AVAHO

Vickie Venne, MS. What is the Genomic Medicine Service (GMS) at the US Department of Veterans Affairs (VA)?

Renee Rider, JD, MS, LCGC. GMS is a telehealth service. We are part of central office and field stationed at the George E. Wahlen VA Medical Center (VAMC) in Salt Lake City, Utah. We provide care to about 90 VAMCs and their associated clinics. Veterans are referred to us by entering an interfacility consult in the VA Computerized Patient Record System (CPRS). We review the consult to determine whether the patient needs to be seen, whether we can answer with an e-consult, or whether we need more information. For the patients who need an appointment, the telehealth department at the veteran’s VA facility will contact the patient to arrange a visit with us. At the time of the appointment, the facility has a staff member available to seat the patient and connect them to us using video equipment.

We provide genetic care for all specialties, including cancer, women’s health, cardiology and neurology. In today’s discussion, we are focusing on cancer care.

Vickie Venne. What do patients do at facilities that don’t get care through GMS?

Renee Rider. There are a handful of facilities that provide their own genetic care in-house. For example, VA Boston Healthcare System in Massachusetts and the Michael E. DeBakey VAMC in Houston, Texas each have their own programs. For veterans who are not at a VA facility that has an agreement with GMS and do not have a different genetics program, their providers need to make referrals to community care.

Vickie Venne. How do patients get referred and what happens at their facility when the patients return to the specialty and primary care providers (PCP)? Ishta, who do you refer to GMS and how do you define them initially?

Ishta Thakar, MD, FACP. Referrals can come at a couple of points during a veteran’s journey at the VA. The VA covers obstetrics care for women veterans. Whenever a PCP or a women’s health provider is doing the initial history and physical on a new patient, if the female veteran has an extensive family history of breast, ovarian, colon, or endometrial cancer, then we take more history and we send a consult to GMS. The second instance would be if she tells us that she has had a personal history of breast, ovarian, or endometrial cancer and she has never had genetic testing. The third instance would be whenever we have a female veteran who is diagnosed with breast, ovarian, endometrial, or colon cancer. We would definitely talk to her about genetic counseling and send a referral to GMS. We would ask for a GMS consult for a patient with advanced maternal age, with exposure to some kind of teratogens, with an abnormal ultrasound, a family history of chromosomal disorders, or if she’s seeing an obstetrician who wants her to be tested. And finally, if a patient has a constellation of multiple cancers in the family and we don’t know what’s going on, we would also refer the patient to GMS.

Vickie Venne. That would be why GMS fields over 150 referrals every week. It is a large list. We also see veterans with personal or family histories of neurologic or cardiologic concerns as well.

Renee, as somebody who fields many of these referrals from unaffected individuals, what is the family history process?

Renee Rider. We don’t expect the referring provider to be a genetic expert. When a provider is seeing a constellation of several different cancers and he or she doesn’t know if there’s anything going on genetically or even if it’s possible, absolutely they should put in a referral to GMS. We have a triage counselor who reviews every consult that comes into our service within 24 hours.

Many cancers are due to exposures that are not concerning for a genetic etiology. We can let you know that it is not concerning, and the PCP can counsel the patient that it is very unlikely to be genetic in nature. We still give feedback even if it’s not someone who is appropriate for genetic counseling and testing. It is important to reach out to GMS even if you don’t know whether a cancer is genetic in nature.

It also is important to take your time when gathering family histories. We get a lot of patients who say, “There’s a lot of cancer in my family. I have no idea who had cancer, but I know a lot of people had cancer.” That’s not the day to put in a referral to GMS. At that point, providers should tell the patient to get as much information as they can about the family history and then reassess. It’s important for us to have accurate information. We’ve had several times where we receive a referral because the veteran says that their sister had ovarian cancer. And then when our staff calls, they later find out it was cervical cancer. That’s not a good use of the veteran’s time, and it’s not a good use of VA resources.

The other important thing about family histories is keeping the questions open-ended. Often a PCP or specialist will ask about a certain type of cancer: “Does anyone in your family have breast cancer, ovarian cancer?” Or if the veteran
is getting a colonoscopy, they ask, “Does anybody have colon cancer?” Where really, we need to be a little bit more open-ended. We prefer questions like, “Has anyone in your family
had cancer?” because that’s the question that prompts a response of, “Yes, 3 people in my family have had thyroid cancer.” That’s very important for us to know, too.

If you do get a positive response, probe a little bit more: what kind of cancer did someone have, how old were they when they had their cancer? And how are they related? Is this an aunt on your mom’s side or on your dad’s side? Those are the types of information that we need to figure out if that person needs a referral.

Vickie Venne. It’s a different story when people already have a cancer diagnosis. Which hematology or oncology patients are good referrals and why?

Lisa Arfons, MD. When patients come in with newly diagnosed cancer, breast for example, it is an emotional diagnosis and psychologicallydistressing. Oftentimes, they want to know why this happened to them. The issues surrounding
genetic testing also becomes very emotional. They want to know whether their children are at risk as well.

Genetic discussions take a long time. I rarely do that on the first visit. I always record for myself in my clinic note if something strikes me regarding the patient’s diagnosis. I quickly run through the National Comprehensive Cancer Network (NCCN) guidelines to remind myself of what I need to go over with the patient at our next meeting. Most patients don’t need to be referred to GMS, and most patients don’t need to be tested once they’re seen.

I often save the referral discussion for after I have established a rapport with a patient, we have a treatment plan, or they already have had their first surgery. Therefore, we are not making decisions about their first surgery based on the genetic medicine results.

If I’m considering a referral, I do a deeper dive with the patient. Is the patient older or younger than 45 years? I pull up NCCN guidelines and we go through the entire checklist.

We have male breast cancer patients at the VA—probably more than the community—so we refer those patients. At the Louis Stokes Cleveland VAMC in Ohio, we have had some in-depth discussions about referring male breast cancer patients for genetic testing and whether it was beneficial to older patients with male breast cancer. Ultimately, we decided that it was important for our male veterans to be tested because it empowered them to have better understanding of their medical conditions that may not just have effect on them but on their offspring, and that that can be a source of psychological and emotional support.

I don’t refer most people to GMS once I go through the checklist. I appreciate the action for an e-consult within the CPRS telemedicine consult itself, as Renee noted. If it is not necessary, GMS makes it an e-consult. I try to communicate that I don’t know whether it is necessary or not so that GMS understands where I’m coming from.

Vickie Venne. In the US Department of Defense (DoD) the process is quite different. Mauricio, can you explain the clinical referral process, who is referred, and how that works from a laboratory perspective?

Maj De Castro, MD, FACMG, USAF. The VA has led the way in demonstrating how to best provide for the medical genetic needs of a large, decentralized population distributed all over the country. Over the last 5 to 10 years, the DoD has made strides in recognizing the role genetics plays in the practice of everyday medicine and redoubling efforts to meet the needs of servicemembers.

The way that it traditionally has worked in the DoD is that military treatment facilities (MTFs) that have dedicated geneticists and genetic counselors: Kessler Medical Center in Mississippi, Walter Reed National Military Medical
Center in Maryland, Tripler Army Medical Center in Hawaii, Madigan Army Medical Center in Washington, Brooke Army Medical Center in Texas, Naval Medical Center San Diego in California, and Naval Medical Center Portsmouth in Virginia. A patient seeking genetic evaluation, counseling, or testing in those larger facilities would be referred to the genetics service by their primary care manager. Wait times vary, but it would usually be weeks, maybe months. However, the great majority of MTFs do not have dedicated genetics support. Most of the time, those patients would have to be referred to the local civilian community—there was no process for them to be seen in in the military healthcare system—with wait times that exceed 6 to 8 months in some cases. This is due to just not a military but a national shortage of genetics professionals (counselors and physicians).

Last year we started the telegenetics initiative, which is small compared to the VA—it is comprised of 2 geneticists and 1 genetic counselor—but with the full intent of growing it over time. Its purpose is to extend the resources we
had to other MTFs. Genetics professionals stationed state-side can provide care to remote facilities with limited access to local genetics support such as Cannon Air Force Base (AFB) or overseas facilities such as Spangdahlem AFB in Germany.

We recognize there are military-specific needs for the DoD regarding the genetic counseling process that have to take into account readiness, genetic discrimination, continued ability to serve and fitness for duty. For this important reason, we are seeking to expand our telegenetics initiative. The goal is to be able to provide 100% of all genetic counseling in-house, so to speak.

Currently, providers at the 4 pilot sites (Cannon AFB, Fort Bragg, Spangdahlem AFB, and Guantanamo Bay) send us referrals. We triage them and assign the patient to see a geneticist or a counselor depending on the indication.

On the laboratory side, it has been a very interesting experience. Because we provide comprehensive germline cancer testing at very little cost to the provider at any MTF, we have had high numbers of test requests over the years.
In addition to saving the DoD millions of dollars in testing, we have learned some interesting lessons in the process. For instance, we have worked closely with several different groups to better understand how to educate providers on the genetic counseling and testing process. This has allowed us to craft a thorough and inclusive consent form that addresses the needs of the DoD. We have also learned valuable lessons about population-based screening vs evidence-based testing, and lessons surrounding narrow-based testing (BRCA1 and BRCA2 only testing) vs ordering a more comprehensive panel that includes other genes supported by strong evidence (such as PALB2, CHEK2, or TP53).

For example, we have found that in a significant proportion of individuals with and without family history, there are clinically relevant variants in genes other than BRCA1 or BRCA2. And so, we have made part of our consent process,
a statement on secondary findings. If the patient consents, we will report pathogenic variants in other genes known to be associated with cancer (with strong evidence) even if the provider ordered a narrow panel such as BRCA1 and BRCA2 testing only. In about 1% to 4% of patients that would otherwise not meet NCCN guidelines, we’ve reported variants that were clinically actionable and changed the medical management of that patient.

We feel strongly that this is a conversation that we need to have in our field, and we realize it’s a complex issue, maybe we need to expand who gets testing. Guideline based testing is missing some patients out there that could benefit from it.

Vickie Venne. There certainly are many sides to the conversation of population-based vs evidence-based genetic testing. Genetic testing policies are changing rapidly. There are teams exploring comprehensive gene sequencing for
newborns and how that potential 1-time test can provide information will be reinterpreted as a person goes from cradle to grave. However, unlike the current DoD process, in the VA there are patients who we don’t see.

Renee Rider. I want to talk about money. When we order a genetic test, that test is paid for by the pathology department at the patient’s VAMC. Most of the pathology departments we work with are clear that they only can provide
genetic testing that is considered medically necessary. Thus, we review each test to make sure it meets established guidelines for testing. We don’t do population genetic screening as there isn’t evidence or guidelines to support offering it. We are strict about who does and does not get genetic testing, partly because we have a responsibility to pathology departments and to the taxpayers.

GMS focuses on conditions that are inherited, that is to say, we deal with germline genetics. Therefore, we discontinue referrals for somatic requests, such as when an OncotypeDX test is requested. It is my understanding that pharmacogenetic referrals may be sent to the new PHASeR initiative, which is a joint collaboration between the VA and Sanford Health and is headed by Deepak Voora, MD.

We generally don’t see patients who still are having diagnostic procedures done. For example, if a veteran has a suspicious breast mass, we recommend that the provider workup the mass before referring to GMS. Regardless of a genetic test result, a suspicious mass needs to be worked up. And, knowing if the mass is cancerous could change how we would proceed with the genetic workup. For example, if the mass were not cancerous, we may recommend that an affected relative have the first genetic evaluation. Furthermore, knowing if the patient has cancer changes how we interpret negative test results.

Another group of patients we don’t see are those who already had genetic testing done by the referring provider. It’s a VA directive that if you order a test, you’re the person who is responsible for giving the results. We agree with
this directive. If you don’t feel comfortable giving back test results, don’t order the test. Often, when a provider sends a patient to us after the test was done, we discover that the patient didn’t have appropriate pretest counseling. A test result, such as a variant of uncertain significance (VUS), should never be a surprise to either the provider or the patient.

Ishta Thakar. For newly diagnosed cancers, the first call is to the patient to inform them that they have cancer. We usually bring up genetic counseling or testing, if applicable, when they are ready to accept the diagnosis and have a conversation about it. All our consults are via telehealth, so none of our patients physically come to GMS in Salt Lake City. All the consults are done virtually.

For newly diagnosed patients, we would send a consult in within a couple of weeks. For patients who had a family history, the referral would not be urgent: They can be seen within about 3 months. The turnaround times for GMS are so much better than what we have available in the community where it’s often at least 6 months, as previously noted.

Vickie Venne. Thank you. We continue to work on that. One of the interesting things that we’ve done, which is the brainchild of Renee, is shared medical appointments.

Renee Rider. We have now created 4 group appointments for people who have concerns surrounding cancer. One group is for people who don’t have cancer but have family members who have cancer who may be the best testing candidate. For example, that might be a 30-year old who tells you that her mother had breast cancer at age 45 years. Her mother is still living, but she’s never had genetic testing. We would put her in a group where we discuss the importance of talking to the family members and encouraging them to go get that first genetic evaluation in the family.

Our second group is for people who don’t have cancer themselves, but have a family history of cancer and those affected relatives have passed away. The family needs a genetic evaluation, and the veteran is the best living testing candidate.

That group is geared towards education about the test and informed consent.

The third group is for people with cancer who qualify for genetic testing. We provide all of the information that they need to make an informed decision on having (or not having) genetic testing.

The final group is for people who have family histories of known genetic mutations in cancer genes. Again, we provide them with all of the information that they need to make an informed decision regarding genetic testing.

With the shared medical appointments, we have been able to greatly increase the number of patients that we can see. Our first 3 groups all meet once a week and can have 10 or 12 veterans. Our last group meets every other week and has a maximum of 6 veterans. Wait times for our groups are generally ≤ 2 weeks. All veterans can choose to have an individual appointment if they prefer. We regularly get unsolicited feedback from veterans that they learn a lot during our groups and appreciate it.

Our group appointments have lowered the wait time for the people in the groups. And, they’ve lowered the wait time for the people who are seen individually. They’ve allowed us to address the backlog of patients waiting to see us in a more timely manner. Our wait time for individual appointment had been approaching 6 months, and it is now about 1.5 months.

We also think that being in a group normalizes the experience. Most people don’t know anyone who has had genetic testing. Now, they are in a group with others going through the same experience. In one of my groups, a male veteran talked about his breast cancer being really rare. Another male in the group volunteer that he had breast cancer, too. They both seemed to appreciate not feeling alone.

Vickie Venne. I want to move to our final piece. What do the referring providers tell the patients about a genetics referral and what should they expect?

Lisa Arfons. First and foremost, I tell the patient that it is a discussion with a genetic counselor. I make it clear that they understand that it is a discussion. They then can agree or not agree to accept genetic testing if it’s recommended.

I talk in general terms about why I think it can be important for them to have the discussion, but that we don’t have great data for decisionmaking. We understand that there are more options for preventive measures but then it ultimately will be a discussion between the PCP, the patient, and their family members about how they proceed about the preventive measures. I want them to start thinking about how the genetic test results, regardless of if they are positive, negative, or a variant that is not yet understood, can impact their offspring.

Probably I am biased, as my mom had breast cancer and she underwent genetic testing. So, I have a bit of an offspring focus as well. I already mentioned that you must discuss about whether or not it’s worth screening or doing any preventive measures on contralateral breast, or screening for things like prostate cancer at age 75 years. And so I focus more on the family members.

I try to stay in my lane. I am extremely uncomfortable when I hear about someone in our facility sending off a blood test and then asking someone else to interpret the results and discuss it with the patient. Just because it’s a blood test and it’s easy to order doesn’t mean that it is easy to know what to do with it, and it needs to be respected as such.

Ishta Thakar. Our PCPs let the patients know that GMS will contact the patient to schedule a video appointment and that if they want to bring any family members along with them, they’re welcome to. We also explain that certain cancers are genetically based and that if they have a genetic mutation, it can be passed on to their offspring. I also explain that if they have certain mutations, then we would be more vigilant in screening them for other kinds of cancers. That’s the reason that we refer that they get counseled. After counseling if they’re ready for the testing, then the counselor orders the test and does the posttest discussion with the patient.

Vickie Venne. In the VA, people are invited to attend a genetic counseling session but can certainly decline. Does the the DoD have a different approach?

Maj De Castro. I would say that the great majority of active duty patients have limited knowledge of what to expect out of a genetics appointment. One of the main things we do is educate them on their rights and protections and the potential risks associated with performing genetic testing, in particular when it comes to their continued ability to serve. Genetic testing for clinical purposes is not mandatory in the DoD, patients can certainly decline testing. Because genetic testing has the potential to alter someone’s career, it is critical we have a very thorough and comprehensive pre- and posttest counseling sessions that includes everything from career implications to the Genetic Information Nondiscrimination Act (GINA) and genetic discrimination in the military, in addition to the standard of care medical information.

Scenarios in which a servicemember is negatively impacted by pursuing a genetic diagnosis are very rare. More than 90% of the time, genetic counseling and/or testing has no adverse career effect. When they do, it is out of concern for the safety and wellbeing of a servicemember. For instance, if we diagnosis a patient with a genetic form of some arrhythmogenic disorder, part of the treatment plan can be to limit that person’s level of exertion, because it could potentially lead to death. We don’t want to put someone in a situation that may trigger that.

Vickie Venne. We also have a certain number of veterans who ask us about their service disability pay and the impact of genetic testing on it. One example is veterans with prostate cancer who were exposed to Agent Orange, which has been associated with increased risk for developing prostate cancer. I have had men who have been referred for genetic evaluation ask, “Well, if I have an identifiable mutation, how will that impact my service disability?” So we discuss the carcinogenic process that may include an inherited component as well as the environmental risk factors. I think that’s a unique issue for a population we’re honored to be able to serve.

Renee Rider. When we are talking about how the population of veterans is unique, I think it is also important to acknowledge mental health. I’ve had several patients tell me that they have posttraumatic stress disorder or anxiety and the idea of getting an indeterminant test result, such as VUS, would really weigh on them.

In the community, a lot of providers order the biggest panel they can, but for these patients who are worried about getting those indeterminant test results, I’ve been able to work with them to limit the size of the panel. I order a small panel that only has genes that have implications for that veteran’s clinical management. For example, in a patient with ductal breast cancer, I remove the genes that cause lobular breast cancer. This takes a bit of knowledge and critical thinking that our VA genetic counselors have because they have experience with veterans and their needs.

