been incorporated. If it was not incorporated, then the second C might have been incorporated and this would explain the small second C peak and the G peak in position 7.

To our knowledge, there is only one case in the literature of a patient with V600R and S602T. It occurred in a patient with V600E-negative hairy cell leukemia.⁵

1. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–819.
2. Huang PH, Marais R. Cancer: melanoma troops massed. Nature. 2009;459(7245):336–337.
3. Capper D, Preusser M, Habel A, et al. Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol. 2011;122(1):11–19.
4. Howitt BE, Sholl LM, Dal Cin P, et al. Targeted genomic analysis of Müllerian adenosarcoma. J Pathol. 2015;235(1):37–49.
5. Tschernitz S, Flossbach L, Bonengel M, et al. Alternative BRAF mutations in BRAF V600E-negative hairy cell leukaemias. Br J Haematol. 2014;165(4):529–533.

Dr. McDonald completed the molecular genetic pathology fellowship at Harvard Medical School. Dr. Kuo is an associate professor of pathology, Brigham and Women’s Hospital, Boston.

Source: Cap Today Online

William Check, PhD

February 2017—With the number of rapid, accurate molecular assays for respiratory pathogens growing, microbiology laboratories have more options than ever. They include, among others, Meridian Bioscience’s Illumigene assays for group A Streptococcus and pertussis and its newest assay, Mycoplasma Direct, as well as Alere’s assays for influenza A/B, respiratory syncytial virus, and Streptococcus on its i molecular platform. No longer are laboratories limited to inaccurate rapid antigen tests, weeks-long culture, or multi-pathogen panels.

Laboratories with different test volumes and patient populations will make different choices.

“I think there is a place for both targeted testing and panel testing,” Beverly B. Rogers, MD, chief of pathology at Children’s Healthcare of Atlanta, says. “I feel strongly that when you admit someone to the hospital with respiratory symptoms, panel testing is far and away the best thing to do. You’d be surprised to see what comes up.”

Holy Cross Hospital in Taos, NM, has chosen single-organism tests. “We looked at a respiratory panel. We had BioFire in to do a demo,” says laboratory director Susan Romansky, BS, MLS(ASCP). Because of the higher cost for the panel, she and colleagues opted for single-organism assays. “We didn’t want the shotgun approach,” she says.

A particular point of divergence is testing for Mycoplasma pneumoniae in patients with respiratory symptoms. This organism, which causes what is often referred to as “walking pneumonia,” is associated with up to 40 percent of community-acquired pneumonias and occurs in children and adults. Its characteristic symptom is a dry, paroxysmal cough. Some say this justifies a single-organism test, others that it makes an organism-specific test less urgent.

Romansky favors a single-organism test for this pathogen. “Mycoplasma has specific clinical manifestations,” she says. “We are not going to be looking for pertussis or viruses in those patients.”

Romansky’s laboratory started using Meridian Mycoplasma Direct in September 2016, three months after the FDA cleared it. Her laboratory had previously been using Meridian Mycoplasma ImmunoCard. “Our reasons for switching were twofold,” Romansky says. First, interpretation of the serology method was too subjective. “On the ImmunoCard you are looking for a blue color. It is somewhat subjective. You can overcall or undercall it,” she says.

Second, compared with ImmunoCard, “There is increased sensitivity and specificity with Mycoplasma Direct.”

Holy Cross was already using other Meridian Illumigene assays in the laboratory. “This has been one of the simplest Illumigene assays we’ve brought in,” she says of Mycoplasma Direct. “It has only a very few steps. We did the validation quickly and had it up and running.” Turnaround time is less than one hour.

Romansky wants to do follow-up studies with the molecular assay. It uses a throat swab, as opposed to the serology with ImmunoCard. She would like to see whether Mycoplasma Direct detects Mycoplasma sooner than serology.

In keeping with the single-organism testing philosophy, Romansky’s laboratory is using Alere i tests for flu and respiratory syncytial virus.

Sarah Drenning, C-PNP, a nurse practitioner at the Taos Clinic for Children and Youth, orders tests from Holy Cross. Drenning says she likes the new test because she can get a swab in the office and have a result quickly, often the same day, which works well for children and families.

Drenning has ordered Mycoplasma Direct for patients who have clinical symptoms and exam findings consistent with Mycoplasma pneumoniae or pneumonia generally. “It is a worthwhile test to do since Mycoplasma pneumoniae can be a prolonged illness if it’s not treated,” she says. She uses rapid antigen tests for flu and RSV in the office. “If those are negative, I might look for Mycoplasma,” Drenning adds. So far she has sent only a handful of samples for the new test, all of which have been negative. “We haven’t used antibiotics in those patients and they have all gotten better,” she says.

At Cabell Huntington (W.Va.) Hospital, microbiology manager Russ Gaskins, MT(ASCP), replaced an IgM card test with Mycoplasma Direct. “There is no doubt that this Mycoplasma test is 100 percent better than what we were using before,” Gaskins says.

Converting was not difficult from a methodologic point of view. However, Gaskins says, “We had to communicate to physicians and nursing units that we had a new test that required a new type of specimen.” They sent a message via the computer ordering system that the old test was being replaced. “Also, now when you put in Mycoplasma test, the only source that comes up is throat swab,” Gaskins says.

In addition to Mycoplasma Direct, Cabell Huntington offers the BioFire FilmArray respiratory panel, which includes Mycoplasma. “Respiratory panels are making a huge difference in patient care,” Gaskins notes. “We are finding things we didn’t see or even look for. It helps to rule in or rule out.” They have five instruments to run the panel throughout the 24-hour cycle, whereas Mycoplasma Direct has a cutoff time for submission of specimens. “We just can’t do everything all day long,” Gaskins explains.