As our time draws to a close, I have one final thought. This has been a heartwarming conversation today. It is really nice to hear that GMS services are appreciated. We in GMS want to partner with our referring providers. Help us help you! When you enter a referral, please let us know how we can help you. The more we understand why you are sending your veteran to GMS, the more we can help meet your needs. If there are any questions or problems, feel free to send us an email or pick up the phone and call us.

Vickie Venne, MS. What is the Genomic Medicine Service (GMS) at the US Department of Veterans Affairs (VA)?

Renee Rider, JD, MS, LCGC. GMS is a telehealth service. We are part of central office and field stationed at the George E. Wahlen VA Medical Center (VAMC) in Salt Lake City, Utah. We provide care to about 90 VAMCs and their associated clinics. Veterans are referred to us by entering an interfacility consult in the VA Computerized Patient Record System (CPRS). We review the consult to determine whether the patient needs to be seen, whether we can answer with an e-consult, or whether we need more information. For the patients who need an appointment, the telehealth department at the veteran’s VA facility will contact the patient to arrange a visit with us. At the time of the appointment, the facility has a staff member available to seat the patient and connect them to us using video equipment.

We provide genetic care for all specialties, including cancer, women’s health, cardiology and neurology. In today’s discussion, we are focusing on cancer care.

Vickie Venne. What do patients do at facilities that don’t get care through GMS?

Renee Rider. There are a handful of facilities that provide their own genetic care in-house. For example, VA Boston Healthcare System in Massachusetts and the Michael E. DeBakey VAMC in Houston, Texas each have their own programs. For veterans who are not at a VA facility that has an agreement with GMS and do not have a different genetics program, their providers need to make referrals to community care.

Vickie Venne. How do patients get referred and what happens at their facility when the patients return to the specialty and primary care providers (PCP)? Ishta, who do you refer to GMS and how do you define them initially?

Ishta Thakar, MD, FACP. Referrals can come at a couple of points during a veteran’s journey at the VA. The VA covers obstetrics care for women veterans. Whenever a PCP or a women’s health provider is doing the initial history and physical on a new patient, if the female veteran has an extensive family history of breast, ovarian, colon, or endometrial cancer, then we take more history and we send a consult to GMS. The second instance would be if she tells us that she has had a personal history of breast, ovarian, or endometrial cancer and she has never had genetic testing. The third instance would be whenever we have a female veteran who is diagnosed with breast, ovarian, endometrial, or colon cancer. We would definitely talk to her about genetic counseling and send a referral to GMS. We would ask for a GMS consult for a patient with advanced maternal age, with exposure to some kind of teratogens, with an abnormal ultrasound, a family history of chromosomal disorders, or if she’s seeing an obstetrician who wants her to be tested. And finally, if a patient has a constellation of multiple cancers in the family and we don’t know what’s going on, we would also refer the patient to GMS.

Vickie Venne. That would be why GMS fields over 150 referrals every week. It is a large list. We also see veterans with personal or family histories of neurologic or cardiologic concerns as well.

Renee, as somebody who fields many of these referrals from unaffected individuals, what is the family history process?

Renee Rider. We don’t expect the referring provider to be a genetic expert. When a provider is seeing a constellation of several different cancers and he or she doesn’t know if there’s anything going on genetically or even if it’s possible, absolutely they should put in a referral to GMS. We have a triage counselor who reviews every consult that comes into our service within 24 hours.

Many cancers are due to exposures that are not concerning for a genetic etiology. We can let you know that it is not concerning, and the PCP can counsel the patient that it is very unlikely to be genetic in nature. We still give feedback even if it’s not someone who is appropriate for genetic counseling and testing. It is important to reach out to GMS even if you don’t know whether a cancer is genetic in nature.

It also is important to take your time when gathering family histories. We get a lot of patients who say, “There’s a lot of cancer in my family. I have no idea who had cancer, but I know a lot of people had cancer.” That’s not the day to put in a referral to GMS. At that point, providers should tell the patient to get as much information as they can about the family history and then reassess. It’s important for us to have accurate information. We’ve had several times where we receive a referral because the veteran says that their sister had ovarian cancer. And then when our staff calls, they later find out it was cervical cancer. That’s not a good use of the veteran’s time, and it’s not a good use of VA resources.

The other important thing about family histories is keeping the questions open-ended. Often a PCP or specialist will ask about a certain type of cancer: “Does anyone in your family have breast cancer, ovarian cancer?” Or if the veteran
is getting a colonoscopy, they ask, “Does anybody have colon cancer?” Where really, we need to be a little bit more open-ended. We prefer questions like, “Has anyone in your family
had cancer?” because that’s the question that prompts a response of, “Yes, 3 people in my family have had thyroid cancer.” That’s very important for us to know, too.

If you do get a positive response, probe a little bit more: what kind of cancer did someone have, how old were they when they had their cancer? And how are they related? Is this an aunt on your mom’s side or on your dad’s side? Those are the types of information that we need to figure out if that person needs a referral.

Vickie Venne. It’s a different story when people already have a cancer diagnosis. Which hematology or oncology patients are good referrals and why?

Lisa Arfons, MD. When patients come in with newly diagnosed cancer, breast for example, it is an emotional diagnosis and psychologicallydistressing. Oftentimes, they want to know why this happened to them. The issues surrounding
genetic testing also becomes very emotional. They want to know whether their children are at risk as well.

Genetic discussions take a long time. I rarely do that on the first visit. I always record for myself in my clinic note if something strikes me regarding the patient’s diagnosis. I quickly run through the National Comprehensive Cancer Network (NCCN) guidelines to remind myself of what I need to go over with the patient at our next meeting. Most patients don’t need to be referred to GMS, and most patients don’t need to be tested once they’re seen.

I often save the referral discussion for after I have established a rapport with a patient, we have a treatment plan, or they already have had their first surgery. Therefore, we are not making decisions about their first surgery based on the genetic medicine results.

If I’m considering a referral, I do a deeper dive with the patient. Is the patient older or younger than 45 years? I pull up NCCN guidelines and we go through the entire checklist.

We have male breast cancer patients at the VA—probably more than the community—so we refer those patients. At the Louis Stokes Cleveland VAMC in Ohio, we have had some in-depth discussions about referring male breast cancer patients for genetic testing and whether it was beneficial to older patients with male breast cancer. Ultimately, we decided that it was important for our male veterans to be tested because it empowered them to have better understanding of their medical conditions that may not just have effect on them but on their offspring, and that that can be a source of psychological and emotional support.

I don’t refer most people to GMS once I go through the checklist. I appreciate the action for an e-consult within the CPRS telemedicine consult itself, as Renee noted. If it is not necessary, GMS makes it an e-consult. I try to communicate that I don’t know whether it is necessary or not so that GMS understands where I’m coming from.

Vickie Venne. In the US Department of Defense (DoD) the process is quite different. Mauricio, can you explain the clinical referral process, who is referred, and how that works from a laboratory perspective?

Maj De Castro, MD, FACMG, USAF. The VA has led the way in demonstrating how to best provide for the medical genetic needs of a large, decentralized population distributed all over the country. Over the last 5 to 10 years, the DoD has made strides in recognizing the role genetics plays in the practice of everyday medicine and redoubling efforts to meet the needs of servicemembers.

The way that it traditionally has worked in the DoD is that military treatment facilities (MTFs) that have dedicated geneticists and genetic counselors: Kessler Medical Center in Mississippi, Walter Reed National Military Medical
Center in Maryland, Tripler Army Medical Center in Hawaii, Madigan Army Medical Center in Washington, Brooke Army Medical Center in Texas, Naval Medical Center San Diego in California, and Naval Medical Center Portsmouth in Virginia. A patient seeking genetic evaluation, counseling, or testing in those larger facilities would be referred to the genetics service by their primary care manager. Wait times vary, but it would usually be weeks, maybe months. However, the great majority of MTFs do not have dedicated genetics support. Most of the time, those patients would have to be referred to the local civilian community—there was no process for them to be seen in in the military healthcare system—with wait times that exceed 6 to 8 months in some cases. This is due to just not a military but a national shortage of genetics professionals (counselors and physicians).

Last year we started the telegenetics initiative, which is small compared to the VA—it is comprised of 2 geneticists and 1 genetic counselor—but with the full intent of growing it over time. Its purpose is to extend the resources we
had to other MTFs. Genetics professionals stationed state-side can provide care to remote facilities with limited access to local genetics support such as Cannon Air Force Base (AFB) or overseas facilities such as Spangdahlem AFB in Germany.

We recognize there are military-specific needs for the DoD regarding the genetic counseling process that have to take into account readiness, genetic discrimination, continued ability to serve and fitness for duty. For this important reason, we are seeking to expand our telegenetics initiative. The goal is to be able to provide 100% of all genetic counseling in-house, so to speak.

Currently, providers at the 4 pilot sites (Cannon AFB, Fort Bragg, Spangdahlem AFB, and Guantanamo Bay) send us referrals. We triage them and assign the patient to see a geneticist or a counselor depending on the indication.

On the laboratory side, it has been a very interesting experience. Because we provide comprehensive germline cancer testing at very little cost to the provider at any MTF, we have had high numbers of test requests over the years.
In addition to saving the DoD millions of dollars in testing, we have learned some interesting lessons in the process. For instance, we have worked closely with several different groups to better understand how to educate providers on the genetic counseling and testing process. This has allowed us to craft a thorough and inclusive consent form that addresses the needs of the DoD. We have also learned valuable lessons about population-based screening vs evidence-based testing, and lessons surrounding narrow-based testing (BRCA1 and BRCA2 only testing) vs ordering a more comprehensive panel that includes other genes supported by strong evidence (such as PALB2, CHEK2, or TP53).

For example, we have found that in a significant proportion of individuals with and without family history, there are clinically relevant variants in genes other than BRCA1 or BRCA2. And so, we have made part of our consent process,
a statement on secondary findings. If the patient consents, we will report pathogenic variants in other genes known to be associated with cancer (with strong evidence) even if the provider ordered a narrow panel such as BRCA1 and BRCA2 testing only. In about 1% to 4% of patients that would otherwise not meet NCCN guidelines, we’ve reported variants that were clinically actionable and changed the medical management of that patient.

We feel strongly that this is a conversation that we need to have in our field, and we realize it’s a complex issue, maybe we need to expand who gets testing. Guideline based testing is missing some patients out there that could benefit from it.

Vickie Venne. There certainly are many sides to the conversation of population-based vs evidence-based genetic testing. Genetic testing policies are changing rapidly. There are teams exploring comprehensive gene sequencing for
newborns and how that potential 1-time test can provide information will be reinterpreted as a person goes from cradle to grave. However, unlike the current DoD process, in the VA there are patients who we don’t see.

Renee Rider. I want to talk about money. When we order a genetic test, that test is paid for by the pathology department at the patient’s VAMC. Most of the pathology departments we work with are clear that they only can provide
genetic testing that is considered medically necessary. Thus, we review each test to make sure it meets established guidelines for testing. We don’t do population genetic screening as there isn’t evidence or guidelines to support offering it. We are strict about who does and does not get genetic testing, partly because we have a responsibility to pathology departments and to the taxpayers.

GMS focuses on conditions that are inherited, that is to say, we deal with germline genetics. Therefore, we discontinue referrals for somatic requests, such as when an OncotypeDX test is requested. It is my understanding that pharmacogenetic referrals may be sent to the new PHASeR initiative, which is a joint collaboration between the VA and Sanford Health and is headed by Deepak Voora, MD.

We generally don’t see patients who still are having diagnostic procedures done. For example, if a veteran has a suspicious breast mass, we recommend that the provider workup the mass before referring to GMS. Regardless of a genetic test result, a suspicious mass needs to be worked up. And, knowing if the mass is cancerous could change how we would proceed with the genetic workup. For example, if the mass were not cancerous, we may recommend that an affected relative have the first genetic evaluation. Furthermore, knowing if the patient has cancer changes how we interpret negative test results.

Another group of patients we don’t see are those who already had genetic testing done by the referring provider. It’s a VA directive that if you order a test, you’re the person who is responsible for giving the results. We agree with
this directive. If you don’t feel comfortable giving back test results, don’t order the test. Often, when a provider sends a patient to us after the test was done, we discover that the patient didn’t have appropriate pretest counseling. A test result, such as a variant of uncertain significance (VUS), should never be a surprise to either the provider or the patient.

Ishta Thakar. For newly diagnosed cancers, the first call is to the patient to inform them that they have cancer. We usually bring up genetic counseling or testing, if applicable, when they are ready to accept the diagnosis and have a conversation about it. All our consults are via telehealth, so none of our patients physically come to GMS in Salt Lake City. All the consults are done virtually.

For newly diagnosed patients, we would send a consult in within a couple of weeks. For patients who had a family history, the referral would not be urgent: They can be seen within about 3 months. The turnaround times for GMS are so much better than what we have available in the community where it’s often at least 6 months, as previously noted.

Vickie Venne. Thank you. We continue to work on that. One of the interesting things that we’ve done, which is the brainchild of Renee, is shared medical appointments.

Renee Rider. We have now created 4 group appointments for people who have concerns surrounding cancer. One group is for people who don’t have cancer but have family members who have cancer who may be the best testing candidate. For example, that might be a 30-year old who tells you that her mother had breast cancer at age 45 years. Her mother is still living, but she’s never had genetic testing. We would put her in a group where we discuss the importance of talking to the family members and encouraging them to go get that first genetic evaluation in the family.

Our second group is for people who don’t have cancer themselves, but have a family history of cancer and those affected relatives have passed away. The family needs a genetic evaluation, and the veteran is the best living testing candidate.

That group is geared towards education about the test and informed consent.

The third group is for people with cancer who qualify for genetic testing. We provide all of the information that they need to make an informed decision on having (or not having) genetic testing.

The final group is for people who have family histories of known genetic mutations in cancer genes. Again, we provide them with all of the information that they need to make an informed decision regarding genetic testing.

With the shared medical appointments, we have been able to greatly increase the number of patients that we can see. Our first 3 groups all meet once a week and can have 10 or 12 veterans. Our last group meets every other week and has a maximum of 6 veterans. Wait times for our groups are generally ≤ 2 weeks. All veterans can choose to have an individual appointment if they prefer. We regularly get unsolicited feedback from veterans that they learn a lot during our groups and appreciate it.

Our group appointments have lowered the wait time for the people in the groups. And, they’ve lowered the wait time for the people who are seen individually. They’ve allowed us to address the backlog of patients waiting to see us in a more timely manner. Our wait time for individual appointment had been approaching 6 months, and it is now about 1.5 months.

We also think that being in a group normalizes the experience. Most people don’t know anyone who has had genetic testing. Now, they are in a group with others going through the same experience. In one of my groups, a male veteran talked about his breast cancer being really rare. Another male in the group volunteer that he had breast cancer, too. They both seemed to appreciate not feeling alone.

Vickie Venne. I want to move to our final piece. What do the referring providers tell the patients about a genetics referral and what should they expect?

Lisa Arfons. First and foremost, I tell the patient that it is a discussion with a genetic counselor. I make it clear that they understand that it is a discussion. They then can agree or not agree to accept genetic testing if it’s recommended.

I talk in general terms about why I think it can be important for them to have the discussion, but that we don’t have great data for decisionmaking. We understand that there are more options for preventive measures but then it ultimately will be a discussion between the PCP, the patient, and their family members about how they proceed about the preventive measures. I want them to start thinking about how the genetic test results, regardless of if they are positive, negative, or a variant that is not yet understood, can impact their offspring.

Probably I am biased, as my mom had breast cancer and she underwent genetic testing. So, I have a bit of an offspring focus as well. I already mentioned that you must discuss about whether or not it’s worth screening or doing any preventive measures on contralateral breast, or screening for things like prostate cancer at age 75 years. And so I focus more on the family members.

I try to stay in my lane. I am extremely uncomfortable when I hear about someone in our facility sending off a blood test and then asking someone else to interpret the results and discuss it with the patient. Just because it’s a blood test and it’s easy to order doesn’t mean that it is easy to know what to do with it, and it needs to be respected as such.

Ishta Thakar. Our PCPs let the patients know that GMS will contact the patient to schedule a video appointment and that if they want to bring any family members along with them, they’re welcome to. We also explain that certain cancers are genetically based and that if they have a genetic mutation, it can be passed on to their offspring. I also explain that if they have certain mutations, then we would be more vigilant in screening them for other kinds of cancers. That’s the reason that we refer that they get counseled. After counseling if they’re ready for the testing, then the counselor orders the test and does the posttest discussion with the patient.

Vickie Venne. In the VA, people are invited to attend a genetic counseling session but can certainly decline. Does the the DoD have a different approach?

Maj De Castro. I would say that the great majority of active duty patients have limited knowledge of what to expect out of a genetics appointment. One of the main things we do is educate them on their rights and protections and the potential risks associated with performing genetic testing, in particular when it comes to their continued ability to serve. Genetic testing for clinical purposes is not mandatory in the DoD, patients can certainly decline testing. Because genetic testing has the potential to alter someone’s career, it is critical we have a very thorough and comprehensive pre- and posttest counseling sessions that includes everything from career implications to the Genetic Information Nondiscrimination Act (GINA) and genetic discrimination in the military, in addition to the standard of care medical information.

Scenarios in which a servicemember is negatively impacted by pursuing a genetic diagnosis are very rare. More than 90% of the time, genetic counseling and/or testing has no adverse career effect. When they do, it is out of concern for the safety and wellbeing of a servicemember. For instance, if we diagnosis a patient with a genetic form of some arrhythmogenic disorder, part of the treatment plan can be to limit that person’s level of exertion, because it could potentially lead to death. We don’t want to put someone in a situation that may trigger that.

Vickie Venne. We also have a certain number of veterans who ask us about their service disability pay and the impact of genetic testing on it. One example is veterans with prostate cancer who were exposed to Agent Orange, which has been associated with increased risk for developing prostate cancer. I have had men who have been referred for genetic evaluation ask, “Well, if I have an identifiable mutation, how will that impact my service disability?” So we discuss the carcinogenic process that may include an inherited component as well as the environmental risk factors. I think that’s a unique issue for a population we’re honored to be able to serve.

Renee Rider. When we are talking about how the population of veterans is unique, I think it is also important to acknowledge mental health. I’ve had several patients tell me that they have posttraumatic stress disorder or anxiety and the idea of getting an indeterminant test result, such as VUS, would really weigh on them.

In the community, a lot of providers order the biggest panel they can, but for these patients who are worried about getting those indeterminant test results, I’ve been able to work with them to limit the size of the panel. I order a small panel that only has genes that have implications for that veteran’s clinical management. For example, in a patient with ductal breast cancer, I remove the genes that cause lobular breast cancer. This takes a bit of knowledge and critical thinking that our VA genetic counselors have because they have experience with veterans and their needs.

As our time draws to a close, I have one final thought. This has been a heartwarming conversation today. It is really nice to hear that GMS services are appreciated. We in GMS want to partner with our referring providers. Help us help you! When you enter a referral, please let us know how we can help you. The more we understand why you are sending your veteran to GMS, the more we can help meet your needs. If there are any questions or problems, feel free to send us an email or pick up the phone and call us.

Vickie Venne, MS. What is the Genomic Medicine Service (GMS) at the US Department of Veterans Affairs (VA)?

Renee Rider, JD, MS, LCGC. GMS is a telehealth service. We are part of central office and field stationed at the George E. Wahlen VA Medical Center (VAMC) in Salt Lake City, Utah. We provide care to about 90 VAMCs and their associated clinics. Veterans are referred to us by entering an interfacility consult in the VA Computerized Patient Record System (CPRS). We review the consult to determine whether the patient needs to be seen, whether we can answer with an e-consult, or whether we need more information. For the patients who need an appointment, the telehealth department at the veteran’s VA facility will contact the patient to arrange a visit with us. At the time of the appointment, the facility has a staff member available to seat the patient and connect them to us using video equipment.

We provide genetic care for all specialties, including cancer, women’s health, cardiology and neurology. In today’s discussion, we are focusing on cancer care.

Vickie Venne. What do patients do at facilities that don’t get care through GMS?

Renee Rider. There are a handful of facilities that provide their own genetic care in-house. For example, VA Boston Healthcare System in Massachusetts and the Michael E. DeBakey VAMC in Houston, Texas each have their own programs. For veterans who are not at a VA facility that has an agreement with GMS and do not have a different genetics program, their providers need to make referrals to community care.

Vickie Venne. How do patients get referred and what happens at their facility when the patients return to the specialty and primary care providers (PCP)? Ishta, who do you refer to GMS and how do you define them initially?

Ishta Thakar, MD, FACP. Referrals can come at a couple of points during a veteran’s journey at the VA. The VA covers obstetrics care for women veterans. Whenever a PCP or a women’s health provider is doing the initial history and physical on a new patient, if the female veteran has an extensive family history of breast, ovarian, colon, or endometrial cancer, then we take more history and we send a consult to GMS. The second instance would be if she tells us that she has had a personal history of breast, ovarian, or endometrial cancer and she has never had genetic testing. The third instance would be whenever we have a female veteran who is diagnosed with breast, ovarian, endometrial, or colon cancer. We would definitely talk to her about genetic counseling and send a referral to GMS. We would ask for a GMS consult for a patient with advanced maternal age, with exposure to some kind of teratogens, with an abnormal ultrasound, a family history of chromosomal disorders, or if she’s seeing an obstetrician who wants her to be tested. And finally, if a patient has a constellation of multiple cancers in the family and we don’t know what’s going on, we would also refer the patient to GMS.

Vickie Venne. That would be why GMS fields over 150 referrals every week. It is a large list. We also see veterans with personal or family histories of neurologic or cardiologic concerns as well.

Renee, as somebody who fields many of these referrals from unaffected individuals, what is the family history process?

Renee Rider. We don’t expect the referring provider to be a genetic expert. When a provider is seeing a constellation of several different cancers and he or she doesn’t know if there’s anything going on genetically or even if it’s possible, absolutely they should put in a referral to GMS. We have a triage counselor who reviews every consult that comes into our service within 24 hours.

Many cancers are due to exposures that are not concerning for a genetic etiology. We can let you know that it is not concerning, and the PCP can counsel the patient that it is very unlikely to be genetic in nature. We still give feedback even if it’s not someone who is appropriate for genetic counseling and testing. It is important to reach out to GMS even if you don’t know whether a cancer is genetic in nature.

It also is important to take your time when gathering family histories. We get a lot of patients who say, “There’s a lot of cancer in my family. I have no idea who had cancer, but I know a lot of people had cancer.” That’s not the day to put in a referral to GMS. At that point, providers should tell the patient to get as much information as they can about the family history and then reassess. It’s important for us to have accurate information. We’ve had several times where we receive a referral because the veteran says that their sister had ovarian cancer. And then when our staff calls, they later find out it was cervical cancer. That’s not a good use of the veteran’s time, and it’s not a good use of VA resources.

The other important thing about family histories is keeping the questions open-ended. Often a PCP or specialist will ask about a certain type of cancer: “Does anyone in your family have breast cancer, ovarian cancer?” Or if the veteran
is getting a colonoscopy, they ask, “Does anybody have colon cancer?” Where really, we need to be a little bit more open-ended. We prefer questions like, “Has anyone in your family
had cancer?” because that’s the question that prompts a response of, “Yes, 3 people in my family have had thyroid cancer.” That’s very important for us to know, too.

If you do get a positive response, probe a little bit more: what kind of cancer did someone have, how old were they when they had their cancer? And how are they related? Is this an aunt on your mom’s side or on your dad’s side? Those are the types of information that we need to figure out if that person needs a referral.

Vickie Venne. It’s a different story when people already have a cancer diagnosis. Which hematology or oncology patients are good referrals and why?

Lisa Arfons, MD. When patients come in with newly diagnosed cancer, breast for example, it is an emotional diagnosis and psychologicallydistressing. Oftentimes, they want to know why this happened to them. The issues surrounding
genetic testing also becomes very emotional. They want to know whether their children are at risk as well.

Genetic discussions take a long time. I rarely do that on the first visit. I always record for myself in my clinic note if something strikes me regarding the patient’s diagnosis. I quickly run through the National Comprehensive Cancer Network (NCCN) guidelines to remind myself of what I need to go over with the patient at our next meeting. Most patients don’t need to be referred to GMS, and most patients don’t need to be tested once they’re seen.

I often save the referral discussion for after I have established a rapport with a patient, we have a treatment plan, or they already have had their first surgery. Therefore, we are not making decisions about their first surgery based on the genetic medicine results.

If I’m considering a referral, I do a deeper dive with the patient. Is the patient older or younger than 45 years? I pull up NCCN guidelines and we go through the entire checklist.

We have male breast cancer patients at the VA—probably more than the community—so we refer those patients. At the Louis Stokes Cleveland VAMC in Ohio, we have had some in-depth discussions about referring male breast cancer patients for genetic testing and whether it was beneficial to older patients with male breast cancer. Ultimately, we decided that it was important for our male veterans to be tested because it empowered them to have better understanding of their medical conditions that may not just have effect on them but on their offspring, and that that can be a source of psychological and emotional support.

I don’t refer most people to GMS once I go through the checklist. I appreciate the action for an e-consult within the CPRS telemedicine consult itself, as Renee noted. If it is not necessary, GMS makes it an e-consult. I try to communicate that I don’t know whether it is necessary or not so that GMS understands where I’m coming from.

Vickie Venne. In the US Department of Defense (DoD) the process is quite different. Mauricio, can you explain the clinical referral process, who is referred, and how that works from a laboratory perspective?

Maj De Castro, MD, FACMG, USAF. The VA has led the way in demonstrating how to best provide for the medical genetic needs of a large, decentralized population distributed all over the country. Over the last 5 to 10 years, the DoD has made strides in recognizing the role genetics plays in the practice of everyday medicine and redoubling efforts to meet the needs of servicemembers.

The way that it traditionally has worked in the DoD is that military treatment facilities (MTFs) that have dedicated geneticists and genetic counselors: Kessler Medical Center in Mississippi, Walter Reed National Military Medical
Center in Maryland, Tripler Army Medical Center in Hawaii, Madigan Army Medical Center in Washington, Brooke Army Medical Center in Texas, Naval Medical Center San Diego in California, and Naval Medical Center Portsmouth in Virginia. A patient seeking genetic evaluation, counseling, or testing in those larger facilities would be referred to the genetics service by their primary care manager. Wait times vary, but it would usually be weeks, maybe months. However, the great majority of MTFs do not have dedicated genetics support. Most of the time, those patients would have to be referred to the local civilian community—there was no process for them to be seen in in the military healthcare system—with wait times that exceed 6 to 8 months in some cases. This is due to just not a military but a national shortage of genetics professionals (counselors and physicians).

Last year we started the telegenetics initiative, which is small compared to the VA—it is comprised of 2 geneticists and 1 genetic counselor—but with the full intent of growing it over time. Its purpose is to extend the resources we
had to other MTFs. Genetics professionals stationed state-side can provide care to remote facilities with limited access to local genetics support such as Cannon Air Force Base (AFB) or overseas facilities such as Spangdahlem AFB in Germany.

We recognize there are military-specific needs for the DoD regarding the genetic counseling process that have to take into account readiness, genetic discrimination, continued ability to serve and fitness for duty. For this important reason, we are seeking to expand our telegenetics initiative. The goal is to be able to provide 100% of all genetic counseling in-house, so to speak.

Currently, providers at the 4 pilot sites (Cannon AFB, Fort Bragg, Spangdahlem AFB, and Guantanamo Bay) send us referrals. We triage them and assign the patient to see a geneticist or a counselor depending on the indication.

On the laboratory side, it has been a very interesting experience. Because we provide comprehensive germline cancer testing at very little cost to the provider at any MTF, we have had high numbers of test requests over the years.
In addition to saving the DoD millions of dollars in testing, we have learned some interesting lessons in the process. For instance, we have worked closely with several different groups to better understand how to educate providers on the genetic counseling and testing process. This has allowed us to craft a thorough and inclusive consent form that addresses the needs of the DoD. We have also learned valuable lessons about population-based screening vs evidence-based testing, and lessons surrounding narrow-based testing (BRCA1 and BRCA2 only testing) vs ordering a more comprehensive panel that includes other genes supported by strong evidence (such as PALB2, CHEK2, or TP53).

For example, we have found that in a significant proportion of individuals with and without family history, there are clinically relevant variants in genes other than BRCA1 or BRCA2. And so, we have made part of our consent process,
a statement on secondary findings. If the patient consents, we will report pathogenic variants in other genes known to be associated with cancer (with strong evidence) even if the provider ordered a narrow panel such as BRCA1 and BRCA2 testing only. In about 1% to 4% of patients that would otherwise not meet NCCN guidelines, we’ve reported variants that were clinically actionable and changed the medical management of that patient.

We feel strongly that this is a conversation that we need to have in our field, and we realize it’s a complex issue, maybe we need to expand who gets testing. Guideline based testing is missing some patients out there that could benefit from it.

Vickie Venne. There certainly are many sides to the conversation of population-based vs evidence-based genetic testing. Genetic testing policies are changing rapidly. There are teams exploring comprehensive gene sequencing for
newborns and how that potential 1-time test can provide information will be reinterpreted as a person goes from cradle to grave. However, unlike the current DoD process, in the VA there are patients who we don’t see.

Renee Rider. I want to talk about money. When we order a genetic test, that test is paid for by the pathology department at the patient’s VAMC. Most of the pathology departments we work with are clear that they only can provide
genetic testing that is considered medically necessary. Thus, we review each test to make sure it meets established guidelines for testing. We don’t do population genetic screening as there isn’t evidence or guidelines to support offering it. We are strict about who does and does not get genetic testing, partly because we have a responsibility to pathology departments and to the taxpayers.

GMS focuses on conditions that are inherited, that is to say, we deal with germline genetics. Therefore, we discontinue referrals for somatic requests, such as when an OncotypeDX test is requested. It is my understanding that pharmacogenetic referrals may be sent to the new PHASeR initiative, which is a joint collaboration between the VA and Sanford Health and is headed by Deepak Voora, MD.

We generally don’t see patients who still are having diagnostic procedures done. For example, if a veteran has a suspicious breast mass, we recommend that the provider workup the mass before referring to GMS. Regardless of a genetic test result, a suspicious mass needs to be worked up. And, knowing if the mass is cancerous could change how we would proceed with the genetic workup. For example, if the mass were not cancerous, we may recommend that an affected relative have the first genetic evaluation. Furthermore, knowing if the patient has cancer changes how we interpret negative test results.

Another group of patients we don’t see are those who already had genetic testing done by the referring provider. It’s a VA directive that if you order a test, you’re the person who is responsible for giving the results. We agree with
this directive. If you don’t feel comfortable giving back test results, don’t order the test. Often, when a provider sends a patient to us after the test was done, we discover that the patient didn’t have appropriate pretest counseling. A test result, such as a variant of uncertain significance (VUS), should never be a surprise to either the provider or the patient.

Ishta Thakar. For newly diagnosed cancers, the first call is to the patient to inform them that they have cancer. We usually bring up genetic counseling or testing, if applicable, when they are ready to accept the diagnosis and have a conversation about it. All our consults are via telehealth, so none of our patients physically come to GMS in Salt Lake City. All the consults are done virtually.

For newly diagnosed patients, we would send a consult in within a couple of weeks. For patients who had a family history, the referral would not be urgent: They can be seen within about 3 months. The turnaround times for GMS are so much better than what we have available in the community where it’s often at least 6 months, as previously noted.

Vickie Venne. Thank you. We continue to work on that. One of the interesting things that we’ve done, which is the brainchild of Renee, is shared medical appointments.

Renee Rider. We have now created 4 group appointments for people who have concerns surrounding cancer. One group is for people who don’t have cancer but have family members who have cancer who may be the best testing candidate. For example, that might be a 30-year old who tells you that her mother had breast cancer at age 45 years. Her mother is still living, but she’s never had genetic testing. We would put her in a group where we discuss the importance of talking to the family members and encouraging them to go get that first genetic evaluation in the family.

Our second group is for people who don’t have cancer themselves, but have a family history of cancer and those affected relatives have passed away. The family needs a genetic evaluation, and the veteran is the best living testing candidate.

That group is geared towards education about the test and informed consent.

The third group is for people with cancer who qualify for genetic testing. We provide all of the information that they need to make an informed decision on having (or not having) genetic testing.

The final group is for people who have family histories of known genetic mutations in cancer genes. Again, we provide them with all of the information that they need to make an informed decision regarding genetic testing.

With the shared medical appointments, we have been able to greatly increase the number of patients that we can see. Our first 3 groups all meet once a week and can have 10 or 12 veterans. Our last group meets every other week and has a maximum of 6 veterans. Wait times for our groups are generally ≤ 2 weeks. All veterans can choose to have an individual appointment if they prefer. We regularly get unsolicited feedback from veterans that they learn a lot during our groups and appreciate it.

Our group appointments have lowered the wait time for the people in the groups. And, they’ve lowered the wait time for the people who are seen individually. They’ve allowed us to address the backlog of patients waiting to see us in a more timely manner. Our wait time for individual appointment had been approaching 6 months, and it is now about 1.5 months.

We also think that being in a group normalizes the experience. Most people don’t know anyone who has had genetic testing. Now, they are in a group with others going through the same experience. In one of my groups, a male veteran talked about his breast cancer being really rare. Another male in the group volunteer that he had breast cancer, too. They both seemed to appreciate not feeling alone.

Vickie Venne. I want to move to our final piece. What do the referring providers tell the patients about a genetics referral and what should they expect?

Lisa Arfons. First and foremost, I tell the patient that it is a discussion with a genetic counselor. I make it clear that they understand that it is a discussion. They then can agree or not agree to accept genetic testing if it’s recommended.

I talk in general terms about why I think it can be important for them to have the discussion, but that we don’t have great data for decisionmaking. We understand that there are more options for preventive measures but then it ultimately will be a discussion between the PCP, the patient, and their family members about how they proceed about the preventive measures. I want them to start thinking about how the genetic test results, regardless of if they are positive, negative, or a variant that is not yet understood, can impact their offspring.

Probably I am biased, as my mom had breast cancer and she underwent genetic testing. So, I have a bit of an offspring focus as well. I already mentioned that you must discuss about whether or not it’s worth screening or doing any preventive measures on contralateral breast, or screening for things like prostate cancer at age 75 years. And so I focus more on the family members.

I try to stay in my lane. I am extremely uncomfortable when I hear about someone in our facility sending off a blood test and then asking someone else to interpret the results and discuss it with the patient. Just because it’s a blood test and it’s easy to order doesn’t mean that it is easy to know what to do with it, and it needs to be respected as such.

Ishta Thakar. Our PCPs let the patients know that GMS will contact the patient to schedule a video appointment and that if they want to bring any family members along with them, they’re welcome to. We also explain that certain cancers are genetically based and that if they have a genetic mutation, it can be passed on to their offspring. I also explain that if they have certain mutations, then we would be more vigilant in screening them for other kinds of cancers. That’s the reason that we refer that they get counseled. After counseling if they’re ready for the testing, then the counselor orders the test and does the posttest discussion with the patient.

Vickie Venne. In the VA, people are invited to attend a genetic counseling session but can certainly decline. Does the the DoD have a different approach?

Maj De Castro. I would say that the great majority of active duty patients have limited knowledge of what to expect out of a genetics appointment. One of the main things we do is educate them on their rights and protections and the potential risks associated with performing genetic testing, in particular when it comes to their continued ability to serve. Genetic testing for clinical purposes is not mandatory in the DoD, patients can certainly decline testing. Because genetic testing has the potential to alter someone’s career, it is critical we have a very thorough and comprehensive pre- and posttest counseling sessions that includes everything from career implications to the Genetic Information Nondiscrimination Act (GINA) and genetic discrimination in the military, in addition to the standard of care medical information.

Scenarios in which a servicemember is negatively impacted by pursuing a genetic diagnosis are very rare. More than 90% of the time, genetic counseling and/or testing has no adverse career effect. When they do, it is out of concern for the safety and wellbeing of a servicemember. For instance, if we diagnosis a patient with a genetic form of some arrhythmogenic disorder, part of the treatment plan can be to limit that person’s level of exertion, because it could potentially lead to death. We don’t want to put someone in a situation that may trigger that.