Perhaps because of the value of the respiratory panel, Gaskins says, “We are really not doing the numbers we thought we would” with Mycoplasma Direct. “I think it’s due to the availability of the rapid panel.” He cites the dry cough, where mucus stays in the lungs, as a particular feature of Mycoplasma pneumoniae that might tip the clinician to order a single-pathogen test. “However,” he notes, “even if clinicians suspect Mycoplasma, they are better off ordering the respiratory panel because if the patient also has coronavirus, for example, they will find out at the same time.”

Gaskins

Physicians find it hard to pass on tests they get back as easily and as fast as a panel, Gaskins notes. “It is more expensive, but it can save hospital days. And compared to the cost of a hospital day, a panel is not much expense.”

The laboratory at Orange Park (Fla.) Medical Center uses the Mycoplasma Direct kit. “Prior to this, we were using the Illumigene Mycoplasma, which had a separate extraction phase with the Qiagen DNA extraction kit,” says microbiology supervisor Michael Ibuoye, MS, MT(AMT). “The Mycoplasma Direct kit bypasses this extraction phase, which makes life much easier for us as a hospital diagnostic microbiology lab.” With the first kit, extraction required 19 steps and tied up a technologist for two hours, Ibuoye says.

Illumigene Mycoplasma Direct incorporates an integral extraction step and uses LAMP (loop-mediated isothermal amplification) technology. In a three-institution comparison reported at the 2016 meeting of the American Society for Microbiology, investigators found that, among the 465 specimens tested, the original Mycoplasma kit detected 25 specimens as positive while the Mycoplasma Direct detected 34 positive specimens. There was no gold standard method so it can’t be determined whether the new assay is more sensitive or less specific.

In the Orange Park laboratory, Mycoplasma is ordered on all patients who come in for bronchoscopy. That’s three to four patients per day, Ibuoye says. “It is done on almost all BALs, except where there is a known cause.”

For more typical flu symptoms, Ibuoye’s laboratory performs flu A/B and RSV rapid enzyme immunoassay screens. They don’t do a respiratory panel in-house; if a clinician orders it, they send it out.

In addition to Children’s Healthcare of Atlanta hospital laboratories, where Dr. Rogers is chief of pathology, the system has six urgent care walk-in clinics with high-complexity labs in the Atlanta area. In these clinics, clinical pathologist Elizabeth Weinzierl, MD, PhD, has brought on the Alere rapid molecular strep and flu A/B molecular amplification assays. The Alere rapid strep assay has been validated and will be in the clinics soon, after which the laboratory will eliminate strep culture.

“I don’t feel it’s worth it to put in a specific Mycoplasma test. We don’t see it as a frequently requested test in our population,” says Dr. Rogers, an adjunct professor of pathology and pediatrics at Emory University School of Medicine.

At Children’s Healthcare of Atlanta, the primary testing mode is the BioFire respiratory panel. Mycoplasma is on the panel. “There is such a high prevalence of people in the community who are walking around without symptoms and are Mycoplasma positive. So you have to be cautious when you get a positive result back and interpret it within the clinical context,” Dr. Rogers points out.

It is not uncommon to have multiple positive reactions on the panel—perhaps RSV with adenovirus or flu. “Those are really sick kids,” she says.

“If there was an adult patient with fever, dry cough, and shortness of breath that didn’t resolve, there would be a tendency to treat them as an outpatient with a Z pack,” she says. To Dr. Rogers, this is not a hypothetical situation. “Several years ago, I had persistent nonproductive cough and shortness of breath. My husband said, ‘You’ve got Mycoplasma.’ He’s a pathologist but he’s also boarded in internal medicine and a good clinician. So I wrote a prescription for a Z pack and got better in two days.”

She and microbiologists Robert Jerris, PhD, and Mark Gonzalez, PhD, are having a conversation with the clinical team about whether during flu season they want to bring into the hospital laboratories a flu-only molecular test for patients seen in the emergency department. “We put in the panel first. Now that there are really good single-organism tests, we may end up having a hybrid for outpatients,” she says.

Dr. Rogers

Dr. Rogers would also see a role for a panel in the outpatient setting, mostly to reassure parents, when a clinician sends home a patient with respiratory symptoms. But the current charge to the patient or insurance for a large panel is very high, so the cost of the panel outweighs the benefit, and therefore the panel is not performed in practice. With panel results in these scenarios, “You could say, ‘Your child has an RSV viral infection and these are the typical symptoms. There is no need for antibiotics.’ ” This could lessen the demand for antibiotics and decrease the development of antibiotic resistance. “If the charge weren’t so high, if you could do a panel and charge maybe $200, that is what I would do for outpatients,” she says.

Of the expense of a respiratory panel, Dr. Rogers says: “Medical economics is interesting. When we say the panel costs are high, does that mean the cost to perform the test or the cost that is charged to the patient? They often differ by a factor of 10 or higher. Therefore, the clinicians and patients see the test as very expensive, when it may not be terribly expensive to run.”
William Check is a writer in Ft. Lauderdale, Fla.

Source: CAP TODAY online

In response to the pathology community, the ABP has created a Physician Scientist Research Pathway with the goals of increasing the number of physician-scientists in pathology, attracting exceptional and committed young physician-scientists to pathology, preparing trainees for careers in academic medicine centered on basic science or clinical research, and providing flexibility in training pathways, while assuring the clinical competency of trainees that select this pathway. For more information, see the Booklet of Information.

Beginning in 2016, program directors were asked to provide resident emails in Resident Tracking. The ABP will then assign residents an ABP identification number. This ID number will allow residents to log into Pathway, create an account, update their contact information, and view the certification application. In 2017, residents will submit their Authorization Form and agreement to the Honor Code electronically.