Vickie Venne. We also have a certain number of veterans who ask us about their service disability pay and the impact of genetic testing on it. One example is veterans with prostate cancer who were exposed to Agent Orange, which has been associated with increased risk for developing prostate cancer. I have had men who have been referred for genetic evaluation ask, “Well, if I have an identifiable mutation, how will that impact my service disability?” So we discuss the carcinogenic process that may include an inherited component as well as the environmental risk factors. I think that’s a unique issue for a population we’re honored to be able to serve.

Renee Rider. When we are talking about how the population of veterans is unique, I think it is also important to acknowledge mental health. I’ve had several patients tell me that they have posttraumatic stress disorder or anxiety and the idea of getting an indeterminant test result, such as VUS, would really weigh on them.

In the community, a lot of providers order the biggest panel they can, but for these patients who are worried about getting those indeterminant test results, I’ve been able to work with them to limit the size of the panel. I order a small panel that only has genes that have implications for that veteran’s clinical management. For example, in a patient with ductal breast cancer, I remove the genes that cause lobular breast cancer. This takes a bit of knowledge and critical thinking that our VA genetic counselors have because they have experience with veterans and their needs.

As our time draws to a close, I have one final thought. This has been a heartwarming conversation today. It is really nice to hear that GMS services are appreciated. We in GMS want to partner with our referring providers. Help us help you! When you enter a referral, please let us know how we can help you. The more we understand why you are sending your veteran to GMS, the more we can help meet your needs. If there are any questions or problems, feel free to send us an email or pick up the phone and call us.

Thyroid nodules are identified incidentally in 4% to 10% of the general population in the US.^1,2 Clinicians and patients often are concerned about potential malignancy when thyroid nodules are identified because 5% to 15% of nodules will be cancerous.¹ The most common form of cancer is papillary carcinoma followed by follicular carcinoma.² Initially, serum thyroid-stimulating hormone (TSH) levels and thyroid ultrasound are used to evaluate a thyroid nodule because both tests can reveal vital information about malignancy potential.³ Ultrasound characteristics, such as macrocalcifications, hypoechogenicity, absence of halo, increased vascularity, and irregular nodular margins, increase suspicion for malignancy and warrant further investigation.³

Ultrasound-guided fine-needle aspiration (FNA) is the modality of choice for evaluation of thyroid nodules with sensitivity and specificity > 90%.^2,4 Most patients receive a definitive diagnosis with this test; however, about 25% of cases are indeterminate based on the Bethesda System and require surgical investigation.³

Currently, it is well accepted clinical practice to refer all nodules > 4 cm for surgical intervention regardless of malignancy risk factors or the mass effect of the nodule.^3-6 The preference for surgery—rather than FNA—is because of the notable false negative rate with FNA in larger nodules; studies have described false negative rates for FNA close to 10%.^7,8 In contrast, Megwalu recently reported a FNA false negative rate of 0%.⁹

The risk of malignancy associated with nodule size has been researched for many years, but studies have produced conflicting results. In this retrospective cohort study, the authors compared malignancy rates between patients with nodules ≥ 3 cm and those with nodules < 3 cm.

Methods

The authors performed a retrospective chart review of the medical records of 329 patients presenting for thyroid nodule evaluation found on physical exam or incidentally identified with imaging at the Dayton Veteran Affairs Medical Center from January 2000 to May 2016. Data collection included sex, age, race, personal history of neck radiation treatment, family history of thyroid cancer, personal history of thyroid cancer, hot nodules/Graves disease, abnormal neck lymph nodes, and serum TSH levels. The authors looked for an association between TSH level and cancer. Hot thyroid nodules are known to have low risk of malignancy.

All patients aged 18 to 99 years with a thyroid nodule evaluated with FNA were included in the study. Patients were divided into 2 groups, those with nodules ≥ 3 cm and those with nodules < 3 cm. For nodules requiring subsequent biopsies, only the initial nodule biopsy was included in our study. The 3-cm cutoff was selected based on previous studies.^1,5,10 Patients who did not undergo a FNA study were excluded. Indications for surgery were positive FNA results, suspicious imaging, size of nodule, or patient preference.

Means and standard deviations are reported for continuous variables and counts and percentages for categorical variables. We used the Mann-Whitney test for comparisons involving continuous variables with 2 groups and the Kruskal-Wallis test for 4 groups. The chi-square test—corrected for continuity if necessary—was used to compare 2 categorical variables. We used multiple logistic regression to adjust for demographic and clinical variables other than nodule size that were related to malignancy. Inferences were made at the 0.05 level of significance.

Results

A total of 329 patients with thyroid nodules were identified: 236 were < 3 cm and 93 were ≥ 3 cm. The 2 groups differed on race, with more white patients in the < 3-cm nodule group (78% vs 67%, P = .036) (Table 1). 

Prevalence of cancer based on FNA in nodules < 3 cm was 6.4% (95% CI, 3.6%–10.3%) and nodules ≥ 3 cm was 8.6% (95% CI, 3.8%–16.2%; P = .23) (Table 2). 

When divided into 4 subgroups, cancer using FNA was found in 35.1% of nodules < 2 cm, 21.1% of nodules 2 cm to < 3 cm, 42.1% of nodules 3 cm to 4 cm, and 18.2% of nodules > 4 cm (P = .32) (Table 3). 

Surgical pathology results showed 17 cases of papillary carcinoma in nodules < 3 cm, whereas there were 9 cases of papillary carcinoma and 1 case of follicular carcinoma in nodules > 3 cm. When correlated with the cytology results, 10 cases were reported as benign, 11 were malignant, and 6 samples were non-diagnostic.

There were 30 nondiagnostic FNA samples: 7 patients had surgery, 19 were monitored with serial imaging, 2 were lost to follow-up, and 2 expired for other reasons. Of the 19 patients who were monitored with serial imaging, the nodules were stable and did not require repeat sampling.

Discussion

The authors found no relationship between thyroid nodule size and malignancy over a 16-year period in a veteran population, either with FNA or surgical pathology. The lack of relationship persists when adjusted for the only nonthyroid variable on which the 2 groups differed (race).

The finding of no relationship between larger thyroid nodule size and cancer is consistent with other studies. In a 10-year chart review of 695 patients at Walter Reed Army Medical Center, Burch and colleagues found a malignancy rate of 18.6% but no association between thyroid nodule size and malignancy.¹¹ They concluded that nodules ≥ 4 cm did not increase malignancy risk. In a 3-year retrospective study of 326 patients, Mangister and colleagues reported that the malignancy rate was higher in nodules < 3 cm (48.4%) compared with nodules ≥ 3 cm (33.3%).¹⁰ This study concluded that the malignancy potential of thyroid nodules peaked at 2 cm and decreased at > 3 cm. Kamran and colleagues reported a nonlinear relationship between nodule size and malignancy with a threshold of 2 cm, beyond which there was no increased risk of malignancy.¹

Conversely, in a prospective study Kuru and colleagues followed 571 patients who had undergone thyroidectomy and found that nodules ≥ 4 cm were associated with increased malignancy risk compared with nodules < 4 cm. However, with a cutoff of 3 cm there was no relationship.⁵ Discrepancies among studies might be because of variability in patient demographics and the prevalence of thyroid cancer in a specific institution. Although the majority of thyroid nodules are seen in females, the current study’s population was predominantly male and entirely veteran. Consequently, interpretation of these studies highlight the need to individualize clinical decision-making for each patient.

Limitations

This study has several limitations. It was conducted at a single institution with a group of veterans, which limits the ability to generalize its results to the general population. Second, data omissions are likely in retrospective chart reviews, and ensuring accuracy of data collection could be challenging. Third, all thyroid nodules found to be benign with cytology did not undergo surgical intervention to confirm the diagnosis; therefore, only 93 of 329 nodules were evaluated with the definitive diagnostic test. Therefore, selection bias was introduced into the nodule size comparisons when surgical intervention was used to measure the outcome. However, because false negative rates for FNA is low, likely few malignant nodules were missed. In addition, all patients with thyroid nodules are not referred for surgery because of potential complications.

Conclusion

This study strongly suggests there is no increased or decreased cancer risk for thyroid nodules ≥ 3 cm compared with those < 3 cm. Current clinical practice is to refer patients with larger nodules for surgical evaluation. In a large systemic review, Shin and colleagues reported higher pretest probability of malignancy in larger nodules and recommended consideration of surgical intervention for nodules > 3 cm because of false negatives and concerns for diagnostic inaccuracy with FNA.⁸ Although data were mixed, Shin and colleagues reported higher incidence of false negative FNA results in larger nodules.⁸ Given the authors’ findings and earlier conflicting results, the decision for surgical intervention cannot be made solely on nodule size and requires consideration of additional factors including FNA results, nodule characteristics, patient risk factors, and patient preference.

Thyroid nodules are identified incidentally in 4% to 10% of the general population in the US.^1,2 Clinicians and patients often are concerned about potential malignancy when thyroid nodules are identified because 5% to 15% of nodules will be cancerous.¹ The most common form of cancer is papillary carcinoma followed by follicular carcinoma.² Initially, serum thyroid-stimulating hormone (TSH) levels and thyroid ultrasound are used to evaluate a thyroid nodule because both tests can reveal vital information about malignancy potential.³ Ultrasound characteristics, such as macrocalcifications, hypoechogenicity, absence of halo, increased vascularity, and irregular nodular margins, increase suspicion for malignancy and warrant further investigation.³

Ultrasound-guided fine-needle aspiration (FNA) is the modality of choice for evaluation of thyroid nodules with sensitivity and specificity > 90%.^2,4 Most patients receive a definitive diagnosis with this test; however, about 25% of cases are indeterminate based on the Bethesda System and require surgical investigation.³

Currently, it is well accepted clinical practice to refer all nodules > 4 cm for surgical intervention regardless of malignancy risk factors or the mass effect of the nodule.^3-6 The preference for surgery—rather than FNA—is because of the notable false negative rate with FNA in larger nodules; studies have described false negative rates for FNA close to 10%.^7,8 In contrast, Megwalu recently reported a FNA false negative rate of 0%.⁹

The risk of malignancy associated with nodule size has been researched for many years, but studies have produced conflicting results. In this retrospective cohort study, the authors compared malignancy rates between patients with nodules ≥ 3 cm and those with nodules < 3 cm.

Methods

The authors performed a retrospective chart review of the medical records of 329 patients presenting for thyroid nodule evaluation found on physical exam or incidentally identified with imaging at the Dayton Veteran Affairs Medical Center from January 2000 to May 2016. Data collection included sex, age, race, personal history of neck radiation treatment, family history of thyroid cancer, personal history of thyroid cancer, hot nodules/Graves disease, abnormal neck lymph nodes, and serum TSH levels. The authors looked for an association between TSH level and cancer. Hot thyroid nodules are known to have low risk of malignancy.

All patients aged 18 to 99 years with a thyroid nodule evaluated with FNA were included in the study. Patients were divided into 2 groups, those with nodules ≥ 3 cm and those with nodules < 3 cm. For nodules requiring subsequent biopsies, only the initial nodule biopsy was included in our study. The 3-cm cutoff was selected based on previous studies.^1,5,10 Patients who did not undergo a FNA study were excluded. Indications for surgery were positive FNA results, suspicious imaging, size of nodule, or patient preference.

Means and standard deviations are reported for continuous variables and counts and percentages for categorical variables. We used the Mann-Whitney test for comparisons involving continuous variables with 2 groups and the Kruskal-Wallis test for 4 groups. The chi-square test—corrected for continuity if necessary—was used to compare 2 categorical variables. We used multiple logistic regression to adjust for demographic and clinical variables other than nodule size that were related to malignancy. Inferences were made at the 0.05 level of significance.

Results

A total of 329 patients with thyroid nodules were identified: 236 were < 3 cm and 93 were ≥ 3 cm. The 2 groups differed on race, with more white patients in the < 3-cm nodule group (78% vs 67%, P = .036) (Table 1). 

Prevalence of cancer based on FNA in nodules < 3 cm was 6.4% (95% CI, 3.6%–10.3%) and nodules ≥ 3 cm was 8.6% (95% CI, 3.8%–16.2%; P = .23) (Table 2). 

When divided into 4 subgroups, cancer using FNA was found in 35.1% of nodules < 2 cm, 21.1% of nodules 2 cm to < 3 cm, 42.1% of nodules 3 cm to 4 cm, and 18.2% of nodules > 4 cm (P = .32) (Table 3). 

Surgical pathology results showed 17 cases of papillary carcinoma in nodules < 3 cm, whereas there were 9 cases of papillary carcinoma and 1 case of follicular carcinoma in nodules > 3 cm. When correlated with the cytology results, 10 cases were reported as benign, 11 were malignant, and 6 samples were non-diagnostic.

There were 30 nondiagnostic FNA samples: 7 patients had surgery, 19 were monitored with serial imaging, 2 were lost to follow-up, and 2 expired for other reasons. Of the 19 patients who were monitored with serial imaging, the nodules were stable and did not require repeat sampling.

Discussion

The authors found no relationship between thyroid nodule size and malignancy over a 16-year period in a veteran population, either with FNA or surgical pathology. The lack of relationship persists when adjusted for the only nonthyroid variable on which the 2 groups differed (race).

The finding of no relationship between larger thyroid nodule size and cancer is consistent with other studies. In a 10-year chart review of 695 patients at Walter Reed Army Medical Center, Burch and colleagues found a malignancy rate of 18.6% but no association between thyroid nodule size and malignancy.¹¹ They concluded that nodules ≥ 4 cm did not increase malignancy risk. In a 3-year retrospective study of 326 patients, Mangister and colleagues reported that the malignancy rate was higher in nodules < 3 cm (48.4%) compared with nodules ≥ 3 cm (33.3%).¹⁰ This study concluded that the malignancy potential of thyroid nodules peaked at 2 cm and decreased at > 3 cm. Kamran and colleagues reported a nonlinear relationship between nodule size and malignancy with a threshold of 2 cm, beyond which there was no increased risk of malignancy.¹

Conversely, in a prospective study Kuru and colleagues followed 571 patients who had undergone thyroidectomy and found that nodules ≥ 4 cm were associated with increased malignancy risk compared with nodules < 4 cm. However, with a cutoff of 3 cm there was no relationship.⁵ Discrepancies among studies might be because of variability in patient demographics and the prevalence of thyroid cancer in a specific institution. Although the majority of thyroid nodules are seen in females, the current study’s population was predominantly male and entirely veteran. Consequently, interpretation of these studies highlight the need to individualize clinical decision-making for each patient.

Limitations

This study has several limitations. It was conducted at a single institution with a group of veterans, which limits the ability to generalize its results to the general population. Second, data omissions are likely in retrospective chart reviews, and ensuring accuracy of data collection could be challenging. Third, all thyroid nodules found to be benign with cytology did not undergo surgical intervention to confirm the diagnosis; therefore, only 93 of 329 nodules were evaluated with the definitive diagnostic test. Therefore, selection bias was introduced into the nodule size comparisons when surgical intervention was used to measure the outcome. However, because false negative rates for FNA is low, likely few malignant nodules were missed. In addition, all patients with thyroid nodules are not referred for surgery because of potential complications.

Conclusion

This study strongly suggests there is no increased or decreased cancer risk for thyroid nodules ≥ 3 cm compared with those < 3 cm. Current clinical practice is to refer patients with larger nodules for surgical evaluation. In a large systemic review, Shin and colleagues reported higher pretest probability of malignancy in larger nodules and recommended consideration of surgical intervention for nodules > 3 cm because of false negatives and concerns for diagnostic inaccuracy with FNA.⁸ Although data were mixed, Shin and colleagues reported higher incidence of false negative FNA results in larger nodules.⁸ Given the authors’ findings and earlier conflicting results, the decision for surgical intervention cannot be made solely on nodule size and requires consideration of additional factors including FNA results, nodule characteristics, patient risk factors, and patient preference.

Thyroid nodules are identified incidentally in 4% to 10% of the general population in the US.^1,2 Clinicians and patients often are concerned about potential malignancy when thyroid nodules are identified because 5% to 15% of nodules will be cancerous.¹ The most common form of cancer is papillary carcinoma followed by follicular carcinoma.² Initially, serum thyroid-stimulating hormone (TSH) levels and thyroid ultrasound are used to evaluate a thyroid nodule because both tests can reveal vital information about malignancy potential.³ Ultrasound characteristics, such as macrocalcifications, hypoechogenicity, absence of halo, increased vascularity, and irregular nodular margins, increase suspicion for malignancy and warrant further investigation.³

Ultrasound-guided fine-needle aspiration (FNA) is the modality of choice for evaluation of thyroid nodules with sensitivity and specificity > 90%.^2,4 Most patients receive a definitive diagnosis with this test; however, about 25% of cases are indeterminate based on the Bethesda System and require surgical investigation.³

Currently, it is well accepted clinical practice to refer all nodules > 4 cm for surgical intervention regardless of malignancy risk factors or the mass effect of the nodule.^3-6 The preference for surgery—rather than FNA—is because of the notable false negative rate with FNA in larger nodules; studies have described false negative rates for FNA close to 10%.^7,8 In contrast, Megwalu recently reported a FNA false negative rate of 0%.⁹

The risk of malignancy associated with nodule size has been researched for many years, but studies have produced conflicting results. In this retrospective cohort study, the authors compared malignancy rates between patients with nodules ≥ 3 cm and those with nodules < 3 cm.

Methods

The authors performed a retrospective chart review of the medical records of 329 patients presenting for thyroid nodule evaluation found on physical exam or incidentally identified with imaging at the Dayton Veteran Affairs Medical Center from January 2000 to May 2016. Data collection included sex, age, race, personal history of neck radiation treatment, family history of thyroid cancer, personal history of thyroid cancer, hot nodules/Graves disease, abnormal neck lymph nodes, and serum TSH levels. The authors looked for an association between TSH level and cancer. Hot thyroid nodules are known to have low risk of malignancy.

All patients aged 18 to 99 years with a thyroid nodule evaluated with FNA were included in the study. Patients were divided into 2 groups, those with nodules ≥ 3 cm and those with nodules < 3 cm. For nodules requiring subsequent biopsies, only the initial nodule biopsy was included in our study. The 3-cm cutoff was selected based on previous studies.^1,5,10 Patients who did not undergo a FNA study were excluded. Indications for surgery were positive FNA results, suspicious imaging, size of nodule, or patient preference.

Means and standard deviations are reported for continuous variables and counts and percentages for categorical variables. We used the Mann-Whitney test for comparisons involving continuous variables with 2 groups and the Kruskal-Wallis test for 4 groups. The chi-square test—corrected for continuity if necessary—was used to compare 2 categorical variables. We used multiple logistic regression to adjust for demographic and clinical variables other than nodule size that were related to malignancy. Inferences were made at the 0.05 level of significance.

Results

A total of 329 patients with thyroid nodules were identified: 236 were < 3 cm and 93 were ≥ 3 cm. The 2 groups differed on race, with more white patients in the < 3-cm nodule group (78% vs 67%, P = .036) (Table 1). 

Prevalence of cancer based on FNA in nodules < 3 cm was 6.4% (95% CI, 3.6%–10.3%) and nodules ≥ 3 cm was 8.6% (95% CI, 3.8%–16.2%; P = .23) (Table 2). 

When divided into 4 subgroups, cancer using FNA was found in 35.1% of nodules < 2 cm, 21.1% of nodules 2 cm to < 3 cm, 42.1% of nodules 3 cm to 4 cm, and 18.2% of nodules > 4 cm (P = .32) (Table 3). 

Surgical pathology results showed 17 cases of papillary carcinoma in nodules < 3 cm, whereas there were 9 cases of papillary carcinoma and 1 case of follicular carcinoma in nodules > 3 cm. When correlated with the cytology results, 10 cases were reported as benign, 11 were malignant, and 6 samples were non-diagnostic.

There were 30 nondiagnostic FNA samples: 7 patients had surgery, 19 were monitored with serial imaging, 2 were lost to follow-up, and 2 expired for other reasons. Of the 19 patients who were monitored with serial imaging, the nodules were stable and did not require repeat sampling.

Discussion

The authors found no relationship between thyroid nodule size and malignancy over a 16-year period in a veteran population, either with FNA or surgical pathology. The lack of relationship persists when adjusted for the only nonthyroid variable on which the 2 groups differed (race).

The finding of no relationship between larger thyroid nodule size and cancer is consistent with other studies. In a 10-year chart review of 695 patients at Walter Reed Army Medical Center, Burch and colleagues found a malignancy rate of 18.6% but no association between thyroid nodule size and malignancy.¹¹ They concluded that nodules ≥ 4 cm did not increase malignancy risk. In a 3-year retrospective study of 326 patients, Mangister and colleagues reported that the malignancy rate was higher in nodules < 3 cm (48.4%) compared with nodules ≥ 3 cm (33.3%).¹⁰ This study concluded that the malignancy potential of thyroid nodules peaked at 2 cm and decreased at > 3 cm. Kamran and colleagues reported a nonlinear relationship between nodule size and malignancy with a threshold of 2 cm, beyond which there was no increased risk of malignancy.¹

Conversely, in a prospective study Kuru and colleagues followed 571 patients who had undergone thyroidectomy and found that nodules ≥ 4 cm were associated with increased malignancy risk compared with nodules < 4 cm. However, with a cutoff of 3 cm there was no relationship.⁵ Discrepancies among studies might be because of variability in patient demographics and the prevalence of thyroid cancer in a specific institution. Although the majority of thyroid nodules are seen in females, the current study’s population was predominantly male and entirely veteran. Consequently, interpretation of these studies highlight the need to individualize clinical decision-making for each patient.

Limitations

This study has several limitations. It was conducted at a single institution with a group of veterans, which limits the ability to generalize its results to the general population. Second, data omissions are likely in retrospective chart reviews, and ensuring accuracy of data collection could be challenging. Third, all thyroid nodules found to be benign with cytology did not undergo surgical intervention to confirm the diagnosis; therefore, only 93 of 329 nodules were evaluated with the definitive diagnostic test. Therefore, selection bias was introduced into the nodule size comparisons when surgical intervention was used to measure the outcome. However, because false negative rates for FNA is low, likely few malignant nodules were missed. In addition, all patients with thyroid nodules are not referred for surgery because of potential complications.

Conclusion

This study strongly suggests there is no increased or decreased cancer risk for thyroid nodules ≥ 3 cm compared with those < 3 cm. Current clinical practice is to refer patients with larger nodules for surgical evaluation. In a large systemic review, Shin and colleagues reported higher pretest probability of malignancy in larger nodules and recommended consideration of surgical intervention for nodules > 3 cm because of false negatives and concerns for diagnostic inaccuracy with FNA.⁸ Although data were mixed, Shin and colleagues reported higher incidence of false negative FNA results in larger nodules.⁸ Given the authors’ findings and earlier conflicting results, the decision for surgical intervention cannot be made solely on nodule size and requires consideration of additional factors including FNA results, nodule characteristics, patient risk factors, and patient preference.

Cancer and cancer-related treatment can cause a myriad of adverse effects.^1,2 Early identification and management of these symptoms is paramount to the success of cancer treatment completion; however, clinic and telephonic strategies for addressing symptoms often result in delays in care.¹ New strategies for patient engagement in the management of cancer and treatment-related symptoms are needed.

The use of online self-management tools can result in improvement in symptoms, reduce cancer symptom distress, improve quality-of-life, and improve medication adherence.^3-9 A meta-analysis concluded that online interventions showed promise, but optimizing interventions would require additional research.¹⁰ Another meta-analysis found that online self-management was effective in managing several symptoms.¹¹ An e-health method of collecting patient self-reported symptoms has been found to be acceptable to patients and feasible for use.^12-14 We postulated that a mobile text messaging strategy may be an effective modality for augmenting symptom management for cancer patients in real time.

In the US Departmant of Veterans Affairs (VA), “Annie,” a self-care tool utilizing a text-messaging system has been implemented. Annie was developed modeling “Flo,” a messaging system in the United Kingdom that has been used for case management of chronic obstructive pulmonary disease, heart failure, stress incontinence, asthma, as a medication reminder tool, and to provide support for weight loss or post-operatively.^15-17 Using Annie in the US, veterans have the ability to receive and track health information. Use of the Annie program has demonstrated improved continuous positive airway pressure monitor utilization in veterans with traumatic brain injury.¹⁸ Other uses within the Veterans Health Administration (VHA) include assisting patients with anger management, liver disease, anxiety, asthma, diabetes, HIV, hypertension, weight loss, and smoking cessation.

Methods

The Hematology/Oncology division of the Minneapolis VA Healthcare System (MVAHCS) is a tertiary care facility that administers about 260 new chemotherapy regimens annually. The MVAHCS interdisciplinary hematology/oncology group initiated a quality improvement project to determine the feasibility, acceptability, and experience of tailoring the Annie tool for self-management of cancer symptoms. The group consisted of 2 physicians, 3 advanced practice registered nurses, 1 physician assistant, 2 registered nurses, and 2 Annie program team members.

We first created a symptom management pilot protocol as a result of multidisciplinary team discussions. Examples of discussion points for consideration included, but were not limited to, timing of texts, amount of information to ask for and provide, what potential symptoms to consider, and which patient population to pilot first.

Results

Through screening new patient consults or those referred for chemotherapy education, 15 male veterans enrolled in the symptom monitoring program over an 8 month period. There were additional patients who were not offered the program or chose not to participate; often due to not having texting capabilities on their phone or not liking the texting feature. The majority of those who participated in the program (n = 14) were enrolled at the start of Cycle 1; the other patient was enrolled at the start of Cycle 2. Patients were enrolled an average of 89 days (range 8-204). Average response rate was 84.2% (range 30-100%).

Although symptoms were not reviewed in real time, we reviewed responses to determine the utilization of the instructions given for the program. No veteran had 0 symptoms reported. There were numerous occurrences of a score of 1 or 2. Many of these patients had baseline symptoms due to their underlying cancer. A score of 3 or 4 on the system prompted the patient to call the clinic or go to the ED. Seven patients (some with multiple occurrences) were prompted to call; only 4 of these made the follow-up call to the clinic. All were offered a same day visit, but each declined. Only 1 patient reported a symptom on a day not prompted for that symptom. Symptoms that were reported are listed in order of frequency: fatigue, appetite loss, numbness, pain, mouth sore, and breathing difficulty. There were no visits to the ED.

Program Evaluation

An evaluation was conducted 30 to 60 days after program enrollment. We elicited feedback to determine who was reading and responding to the text message: the patient, a family member, or a caregiver; whether they found the prompts helpful and took action; how they felt about the number of texts; if they felt the program was helpful; and any other feedback that would improve the program. In general, the patients (8) answered the texts independently. In 4 cases, the spouse answered the texts, and 3 patients answered the texts together with their spouses. Most patients (11) found the amount of texting to be “just right.” However, 3 found it to be too many texts and 1 didn’t find the amount of texting to be enough.

Three veterans did not have enough symptoms to feel the program was of benefit to them, but they did feel it would have been helpful if they had been more symptomatic. One veteran recalled taking loperamide as needed, as a result of prompting. No veterans felt as though the texting feature was difficult to use; and overall, were very positive about the program. Several appreciated receiving messages that validated when they were doing well, and they felt empowered by self-management. One of the spouses was a registered nurse and found the information too basic to be of use.

Discussion

Initial evaluation of the program via survey found no technology challenges. Patients have been very positive about the program including ease of use, appreciation of messages that validated when they were doing well, empowerment of self-management, and some utilization of the texting advice for symptom management. Educational hyperlinks for constipation, fatigue, diarrhea, and nausea/vomiting were added after this evaluation, and patients felt that these additions provided a higher level of education.

Staff time for this intervention was minimal. A nurse navigator offered the texting program to the patient during chemotherapy education, along with some instructions, which generally took about 5 minutes. One of the Annie program staff enrolled the patient. From that point forward, this was a self-management tool, beyond checking to ensure that the patient was successful in starting the program and evaluating use for the purposes of this quality improvement project. This self-management tool did not replace any other mechanism that a patient would normally have in our department for seeking help for symptoms. The MVAHSC typical process for symptom management is to have patients call a 24/7 nurse line. If the triage nurse feels the symptoms are related to the patient’s cancer or cancer treatment, they are referred to the physician assistant who is assigned to take those calls and has the option to see the patient the same day. Patients could continue to call the nurse line or speak with providers at the next appointment at their discretion.

Conclusion

Although Annie has the option of using either text messaging or a mobile application, this project only utilized text messaging. The study by Basch and colleagues was the closest randomized trial we could identify to compare to our quality improvement intervention.⁵ The 2 main, distinct differences were that Basch and colleagues utilized online monitoring; and nurses were utilized to screen and intervene on responses, as appropriate.

The ability of our program to text patients without the use of an application or tablet, may enable more patients to participate due to ease of use. There would be no increased in expected workload for clinical staff, and may lead to decreased call burden. Since our program is automated, while still providing patients with the option to call and speak with a staff member as needed, this is a cost-effective, first-line option for symptom management for those experiencing cancer-related symptoms. We believe this text messaging tool can have system wide use and benefit throughout the VHA.

Cancer and cancer-related treatment can cause a myriad of adverse effects.^1,2 Early identification and management of these symptoms is paramount to the success of cancer treatment completion; however, clinic and telephonic strategies for addressing symptoms often result in delays in care.¹ New strategies for patient engagement in the management of cancer and treatment-related symptoms are needed.

The use of online self-management tools can result in improvement in symptoms, reduce cancer symptom distress, improve quality-of-life, and improve medication adherence.^3-9 A meta-analysis concluded that online interventions showed promise, but optimizing interventions would require additional research.¹⁰ Another meta-analysis found that online self-management was effective in managing several symptoms.¹¹ An e-health method of collecting patient self-reported symptoms has been found to be acceptable to patients and feasible for use.^12-14 We postulated that a mobile text messaging strategy may be an effective modality for augmenting symptom management for cancer patients in real time.

In the US Departmant of Veterans Affairs (VA), “Annie,” a self-care tool utilizing a text-messaging system has been implemented. Annie was developed modeling “Flo,” a messaging system in the United Kingdom that has been used for case management of chronic obstructive pulmonary disease, heart failure, stress incontinence, asthma, as a medication reminder tool, and to provide support for weight loss or post-operatively.^15-17 Using Annie in the US, veterans have the ability to receive and track health information. Use of the Annie program has demonstrated improved continuous positive airway pressure monitor utilization in veterans with traumatic brain injury.¹⁸ Other uses within the Veterans Health Administration (VHA) include assisting patients with anger management, liver disease, anxiety, asthma, diabetes, HIV, hypertension, weight loss, and smoking cessation.

Methods

The Hematology/Oncology division of the Minneapolis VA Healthcare System (MVAHCS) is a tertiary care facility that administers about 260 new chemotherapy regimens annually. The MVAHCS interdisciplinary hematology/oncology group initiated a quality improvement project to determine the feasibility, acceptability, and experience of tailoring the Annie tool for self-management of cancer symptoms. The group consisted of 2 physicians, 3 advanced practice registered nurses, 1 physician assistant, 2 registered nurses, and 2 Annie program team members.

We first created a symptom management pilot protocol as a result of multidisciplinary team discussions. Examples of discussion points for consideration included, but were not limited to, timing of texts, amount of information to ask for and provide, what potential symptoms to consider, and which patient population to pilot first.

Results

Through screening new patient consults or those referred for chemotherapy education, 15 male veterans enrolled in the symptom monitoring program over an 8 month period. There were additional patients who were not offered the program or chose not to participate; often due to not having texting capabilities on their phone or not liking the texting feature. The majority of those who participated in the program (n = 14) were enrolled at the start of Cycle 1; the other patient was enrolled at the start of Cycle 2. Patients were enrolled an average of 89 days (range 8-204). Average response rate was 84.2% (range 30-100%).

Although symptoms were not reviewed in real time, we reviewed responses to determine the utilization of the instructions given for the program. No veteran had 0 symptoms reported. There were numerous occurrences of a score of 1 or 2. Many of these patients had baseline symptoms due to their underlying cancer. A score of 3 or 4 on the system prompted the patient to call the clinic or go to the ED. Seven patients (some with multiple occurrences) were prompted to call; only 4 of these made the follow-up call to the clinic. All were offered a same day visit, but each declined. Only 1 patient reported a symptom on a day not prompted for that symptom. Symptoms that were reported are listed in order of frequency: fatigue, appetite loss, numbness, pain, mouth sore, and breathing difficulty. There were no visits to the ED.

Program Evaluation

An evaluation was conducted 30 to 60 days after program enrollment. We elicited feedback to determine who was reading and responding to the text message: the patient, a family member, or a caregiver; whether they found the prompts helpful and took action; how they felt about the number of texts; if they felt the program was helpful; and any other feedback that would improve the program. In general, the patients (8) answered the texts independently. In 4 cases, the spouse answered the texts, and 3 patients answered the texts together with their spouses. Most patients (11) found the amount of texting to be “just right.” However, 3 found it to be too many texts and 1 didn’t find the amount of texting to be enough.

Three veterans did not have enough symptoms to feel the program was of benefit to them, but they did feel it would have been helpful if they had been more symptomatic. One veteran recalled taking loperamide as needed, as a result of prompting. No veterans felt as though the texting feature was difficult to use; and overall, were very positive about the program. Several appreciated receiving messages that validated when they were doing well, and they felt empowered by self-management. One of the spouses was a registered nurse and found the information too basic to be of use.

Discussion

Initial evaluation of the program via survey found no technology challenges. Patients have been very positive about the program including ease of use, appreciation of messages that validated when they were doing well, empowerment of self-management, and some utilization of the texting advice for symptom management. Educational hyperlinks for constipation, fatigue, diarrhea, and nausea/vomiting were added after this evaluation, and patients felt that these additions provided a higher level of education.

Staff time for this intervention was minimal. A nurse navigator offered the texting program to the patient during chemotherapy education, along with some instructions, which generally took about 5 minutes. One of the Annie program staff enrolled the patient. From that point forward, this was a self-management tool, beyond checking to ensure that the patient was successful in starting the program and evaluating use for the purposes of this quality improvement project. This self-management tool did not replace any other mechanism that a patient would normally have in our department for seeking help for symptoms. The MVAHSC typical process for symptom management is to have patients call a 24/7 nurse line. If the triage nurse feels the symptoms are related to the patient’s cancer or cancer treatment, they are referred to the physician assistant who is assigned to take those calls and has the option to see the patient the same day. Patients could continue to call the nurse line or speak with providers at the next appointment at their discretion.

Conclusion

Although Annie has the option of using either text messaging or a mobile application, this project only utilized text messaging. The study by Basch and colleagues was the closest randomized trial we could identify to compare to our quality improvement intervention.⁵ The 2 main, distinct differences were that Basch and colleagues utilized online monitoring; and nurses were utilized to screen and intervene on responses, as appropriate.

The ability of our program to text patients without the use of an application or tablet, may enable more patients to participate due to ease of use. There would be no increased in expected workload for clinical staff, and may lead to decreased call burden. Since our program is automated, while still providing patients with the option to call and speak with a staff member as needed, this is a cost-effective, first-line option for symptom management for those experiencing cancer-related symptoms. We believe this text messaging tool can have system wide use and benefit throughout the VHA.

Cancer and cancer-related treatment can cause a myriad of adverse effects.^1,2 Early identification and management of these symptoms is paramount to the success of cancer treatment completion; however, clinic and telephonic strategies for addressing symptoms often result in delays in care.¹ New strategies for patient engagement in the management of cancer and treatment-related symptoms are needed.

The use of online self-management tools can result in improvement in symptoms, reduce cancer symptom distress, improve quality-of-life, and improve medication adherence.^3-9 A meta-analysis concluded that online interventions showed promise, but optimizing interventions would require additional research.¹⁰ Another meta-analysis found that online self-management was effective in managing several symptoms.¹¹ An e-health method of collecting patient self-reported symptoms has been found to be acceptable to patients and feasible for use.^12-14 We postulated that a mobile text messaging strategy may be an effective modality for augmenting symptom management for cancer patients in real time.

In the US Departmant of Veterans Affairs (VA), “Annie,” a self-care tool utilizing a text-messaging system has been implemented. Annie was developed modeling “Flo,” a messaging system in the United Kingdom that has been used for case management of chronic obstructive pulmonary disease, heart failure, stress incontinence, asthma, as a medication reminder tool, and to provide support for weight loss or post-operatively.^15-17 Using Annie in the US, veterans have the ability to receive and track health information. Use of the Annie program has demonstrated improved continuous positive airway pressure monitor utilization in veterans with traumatic brain injury.¹⁸ Other uses within the Veterans Health Administration (VHA) include assisting patients with anger management, liver disease, anxiety, asthma, diabetes, HIV, hypertension, weight loss, and smoking cessation.

Methods

The Hematology/Oncology division of the Minneapolis VA Healthcare System (MVAHCS) is a tertiary care facility that administers about 260 new chemotherapy regimens annually. The MVAHCS interdisciplinary hematology/oncology group initiated a quality improvement project to determine the feasibility, acceptability, and experience of tailoring the Annie tool for self-management of cancer symptoms. The group consisted of 2 physicians, 3 advanced practice registered nurses, 1 physician assistant, 2 registered nurses, and 2 Annie program team members.

We first created a symptom management pilot protocol as a result of multidisciplinary team discussions. Examples of discussion points for consideration included, but were not limited to, timing of texts, amount of information to ask for and provide, what potential symptoms to consider, and which patient population to pilot first.

Results

Through screening new patient consults or those referred for chemotherapy education, 15 male veterans enrolled in the symptom monitoring program over an 8 month period. There were additional patients who were not offered the program or chose not to participate; often due to not having texting capabilities on their phone or not liking the texting feature. The majority of those who participated in the program (n = 14) were enrolled at the start of Cycle 1; the other patient was enrolled at the start of Cycle 2. Patients were enrolled an average of 89 days (range 8-204). Average response rate was 84.2% (range 30-100%).

Although symptoms were not reviewed in real time, we reviewed responses to determine the utilization of the instructions given for the program. No veteran had 0 symptoms reported. There were numerous occurrences of a score of 1 or 2. Many of these patients had baseline symptoms due to their underlying cancer. A score of 3 or 4 on the system prompted the patient to call the clinic or go to the ED. Seven patients (some with multiple occurrences) were prompted to call; only 4 of these made the follow-up call to the clinic. All were offered a same day visit, but each declined. Only 1 patient reported a symptom on a day not prompted for that symptom. Symptoms that were reported are listed in order of frequency: fatigue, appetite loss, numbness, pain, mouth sore, and breathing difficulty. There were no visits to the ED.

Program Evaluation

An evaluation was conducted 30 to 60 days after program enrollment. We elicited feedback to determine who was reading and responding to the text message: the patient, a family member, or a caregiver; whether they found the prompts helpful and took action; how they felt about the number of texts; if they felt the program was helpful; and any other feedback that would improve the program. In general, the patients (8) answered the texts independently. In 4 cases, the spouse answered the texts, and 3 patients answered the texts together with their spouses. Most patients (11) found the amount of texting to be “just right.” However, 3 found it to be too many texts and 1 didn’t find the amount of texting to be enough.

Three veterans did not have enough symptoms to feel the program was of benefit to them, but they did feel it would have been helpful if they had been more symptomatic. One veteran recalled taking loperamide as needed, as a result of prompting. No veterans felt as though the texting feature was difficult to use; and overall, were very positive about the program. Several appreciated receiving messages that validated when they were doing well, and they felt empowered by self-management. One of the spouses was a registered nurse and found the information too basic to be of use.

Discussion

Initial evaluation of the program via survey found no technology challenges. Patients have been very positive about the program including ease of use, appreciation of messages that validated when they were doing well, empowerment of self-management, and some utilization of the texting advice for symptom management. Educational hyperlinks for constipation, fatigue, diarrhea, and nausea/vomiting were added after this evaluation, and patients felt that these additions provided a higher level of education.

Staff time for this intervention was minimal. A nurse navigator offered the texting program to the patient during chemotherapy education, along with some instructions, which generally took about 5 minutes. One of the Annie program staff enrolled the patient. From that point forward, this was a self-management tool, beyond checking to ensure that the patient was successful in starting the program and evaluating use for the purposes of this quality improvement project. This self-management tool did not replace any other mechanism that a patient would normally have in our department for seeking help for symptoms. The MVAHSC typical process for symptom management is to have patients call a 24/7 nurse line. If the triage nurse feels the symptoms are related to the patient’s cancer or cancer treatment, they are referred to the physician assistant who is assigned to take those calls and has the option to see the patient the same day. Patients could continue to call the nurse line or speak with providers at the next appointment at their discretion.

Conclusion

Although Annie has the option of using either text messaging or a mobile application, this project only utilized text messaging. The study by Basch and colleagues was the closest randomized trial we could identify to compare to our quality improvement intervention.⁵ The 2 main, distinct differences were that Basch and colleagues utilized online monitoring; and nurses were utilized to screen and intervene on responses, as appropriate.

The ability of our program to text patients without the use of an application or tablet, may enable more patients to participate due to ease of use. There would be no increased in expected workload for clinical staff, and may lead to decreased call burden. Since our program is automated, while still providing patients with the option to call and speak with a staff member as needed, this is a cost-effective, first-line option for symptom management for those experiencing cancer-related symptoms. We believe this text messaging tool can have system wide use and benefit throughout the VHA.

Central nervous system (CNS) lymphoma can be classified into 2 categories: primary CNS lymphoma (PCNSL), which includes disease limited to brain, eyes, spinal cord; and leptomeninges without coexisting or previous systemic lymphoma. Secondary CNS lymphoma (SCNSL) is essentially metastatic disease from a systemic primary site.¹ The focus of this case presentation is PCNSL, with an emphasis on imaging characteristics and differential diagnosis.

The median age at diagnosis for PCNSL is 65 years, and the overall incidence has been decreasing since the mid-1990s, likely related to the increased use of highly-active antiretroviral therapy (HAART) in patients with AIDS.^2,3 Although overall incidence has decreased, incidence in the elderly population has increased.⁴ Historically, PCNSL has been considered an AIDS-defining illness.⁵ These patients, among other immunocompromised patients, such as those on chronic immunosuppressive therapy, are at a higher risk for developing the malignancy.⁶

Clinical presentation varies because of the location of CNS involvement and may present with headache, mood or personality disturbances, or focal neurologic deficits. Seizures are less likely due to the tendency of PCNSL to spare gray matter. Initial workup generally includes a head computed tomography (CT) scan, as well as a contrast-enhanced magnetic resonance image (MRI), which may help direct clinicians to the appropriate diagnosis. However, there is significant overlap between the imaging characteristics of PCNSL and numerous other disease processes, including glioblastoma and demyelination. The imaging characteristics of PCNSL are considerably different depending on the patient’s immune status.⁷

This case illustrates a rare presentation of PCNSL in an immunocompetent patient whose MRI characteristics were seemingly more consistent with those seen in patients with immunodeficiency. The main differential diagnoses and key imaging characteristics, which may help obtain accurate diagnosis, will be discussed.

Case Presentation

A 72-year-old male veteran presented with a 2-month history of subjective weakness in his upper and lower extremities progressing to multiple falls at home. He had no significant medical history other than a thymectomy at age 15 for an enlarged thymus, which per patient report, was benign. An initial laboratory test that included vitamin B₁₂, folate, thyroid-stimulating hormone, complete blood cell count, and comprehensive metabolic panel, were unremarkable, with a white blood cell count of 8.5 K/uL. The initial neurologic evaluation did not show any focal neurologic deficits; however, during the initial hospital stay, the patient developed increasing lower extremity weakness on examination. A noncontrast CT head scan showed extensive nonspecific hypodensities within the periventricular white matter (Figure 1). A contrast-enhanced MRI showed enhancing lesions involving the corpus callosum, left cerebral peduncle, and right temporal lobe (Figures 2, 3, and 4). These lesions also exhibited significant restricted diffusion and a mild amount of surrounding vasogenic edema. The working diagnosis after the MRI included primary CNS lymphoma, multifocal glioblastoma, and tumefactive demyelinating disease. The patient was started on IV steroids and transferred for neurosurgical evaluation and biopsy at an outside hospital. The frontal lesion was biopsied, and the initial frozen section was consistent with lymphoma; a bone marrow biopsy was negative. The workup for immunodeficiency was unremarkable. Pathology revealed high-grade B-cell lymphoma, and the patient began a chemotherapy regimen.

Discussion

The workup of altered mental status, focal neurologic deficits, headaches, or other neurologic conditions often begins with a noncontrast CT scan. On CT, PCNSL generally appears isodense to hyperdense to gray matter, but appearance is variable. The often hyperdense appearance is attributable to the hypercellular nature of lymphoma. Many times, as in this case, CT may show only vague hypodensities, some of which may be associated with surrounding edema. This presentation is nonspecific and may be seen with advancing age due to changes of chronic microvascular ischemia as well as demyelination, other malignancies, and several other disease processes, both benign and malignant. After the initial CT scan, further workup requires evaluation with MRI. PCNSL exhibits restricted diffusion and variable signal intensity on T2-weighted imaging.

PCNSL is frequently centrally located within the periventricular white matter, often within the frontal lobe but can involve other lobes, the basal ganglia, brainstem, cerebellum, or less likely, the spinal canal.⁷ Contrary to primary CNS disease, secondary lymphoma within the CNS has been described classically as affecting a leptomeningeal (pia and arachnoid mater) distribution two-thirds of the time, with parenchymal involvement occurring in the other one-third of patients. A recent study by Malikova and colleagues found parenchymal involvement may be much more common than previously thought.¹ Leptomeningeal spread of disease often involves the cranial nerves, subependymal regions, spinal cord, or spinal nerve roots. Dural involvement in primary or secondary lymphoma is rare.

PCNSL nearly always shows enhancement. Linear enhancement along perivascular spaces is highly characteristic of PCNSL. The typical appearance of PCNSL associated with immunodeficiency varies from that seen in an otherwise immunocompetent patient. Patients with immunodeficiency usually have multifocal involvement, central necrosis leading to a ring enhancement appearance, and have more propensity for spontaneous hemorrhage.⁷ Immunocompetent patients are less likely to present with multifocal disease and rarely show ring enhancement. Also, spontaneous hemorrhage is rare in immunocompetent patients. In our case, extensive multifocal involvement was present, whereas typically immunocompetent patients will present with a solitary homogeneously enhancing parenchymal mass.

The primary differential for PCNSL includes malignant glioma, tumefactive multiple sclerosis, metastatic disease, and in an immunocompromised patient, toxoplasmosis. The degree of associated vasogenic edema and mass effect is generally lower in PCNSL than that of malignant gliomas and metastasis. Also, PCNSL tends to spare the cerebral cortex.⁸

Classically, PCNSL, malignant gliomas, and demyelinating disease have been considered the main differential for lesions that cross midline and involve both cerebral hemispheres. Lymphoma generally exhibits more restricted diffusion than malignant gliomas and metastasis, attributable to the highly cellular nature of lymphoma.⁷ Tumefactive multiple sclerosis is associated with relatively minimal mass effect for lesion size and exhibits less restricted diffusion values when compared to high grade gliomas and PCNSL. One fairly specific finding for tumefactive demyelinating lesions is incomplete rim enhancement.⁹ Unfortunately, an MRI is not reliable in differentiating these entities, and biopsy is required for definitive diagnosis. Many advancing imaging modalities may help provide the correct diagnosis of PCNSL, including diffusion-weighted and apparent diffusion coefficient imaging, diffusion tensor imaging, MR spectroscopy and PET imaging.⁷

Conclusion

With the increasing use of HAART, the paradigm of PCNSL is shifting toward one predominantly affecting immunocompetent patients. PCNSL should be considered in any patient with multiple enhancing CNS lesions, regardless of immune status. Several key imaging characteristics may help differentiate PCNSL and other disease processes; however, at this time, biopsy is recommended for definitive diagnosis.

Central nervous system (CNS) lymphoma can be classified into 2 categories: primary CNS lymphoma (PCNSL), which includes disease limited to brain, eyes, spinal cord; and leptomeninges without coexisting or previous systemic lymphoma. Secondary CNS lymphoma (SCNSL) is essentially metastatic disease from a systemic primary site.¹ The focus of this case presentation is PCNSL, with an emphasis on imaging characteristics and differential diagnosis.

The median age at diagnosis for PCNSL is 65 years, and the overall incidence has been decreasing since the mid-1990s, likely related to the increased use of highly-active antiretroviral therapy (HAART) in patients with AIDS.^2,3 Although overall incidence has decreased, incidence in the elderly population has increased.⁴ Historically, PCNSL has been considered an AIDS-defining illness.⁵ These patients, among other immunocompromised patients, such as those on chronic immunosuppressive therapy, are at a higher risk for developing the malignancy.⁶

Clinical presentation varies because of the location of CNS involvement and may present with headache, mood or personality disturbances, or focal neurologic deficits. Seizures are less likely due to the tendency of PCNSL to spare gray matter. Initial workup generally includes a head computed tomography (CT) scan, as well as a contrast-enhanced magnetic resonance image (MRI), which may help direct clinicians to the appropriate diagnosis. However, there is significant overlap between the imaging characteristics of PCNSL and numerous other disease processes, including glioblastoma and demyelination. The imaging characteristics of PCNSL are considerably different depending on the patient’s immune status.⁷

This case illustrates a rare presentation of PCNSL in an immunocompetent patient whose MRI characteristics were seemingly more consistent with those seen in patients with immunodeficiency. The main differential diagnoses and key imaging characteristics, which may help obtain accurate diagnosis, will be discussed.

Case Presentation

A 72-year-old male veteran presented with a 2-month history of subjective weakness in his upper and lower extremities progressing to multiple falls at home. He had no significant medical history other than a thymectomy at age 15 for an enlarged thymus, which per patient report, was benign. An initial laboratory test that included vitamin B₁₂, folate, thyroid-stimulating hormone, complete blood cell count, and comprehensive metabolic panel, were unremarkable, with a white blood cell count of 8.5 K/uL. The initial neurologic evaluation did not show any focal neurologic deficits; however, during the initial hospital stay, the patient developed increasing lower extremity weakness on examination. A noncontrast CT head scan showed extensive nonspecific hypodensities within the periventricular white matter (Figure 1). A contrast-enhanced MRI showed enhancing lesions involving the corpus callosum, left cerebral peduncle, and right temporal lobe (Figures 2, 3, and 4). These lesions also exhibited significant restricted diffusion and a mild amount of surrounding vasogenic edema. The working diagnosis after the MRI included primary CNS lymphoma, multifocal glioblastoma, and tumefactive demyelinating disease. The patient was started on IV steroids and transferred for neurosurgical evaluation and biopsy at an outside hospital. The frontal lesion was biopsied, and the initial frozen section was consistent with lymphoma; a bone marrow biopsy was negative. The workup for immunodeficiency was unremarkable. Pathology revealed high-grade B-cell lymphoma, and the patient began a chemotherapy regimen.

Discussion

The workup of altered mental status, focal neurologic deficits, headaches, or other neurologic conditions often begins with a noncontrast CT scan. On CT, PCNSL generally appears isodense to hyperdense to gray matter, but appearance is variable. The often hyperdense appearance is attributable to the hypercellular nature of lymphoma. Many times, as in this case, CT may show only vague hypodensities, some of which may be associated with surrounding edema. This presentation is nonspecific and may be seen with advancing age due to changes of chronic microvascular ischemia as well as demyelination, other malignancies, and several other disease processes, both benign and malignant. After the initial CT scan, further workup requires evaluation with MRI. PCNSL exhibits restricted diffusion and variable signal intensity on T2-weighted imaging.

PCNSL is frequently centrally located within the periventricular white matter, often within the frontal lobe but can involve other lobes, the basal ganglia, brainstem, cerebellum, or less likely, the spinal canal.⁷ Contrary to primary CNS disease, secondary lymphoma within the CNS has been described classically as affecting a leptomeningeal (pia and arachnoid mater) distribution two-thirds of the time, with parenchymal involvement occurring in the other one-third of patients. A recent study by Malikova and colleagues found parenchymal involvement may be much more common than previously thought.¹ Leptomeningeal spread of disease often involves the cranial nerves, subependymal regions, spinal cord, or spinal nerve roots. Dural involvement in primary or secondary lymphoma is rare.

PCNSL nearly always shows enhancement. Linear enhancement along perivascular spaces is highly characteristic of PCNSL. The typical appearance of PCNSL associated with immunodeficiency varies from that seen in an otherwise immunocompetent patient. Patients with immunodeficiency usually have multifocal involvement, central necrosis leading to a ring enhancement appearance, and have more propensity for spontaneous hemorrhage.⁷ Immunocompetent patients are less likely to present with multifocal disease and rarely show ring enhancement. Also, spontaneous hemorrhage is rare in immunocompetent patients. In our case, extensive multifocal involvement was present, whereas typically immunocompetent patients will present with a solitary homogeneously enhancing parenchymal mass.

The primary differential for PCNSL includes malignant glioma, tumefactive multiple sclerosis, metastatic disease, and in an immunocompromised patient, toxoplasmosis. The degree of associated vasogenic edema and mass effect is generally lower in PCNSL than that of malignant gliomas and metastasis. Also, PCNSL tends to spare the cerebral cortex.⁸

Classically, PCNSL, malignant gliomas, and demyelinating disease have been considered the main differential for lesions that cross midline and involve both cerebral hemispheres. Lymphoma generally exhibits more restricted diffusion than malignant gliomas and metastasis, attributable to the highly cellular nature of lymphoma.⁷ Tumefactive multiple sclerosis is associated with relatively minimal mass effect for lesion size and exhibits less restricted diffusion values when compared to high grade gliomas and PCNSL. One fairly specific finding for tumefactive demyelinating lesions is incomplete rim enhancement.⁹ Unfortunately, an MRI is not reliable in differentiating these entities, and biopsy is required for definitive diagnosis. Many advancing imaging modalities may help provide the correct diagnosis of PCNSL, including diffusion-weighted and apparent diffusion coefficient imaging, diffusion tensor imaging, MR spectroscopy and PET imaging.⁷

Conclusion

With the increasing use of HAART, the paradigm of PCNSL is shifting toward one predominantly affecting immunocompetent patients. PCNSL should be considered in any patient with multiple enhancing CNS lesions, regardless of immune status. Several key imaging characteristics may help differentiate PCNSL and other disease processes; however, at this time, biopsy is recommended for definitive diagnosis.

Central nervous system (CNS) lymphoma can be classified into 2 categories: primary CNS lymphoma (PCNSL), which includes disease limited to brain, eyes, spinal cord; and leptomeninges without coexisting or previous systemic lymphoma. Secondary CNS lymphoma (SCNSL) is essentially metastatic disease from a systemic primary site.¹ The focus of this case presentation is PCNSL, with an emphasis on imaging characteristics and differential diagnosis.

The median age at diagnosis for PCNSL is 65 years, and the overall incidence has been decreasing since the mid-1990s, likely related to the increased use of highly-active antiretroviral therapy (HAART) in patients with AIDS.^2,3 Although overall incidence has decreased, incidence in the elderly population has increased.⁴ Historically, PCNSL has been considered an AIDS-defining illness.⁵ These patients, among other immunocompromised patients, such as those on chronic immunosuppressive therapy, are at a higher risk for developing the malignancy.⁶

Clinical presentation varies because of the location of CNS involvement and may present with headache, mood or personality disturbances, or focal neurologic deficits. Seizures are less likely due to the tendency of PCNSL to spare gray matter. Initial workup generally includes a head computed tomography (CT) scan, as well as a contrast-enhanced magnetic resonance image (MRI), which may help direct clinicians to the appropriate diagnosis. However, there is significant overlap between the imaging characteristics of PCNSL and numerous other disease processes, including glioblastoma and demyelination. The imaging characteristics of PCNSL are considerably different depending on the patient’s immune status.⁷

This case illustrates a rare presentation of PCNSL in an immunocompetent patient whose MRI characteristics were seemingly more consistent with those seen in patients with immunodeficiency. The main differential diagnoses and key imaging characteristics, which may help obtain accurate diagnosis, will be discussed.

Case Presentation

A 72-year-old male veteran presented with a 2-month history of subjective weakness in his upper and lower extremities progressing to multiple falls at home. He had no significant medical history other than a thymectomy at age 15 for an enlarged thymus, which per patient report, was benign. An initial laboratory test that included vitamin B₁₂, folate, thyroid-stimulating hormone, complete blood cell count, and comprehensive metabolic panel, were unremarkable, with a white blood cell count of 8.5 K/uL. The initial neurologic evaluation did not show any focal neurologic deficits; however, during the initial hospital stay, the patient developed increasing lower extremity weakness on examination. A noncontrast CT head scan showed extensive nonspecific hypodensities within the periventricular white matter (Figure 1). A contrast-enhanced MRI showed enhancing lesions involving the corpus callosum, left cerebral peduncle, and right temporal lobe (Figures 2, 3, and 4). These lesions also exhibited significant restricted diffusion and a mild amount of surrounding vasogenic edema. The working diagnosis after the MRI included primary CNS lymphoma, multifocal glioblastoma, and tumefactive demyelinating disease. The patient was started on IV steroids and transferred for neurosurgical evaluation and biopsy at an outside hospital. The frontal lesion was biopsied, and the initial frozen section was consistent with lymphoma; a bone marrow biopsy was negative. The workup for immunodeficiency was unremarkable. Pathology revealed high-grade B-cell lymphoma, and the patient began a chemotherapy regimen.

Discussion

The workup of altered mental status, focal neurologic deficits, headaches, or other neurologic conditions often begins with a noncontrast CT scan. On CT, PCNSL generally appears isodense to hyperdense to gray matter, but appearance is variable. The often hyperdense appearance is attributable to the hypercellular nature of lymphoma. Many times, as in this case, CT may show only vague hypodensities, some of which may be associated with surrounding edema. This presentation is nonspecific and may be seen with advancing age due to changes of chronic microvascular ischemia as well as demyelination, other malignancies, and several other disease processes, both benign and malignant. After the initial CT scan, further workup requires evaluation with MRI. PCNSL exhibits restricted diffusion and variable signal intensity on T2-weighted imaging.

PCNSL is frequently centrally located within the periventricular white matter, often within the frontal lobe but can involve other lobes, the basal ganglia, brainstem, cerebellum, or less likely, the spinal canal.⁷ Contrary to primary CNS disease, secondary lymphoma within the CNS has been described classically as affecting a leptomeningeal (pia and arachnoid mater) distribution two-thirds of the time, with parenchymal involvement occurring in the other one-third of patients. A recent study by Malikova and colleagues found parenchymal involvement may be much more common than previously thought.¹ Leptomeningeal spread of disease often involves the cranial nerves, subependymal regions, spinal cord, or spinal nerve roots. Dural involvement in primary or secondary lymphoma is rare.

PCNSL nearly always shows enhancement. Linear enhancement along perivascular spaces is highly characteristic of PCNSL. The typical appearance of PCNSL associated with immunodeficiency varies from that seen in an otherwise immunocompetent patient. Patients with immunodeficiency usually have multifocal involvement, central necrosis leading to a ring enhancement appearance, and have more propensity for spontaneous hemorrhage.⁷ Immunocompetent patients are less likely to present with multifocal disease and rarely show ring enhancement. Also, spontaneous hemorrhage is rare in immunocompetent patients. In our case, extensive multifocal involvement was present, whereas typically immunocompetent patients will present with a solitary homogeneously enhancing parenchymal mass.

The primary differential for PCNSL includes malignant glioma, tumefactive multiple sclerosis, metastatic disease, and in an immunocompromised patient, toxoplasmosis. The degree of associated vasogenic edema and mass effect is generally lower in PCNSL than that of malignant gliomas and metastasis. Also, PCNSL tends to spare the cerebral cortex.⁸

Classically, PCNSL, malignant gliomas, and demyelinating disease have been considered the main differential for lesions that cross midline and involve both cerebral hemispheres. Lymphoma generally exhibits more restricted diffusion than malignant gliomas and metastasis, attributable to the highly cellular nature of lymphoma.⁷ Tumefactive multiple sclerosis is associated with relatively minimal mass effect for lesion size and exhibits less restricted diffusion values when compared to high grade gliomas and PCNSL. One fairly specific finding for tumefactive demyelinating lesions is incomplete rim enhancement.⁹ Unfortunately, an MRI is not reliable in differentiating these entities, and biopsy is required for definitive diagnosis. Many advancing imaging modalities may help provide the correct diagnosis of PCNSL, including diffusion-weighted and apparent diffusion coefficient imaging, diffusion tensor imaging, MR spectroscopy and PET imaging.⁷

Conclusion

With the increasing use of HAART, the paradigm of PCNSL is shifting toward one predominantly affecting immunocompetent patients. PCNSL should be considered in any patient with multiple enhancing CNS lesions, regardless of immune status. Several key imaging characteristics may help differentiate PCNSL and other disease processes; however, at this time, biopsy is recommended for definitive diagnosis.

Colorectal cancer is the second most common cause of cancer death in the US, with one-third of all colorectal cancers occurring within the rectum. Each year, an estimated 40000 Americans are diagnosed with rectal cancer (RC).^1,2 The prognosis and treatment of RC depends on both T and N stage at the time of diagnosis.^3-5 According to the most recent National Comprehensive Cancer Network guidelines from May 2019, patients with T1 to T2N0 tumors should undergo transanal or transabdominal surgery upfront, whereas patients with T3 to T4N0 or any TN1 to 2 should start with neoadjuvant therapy for better locoregional control, followed by surgery.⁶ Therefore, the appropriate management of RC requires adequate staging.

Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and computed tomography (CT) are the imaging techniques currently used to stage RC. In a meta-analysis of 90 articles published between 1985 and 2002 that compared the 3 radiologic modalities, Bipat and colleagues found that MRI and EUS had a similar sensitivity of 94%, whereas the specificity of EUS (86%) was significantly higher than that of MRI (69%) for muscularis propria invasion.⁷ CT was performed only in a limited number of trials because CT was considered inadequate to assess early T stage. For perirectal tissue invasion, the sensitivity of EUS was statistically higher than that of CT and MRI imaging: 90% compared with 79% and 82%, respectively. The specificity estimates for EUS, CT, and MRI were comparable: 75%, 78%, and 76%, respectively. The respective sensitivity and specificity of the 3 imaging modalities to evaluate lymph nodes were also comparable: EUS, 67% and 78%; CT, 55% and 74%; and MRI, 66% and 76%.

The role of EUS in the diagnosis and treatment of RC has long been validated.^1,2-5 A meta-analysis of 42 studies involving 5039 patients found EUS to be highly accurate for differentiating various T stages.⁸ However, EUS cannot assess iliac and mesenteric lymph nodes or posterior tumor extension beyond endopelvic fascia in advanced RC. Notable heterogeneity was found among the studies in the meta-analyses with regard to the type of equipment used for staging, as well as the criteria used to assess the depth of penetration and nodal status. The recent introduction of phased-array coils and the development of T2-weighted fast spin sequences have improved the resolution of MRI. The MERCURY trial showed that extension of tumor to within 1 mm of the circumferential margin on high-resolution MRI correctly predicted margin involvement at the time of surgery in 92% of the patients.⁹ In the retrospective study by Balyasnikova and colleagues, MRI was found to correctly identify partial submucosal invasion and suitability for local excision in 89% of the cases.¹⁰

Therefore, both EUS and MRI are useful, more so than CT, in assessment of the depth of tumor invasion, nodal staging, and predicting the circumferential resection margin. The use of EUS, however, does not preclude the use of MRI, or vice versa. Rather, the 2 modalities can complement each other in staging and proper patient selection for treatment.¹¹

Despite data supporting the value of EUS in staging RC, its use is limited by a high degree of operator dependence and a substantial learning curve,^12-17 which may explain the low EUS accuracy observed in some reports.^7,13,15 Given the presence of recognized alternatives such as MRI, we decided to reevaluate EUS accuracy for the staging of RC outside high-volume specialized centers and prospective clinical trials.

Methods

A retrospective chart review was performed that included all consecutive patients undergoing rectal ultrasound from January 2011 to August 2015 at the US Department of Veterans Affairs Medical Center (VAMC) in Memphis, Tennessee. Sixty-five patients with short-stocked or sessile lesions < 15 cm from anal margin staged T2N0M0 or lower by endorectal ultrasound (ERUS) were included. The patients with neoplasms staged in excess of T2 or N0 were excluded from the study because treatment protocol dictates immediate neoadjuvant treatment, the administration of which would affect subsequent histopathology.

For the 37 patients included in the final analysis, ERUS results were compared with surgical pathology to ascertain accuracy. The resections were performed endoscopically or surgically with a goal of obtaining clear margins. The choice of procedure depended on size, shape, location, and depth of invasion. All patients underwent clinical and endoscopic surveillance with flexible sigmoidoscopy/EUS every 3 to 6 months for the first 2 years. We used 2 different gold standards for surveillance depending on the type of procedure performed to remove the lesion. A pathology report was the gold standard used for patients who underwent surgery. In patients who underwent endoscopic resection, we used the lack of recurrent disease, determined by normal endoscopic and endoscopic ultrasound examination, to signify complete endoscopic resection and therefore adequate staging as an early neoplasm.

Results

From January 2011 to August 2015, 65 rectal ultrasounds were performed. All EUS procedures were performed by 1 physician (C Ruben Tombazzi). All patients had previous endoscopic evaluation and tissue diagnoses. Twenty-eight patients were excluded: 18 had T3 or N1 disease, 2 had T2N0 but refused surgery, 2 had anal cancer, 3 patients with suspected cancer had benign nonneoplastic disease (2 radiation proctitis, 1 normal rectal wall), and 3 underwent EUS for benign tumors (1 ganglioneuroma and 2 lipomas).

Thirty-seven patients were included in the study, 3 of whom were staged as T2N0 and 34 as T1N0 or lower by EUS. All patients were men ranging in age from 43 to 73 years (mean, 59 years). All 37 patients underwent endoscopic or surgical resection of their early rectal neoplasm. The final pathologic evaluation of the specimens demonstrated 14 carcinoid tumors, 11 adenocarcinomas, 6 tubular adenomas with high-grade dysplasia, and 6 benign adenomas. The preoperative EUS staging was confirmed for all patients, with 100% sensitivity, specificity, and accuracy. None of the patients who underwent endoscopic or surgical transanal resection had recurrence, determined by normal endoscopic and endoscopic ultrasound appearance, during a mean of 32.6 months surveillance.

Discussion

EUS has long been a recognized method for T and N staging of RC.^1,3-5,7,8 Our data confirm that, in experienced hands, EUS is highly accurate in the staging of early rectal cancers.

The impact of EUS on the management of RC was demonstrated in a Mayo Clinic prospective blinded study.¹ In that cohort of 80 consecutive patients who had previously had a CT for staging, EUS altered patient management in about 30% of cases. The most common change precipatated by EUS was the indication for additional neoadjuvant treatment.

However, the results have not been as encouraging when ERUS is performed outside of strict research protocol. A multicenter, prospective, country-wide quality assurance study from > 300 German hospitals was designed to assess the diagnostic accuracy of EUS in RC.¹³ Of 29206 patients, 7096 underwent surgery, without neoadjuvant treatment, and were included in the final analysis. The correspondence of tumor invasion with histopathology was 64.7%, with understaging of 18% and overstaging of 17.3%.¹³ These numbers were better in hospitals with greater experience performing ERUS: 73% accuracy in the centers with a case load of > 30 cases per year compared with 63.2% accuracy for the centers with < 10 cases a year. Marusch and colleagues had previously demonstrated an EUS accuracy of 63.3% in a study of 1463 patients with RC in Germany.¹⁴ Another study based out of the UK had similar findings. Ashraf and colleagues performed a database analyses from 20 UK centers and identified 165 patients with RC who underwent ERUS and endoscopic microsurgery.¹⁵ Compared with histopathology, EUS had 57.1% sensitivity, 73% specificity, and 42.9% accuracy for T1 cancers; EUS accuracy was 50% for T2 and 58% for T3 tumors. The authors concluded that the general accuracy of EUS in determining stage was around 50%, the statistical equivalent of flipping a coin.

The low accuracy of EUS observed by German and British multicenter studies^13-15 was attributed to the difference that may exist in clinical trials at specialized centers compared with wider use of EUS in a community setting. As seen by our data, the Memphis VAMC is not a high-volume center for the treatment of RC. However, all our EUS procedures were performed and interpreted by a single operator (C. Ruben Tombazzi) with 18 years of EUS experience. We cannot conclude that no patient was overstaged, as patients receiving a stage of T3N0 or T > N0 received neoadjuvant treatment and were not included. However, we can conclude that no patient was understaged. All patients deemed to be T1 to T2N0 included in our study received accurate staging. Our results are consistent with the high accuracy of EUS reported from other centers with experience in diagnosis and treatment of RC.^1,3-5,17,18

Although EUS is accurate in differentiating T1 from T2 tumors, it cannot reliably differentiate T1 from T0 lesions. In one study, 57.6% of adenomas and 30.7% of carcinomas in situ were staged as T1 on EUS, while almost half of T1 cancers were interpreted as T0.¹⁷ This drawback is a well-known limitation of EUS; although, the misinterpretation does not affect treatment, as both T0 and T1 lesions can be treated successfully by local excision alone, which was the algorithm used for our patients. The choice of the specific procedure for local excision was left to the clinicians and included transanal endoscopic or surgical resections. At a mean follow-up of 32.6 months, none of the 37 patients who underwent endoscopic or surgical transanal resection had evidence of recurrent disease.

A limitation of EUS, or any other imaging modality, is differentiating tumor invasion from peritumoral inflammation. The inflammation can render images of tumor borders ill-defined and irregular, which hinders precise staging. However, the accurate identification of tumors with deep involvement of the submucosa (T1sm3) is of importance, because these tumors are more advanced than the superficial and intermediate T1 lesions (T1sm1 and T1sm2, respectively).

Patients with RC whose lesions are considered T1sm3 are at higher risk of harboring lymph node metastases.¹⁸ Nascimbeni and colleagues had shown that the invasion into the lower third of the submucosa (sm3) was an independent risk factor for lower cancer-free survival among patients with T1 RC.¹⁹We did not measure the distance of the tumor to muscular layer in our study, but we relied on EUS to predict the circumferential tumor margins and guide the surgical resection. Of the 11 patients with T1 rectal adenocarcinomas and the 6 patients with tubular adenoma with high-grade dysplasia, all treated by local excision, none developed a local or distant recurrence during follow-up.

Unlike rectal adenocarcinomas, the prognosis for carcinoid tumors correlates not only with the depth of invasion but also with the size of the tumor. The other adverse prognostic features include poor differentiation, high mitosis index, and lymphovascular invasion.²⁰

EUS had been shown to be highly accurate in determining the precise carcinoid tumor size, depth of invasion, and lymph node metastases.^20,21 In a study of 66 resected rectal carcinoid tumors by Ishii and colleagues, 57 lesions had a diameter of ≤ 10 mm and 9 lesions had a diameter of > 10 mm.²¹ All of the 57 carcinoid tumors with a diameter of ≤ 10 mm were confined to the submucosa. In contrast, 5 of the 9 lesions > 10 mm invaded the muscularis propria, 6 had a lymphovascular invasion, 4 were lymph node metastases, and 1 was a liver metastasis.

In our series, 4 of the 14 carcinoid tumors were > 10 mm but none were > 20 mm. None of the carcinoids with a diameter ≤ 10 mm invaded the muscularis propria. Of the 4 carcinoids > 10 mm, 1 was T2N0 and 3 were T1N0. All carcinoid tumors in our series were low grade and with low proliferation indexes, and all were treated successfully by local excision.

Conclusion

We believe our study shows that EUS can be highly accurate in staging rectal lesions, specifically lesions that are T1-T2N0, be they adenocarcinoma or carcinoid. Although we could not assess overstaging for lesions that were staged > T2 or > N0, we were able to determine no understaging for all of our patients. In experienced hands, EUS remains a highly accurate staging tool for early rectal carcinoma.

Colorectal cancer is the second most common cause of cancer death in the US, with one-third of all colorectal cancers occurring within the rectum. Each year, an estimated 40000 Americans are diagnosed with rectal cancer (RC).^1,2 The prognosis and treatment of RC depends on both T and N stage at the time of diagnosis.^3-5 According to the most recent National Comprehensive Cancer Network guidelines from May 2019, patients with T1 to T2N0 tumors should undergo transanal or transabdominal surgery upfront, whereas patients with T3 to T4N0 or any TN1 to 2 should start with neoadjuvant therapy for better locoregional control, followed by surgery.⁶ Therefore, the appropriate management of RC requires adequate staging.

Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and computed tomography (CT) are the imaging techniques currently used to stage RC. In a meta-analysis of 90 articles published between 1985 and 2002 that compared the 3 radiologic modalities, Bipat and colleagues found that MRI and EUS had a similar sensitivity of 94%, whereas the specificity of EUS (86%) was significantly higher than that of MRI (69%) for muscularis propria invasion.⁷ CT was performed only in a limited number of trials because CT was considered inadequate to assess early T stage. For perirectal tissue invasion, the sensitivity of EUS was statistically higher than that of CT and MRI imaging: 90% compared with 79% and 82%, respectively. The specificity estimates for EUS, CT, and MRI were comparable: 75%, 78%, and 76%, respectively. The respective sensitivity and specificity of the 3 imaging modalities to evaluate lymph nodes were also comparable: EUS, 67% and 78%; CT, 55% and 74%; and MRI, 66% and 76%.

The role of EUS in the diagnosis and treatment of RC has long been validated.^1,2-5 A meta-analysis of 42 studies involving 5039 patients found EUS to be highly accurate for differentiating various T stages.⁸ However, EUS cannot assess iliac and mesenteric lymph nodes or posterior tumor extension beyond endopelvic fascia in advanced RC. Notable heterogeneity was found among the studies in the meta-analyses with regard to the type of equipment used for staging, as well as the criteria used to assess the depth of penetration and nodal status. The recent introduction of phased-array coils and the development of T2-weighted fast spin sequences have improved the resolution of MRI. The MERCURY trial showed that extension of tumor to within 1 mm of the circumferential margin on high-resolution MRI correctly predicted margin involvement at the time of surgery in 92% of the patients.⁹ In the retrospective study by Balyasnikova and colleagues, MRI was found to correctly identify partial submucosal invasion and suitability for local excision in 89% of the cases.¹⁰

Therefore, both EUS and MRI are useful, more so than CT, in assessment of the depth of tumor invasion, nodal staging, and predicting the circumferential resection margin. The use of EUS, however, does not preclude the use of MRI, or vice versa. Rather, the 2 modalities can complement each other in staging and proper patient selection for treatment.¹¹

Despite data supporting the value of EUS in staging RC, its use is limited by a high degree of operator dependence and a substantial learning curve,^12-17 which may explain the low EUS accuracy observed in some reports.^7,13,15 Given the presence of recognized alternatives such as MRI, we decided to reevaluate EUS accuracy for the staging of RC outside high-volume specialized centers and prospective clinical trials.

Methods

A retrospective chart review was performed that included all consecutive patients undergoing rectal ultrasound from January 2011 to August 2015 at the US Department of Veterans Affairs Medical Center (VAMC) in Memphis, Tennessee. Sixty-five patients with short-stocked or sessile lesions < 15 cm from anal margin staged T2N0M0 or lower by endorectal ultrasound (ERUS) were included. The patients with neoplasms staged in excess of T2 or N0 were excluded from the study because treatment protocol dictates immediate neoadjuvant treatment, the administration of which would affect subsequent histopathology.

For the 37 patients included in the final analysis, ERUS results were compared with surgical pathology to ascertain accuracy. The resections were performed endoscopically or surgically with a goal of obtaining clear margins. The choice of procedure depended on size, shape, location, and depth of invasion. All patients underwent clinical and endoscopic surveillance with flexible sigmoidoscopy/EUS every 3 to 6 months for the first 2 years. We used 2 different gold standards for surveillance depending on the type of procedure performed to remove the lesion. A pathology report was the gold standard used for patients who underwent surgery. In patients who underwent endoscopic resection, we used the lack of recurrent disease, determined by normal endoscopic and endoscopic ultrasound examination, to signify complete endoscopic resection and therefore adequate staging as an early neoplasm.

Results

From January 2011 to August 2015, 65 rectal ultrasounds were performed. All EUS procedures were performed by 1 physician (C Ruben Tombazzi). All patients had previous endoscopic evaluation and tissue diagnoses. Twenty-eight patients were excluded: 18 had T3 or N1 disease, 2 had T2N0 but refused surgery, 2 had anal cancer, 3 patients with suspected cancer had benign nonneoplastic disease (2 radiation proctitis, 1 normal rectal wall), and 3 underwent EUS for benign tumors (1 ganglioneuroma and 2 lipomas).

Thirty-seven patients were included in the study, 3 of whom were staged as T2N0 and 34 as T1N0 or lower by EUS. All patients were men ranging in age from 43 to 73 years (mean, 59 years). All 37 patients underwent endoscopic or surgical resection of their early rectal neoplasm. The final pathologic evaluation of the specimens demonstrated 14 carcinoid tumors, 11 adenocarcinomas, 6 tubular adenomas with high-grade dysplasia, and 6 benign adenomas. The preoperative EUS staging was confirmed for all patients, with 100% sensitivity, specificity, and accuracy. None of the patients who underwent endoscopic or surgical transanal resection had recurrence, determined by normal endoscopic and endoscopic ultrasound appearance, during a mean of 32.6 months surveillance.

Discussion

EUS has long been a recognized method for T and N staging of RC.^1,3-5,7,8 Our data confirm that, in experienced hands, EUS is highly accurate in the staging of early rectal cancers.

The impact of EUS on the management of RC was demonstrated in a Mayo Clinic prospective blinded study.¹ In that cohort of 80 consecutive patients who had previously had a CT for staging, EUS altered patient management in about 30% of cases. The most common change precipatated by EUS was the indication for additional neoadjuvant treatment.

However, the results have not been as encouraging when ERUS is performed outside of strict research protocol. A multicenter, prospective, country-wide quality assurance study from > 300 German hospitals was designed to assess the diagnostic accuracy of EUS in RC.¹³ Of 29206 patients, 7096 underwent surgery, without neoadjuvant treatment, and were included in the final analysis. The correspondence of tumor invasion with histopathology was 64.7%, with understaging of 18% and overstaging of 17.3%.¹³ These numbers were better in hospitals with greater experience performing ERUS: 73% accuracy in the centers with a case load of > 30 cases per year compared with 63.2% accuracy for the centers with < 10 cases a year. Marusch and colleagues had previously demonstrated an EUS accuracy of 63.3% in a study of 1463 patients with RC in Germany.¹⁴ Another study based out of the UK had similar findings. Ashraf and colleagues performed a database analyses from 20 UK centers and identified 165 patients with RC who underwent ERUS and endoscopic microsurgery.¹⁵ Compared with histopathology, EUS had 57.1% sensitivity, 73% specificity, and 42.9% accuracy for T1 cancers; EUS accuracy was 50% for T2 and 58% for T3 tumors. The authors concluded that the general accuracy of EUS in determining stage was around 50%, the statistical equivalent of flipping a coin.

The low accuracy of EUS observed by German and British multicenter studies^13-15 was attributed to the difference that may exist in clinical trials at specialized centers compared with wider use of EUS in a community setting. As seen by our data, the Memphis VAMC is not a high-volume center for the treatment of RC. However, all our EUS procedures were performed and interpreted by a single operator (C. Ruben Tombazzi) with 18 years of EUS experience. We cannot conclude that no patient was overstaged, as patients receiving a stage of T3N0 or T > N0 received neoadjuvant treatment and were not included. However, we can conclude that no patient was understaged. All patients deemed to be T1 to T2N0 included in our study received accurate staging. Our results are consistent with the high accuracy of EUS reported from other centers with experience in diagnosis and treatment of RC.^1,3-5,17,18

Although EUS is accurate in differentiating T1 from T2 tumors, it cannot reliably differentiate T1 from T0 lesions. In one study, 57.6% of adenomas and 30.7% of carcinomas in situ were staged as T1 on EUS, while almost half of T1 cancers were interpreted as T0.¹⁷ This drawback is a well-known limitation of EUS; although, the misinterpretation does not affect treatment, as both T0 and T1 lesions can be treated successfully by local excision alone, which was the algorithm used for our patients. The choice of the specific procedure for local excision was left to the clinicians and included transanal endoscopic or surgical resections. At a mean follow-up of 32.6 months, none of the 37 patients who underwent endoscopic or surgical transanal resection had evidence of recurrent disease.

A limitation of EUS, or any other imaging modality, is differentiating tumor invasion from peritumoral inflammation. The inflammation can render images of tumor borders ill-defined and irregular, which hinders precise staging. However, the accurate identification of tumors with deep involvement of the submucosa (T1sm3) is of importance, because these tumors are more advanced than the superficial and intermediate T1 lesions (T1sm1 and T1sm2, respectively).

Patients with RC whose lesions are considered T1sm3 are at higher risk of harboring lymph node metastases.¹⁸ Nascimbeni and colleagues had shown that the invasion into the lower third of the submucosa (sm3) was an independent risk factor for lower cancer-free survival among patients with T1 RC.¹⁹We did not measure the distance of the tumor to muscular layer in our study, but we relied on EUS to predict the circumferential tumor margins and guide the surgical resection. Of the 11 patients with T1 rectal adenocarcinomas and the 6 patients with tubular adenoma with high-grade dysplasia, all treated by local excision, none developed a local or distant recurrence during follow-up.

Unlike rectal adenocarcinomas, the prognosis for carcinoid tumors correlates not only with the depth of invasion but also with the size of the tumor. The other adverse prognostic features include poor differentiation, high mitosis index, and lymphovascular invasion.²⁰

EUS had been shown to be highly accurate in determining the precise carcinoid tumor size, depth of invasion, and lymph node metastases.^20,21 In a study of 66 resected rectal carcinoid tumors by Ishii and colleagues, 57 lesions had a diameter of ≤ 10 mm and 9 lesions had a diameter of > 10 mm.²¹ All of the 57 carcinoid tumors with a diameter of ≤ 10 mm were confined to the submucosa. In contrast, 5 of the 9 lesions > 10 mm invaded the muscularis propria, 6 had a lymphovascular invasion, 4 were lymph node metastases, and 1 was a liver metastasis.

In our series, 4 of the 14 carcinoid tumors were > 10 mm but none were > 20 mm. None of the carcinoids with a diameter ≤ 10 mm invaded the muscularis propria. Of the 4 carcinoids > 10 mm, 1 was T2N0 and 3 were T1N0. All carcinoid tumors in our series were low grade and with low proliferation indexes, and all were treated successfully by local excision.

Conclusion

We believe our study shows that EUS can be highly accurate in staging rectal lesions, specifically lesions that are T1-T2N0, be they adenocarcinoma or carcinoid. Although we could not assess overstaging for lesions that were staged > T2 or > N0, we were able to determine no understaging for all of our patients. In experienced hands, EUS remains a highly accurate staging tool for early rectal carcinoma.

Colorectal cancer is the second most common cause of cancer death in the US, with one-third of all colorectal cancers occurring within the rectum. Each year, an estimated 40000 Americans are diagnosed with rectal cancer (RC).^1,2 The prognosis and treatment of RC depends on both T and N stage at the time of diagnosis.^3-5 According to the most recent National Comprehensive Cancer Network guidelines from May 2019, patients with T1 to T2N0 tumors should undergo transanal or transabdominal surgery upfront, whereas patients with T3 to T4N0 or any TN1 to 2 should start with neoadjuvant therapy for better locoregional control, followed by surgery.⁶ Therefore, the appropriate management of RC requires adequate staging.

Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and computed tomography (CT) are the imaging techniques currently used to stage RC. In a meta-analysis of 90 articles published between 1985 and 2002 that compared the 3 radiologic modalities, Bipat and colleagues found that MRI and EUS had a similar sensitivity of 94%, whereas the specificity of EUS (86%) was significantly higher than that of MRI (69%) for muscularis propria invasion.⁷ CT was performed only in a limited number of trials because CT was considered inadequate to assess early T stage. For perirectal tissue invasion, the sensitivity of EUS was statistically higher than that of CT and MRI imaging: 90% compared with 79% and 82%, respectively. The specificity estimates for EUS, CT, and MRI were comparable: 75%, 78%, and 76%, respectively. The respective sensitivity and specificity of the 3 imaging modalities to evaluate lymph nodes were also comparable: EUS, 67% and 78%; CT, 55% and 74%; and MRI, 66% and 76%.

The role of EUS in the diagnosis and treatment of RC has long been validated.^1,2-5 A meta-analysis of 42 studies involving 5039 patients found EUS to be highly accurate for differentiating various T stages.⁸ However, EUS cannot assess iliac and mesenteric lymph nodes or posterior tumor extension beyond endopelvic fascia in advanced RC. Notable heterogeneity was found among the studies in the meta-analyses with regard to the type of equipment used for staging, as well as the criteria used to assess the depth of penetration and nodal status. The recent introduction of phased-array coils and the development of T2-weighted fast spin sequences have improved the resolution of MRI. The MERCURY trial showed that extension of tumor to within 1 mm of the circumferential margin on high-resolution MRI correctly predicted margin involvement at the time of surgery in 92% of the patients.⁹ In the retrospective study by Balyasnikova and colleagues, MRI was found to correctly identify partial submucosal invasion and suitability for local excision in 89% of the cases.¹⁰

Therefore, both EUS and MRI are useful, more so than CT, in assessment of the depth of tumor invasion, nodal staging, and predicting the circumferential resection margin. The use of EUS, however, does not preclude the use of MRI, or vice versa. Rather, the 2 modalities can complement each other in staging and proper patient selection for treatment.¹¹

Despite data supporting the value of EUS in staging RC, its use is limited by a high degree of operator dependence and a substantial learning curve,^12-17 which may explain the low EUS accuracy observed in some reports.^7,13,15 Given the presence of recognized alternatives such as MRI, we decided to reevaluate EUS accuracy for the staging of RC outside high-volume specialized centers and prospective clinical trials.

Methods

A retrospective chart review was performed that included all consecutive patients undergoing rectal ultrasound from January 2011 to August 2015 at the US Department of Veterans Affairs Medical Center (VAMC) in Memphis, Tennessee. Sixty-five patients with short-stocked or sessile lesions < 15 cm from anal margin staged T2N0M0 or lower by endorectal ultrasound (ERUS) were included. The patients with neoplasms staged in excess of T2 or N0 were excluded from the study because treatment protocol dictates immediate neoadjuvant treatment, the administration of which would affect subsequent histopathology.

For the 37 patients included in the final analysis, ERUS results were compared with surgical pathology to ascertain accuracy. The resections were performed endoscopically or surgically with a goal of obtaining clear margins. The choice of procedure depended on size, shape, location, and depth of invasion. All patients underwent clinical and endoscopic surveillance with flexible sigmoidoscopy/EUS every 3 to 6 months for the first 2 years. We used 2 different gold standards for surveillance depending on the type of procedure performed to remove the lesion. A pathology report was the gold standard used for patients who underwent surgery. In patients who underwent endoscopic resection, we used the lack of recurrent disease, determined by normal endoscopic and endoscopic ultrasound examination, to signify complete endoscopic resection and therefore adequate staging as an early neoplasm.

Results

From January 2011 to August 2015, 65 rectal ultrasounds were performed. All EUS procedures were performed by 1 physician (C Ruben Tombazzi). All patients had previous endoscopic evaluation and tissue diagnoses. Twenty-eight patients were excluded: 18 had T3 or N1 disease, 2 had T2N0 but refused surgery, 2 had anal cancer, 3 patients with suspected cancer had benign nonneoplastic disease (2 radiation proctitis, 1 normal rectal wall), and 3 underwent EUS for benign tumors (1 ganglioneuroma and 2 lipomas).

Thirty-seven patients were included in the study, 3 of whom were staged as T2N0 and 34 as T1N0 or lower by EUS. All patients were men ranging in age from 43 to 73 years (mean, 59 years). All 37 patients underwent endoscopic or surgical resection of their early rectal neoplasm. The final pathologic evaluation of the specimens demonstrated 14 carcinoid tumors, 11 adenocarcinomas, 6 tubular adenomas with high-grade dysplasia, and 6 benign adenomas. The preoperative EUS staging was confirmed for all patients, with 100% sensitivity, specificity, and accuracy. None of the patients who underwent endoscopic or surgical transanal resection had recurrence, determined by normal endoscopic and endoscopic ultrasound appearance, during a mean of 32.6 months surveillance.

Discussion

EUS has long been a recognized method for T and N staging of RC.^1,3-5,7,8 Our data confirm that, in experienced hands, EUS is highly accurate in the staging of early rectal cancers.

The impact of EUS on the management of RC was demonstrated in a Mayo Clinic prospective blinded study.¹ In that cohort of 80 consecutive patients who had previously had a CT for staging, EUS altered patient management in about 30% of cases. The most common change precipatated by EUS was the indication for additional neoadjuvant treatment.

However, the results have not been as encouraging when ERUS is performed outside of strict research protocol. A multicenter, prospective, country-wide quality assurance study from > 300 German hospitals was designed to assess the diagnostic accuracy of EUS in RC.¹³ Of 29206 patients, 7096 underwent surgery, without neoadjuvant treatment, and were included in the final analysis. The correspondence of tumor invasion with histopathology was 64.7%, with understaging of 18% and overstaging of 17.3%.¹³ These numbers were better in hospitals with greater experience performing ERUS: 73% accuracy in the centers with a case load of > 30 cases per year compared with 63.2% accuracy for the centers with < 10 cases a year. Marusch and colleagues had previously demonstrated an EUS accuracy of 63.3% in a study of 1463 patients with RC in Germany.¹⁴ Another study based out of the UK had similar findings. Ashraf and colleagues performed a database analyses from 20 UK centers and identified 165 patients with RC who underwent ERUS and endoscopic microsurgery.¹⁵ Compared with histopathology, EUS had 57.1% sensitivity, 73% specificity, and 42.9% accuracy for T1 cancers; EUS accuracy was 50% for T2 and 58% for T3 tumors. The authors concluded that the general accuracy of EUS in determining stage was around 50%, the statistical equivalent of flipping a coin.

The low accuracy of EUS observed by German and British multicenter studies^13-15 was attributed to the difference that may exist in clinical trials at specialized centers compared with wider use of EUS in a community setting. As seen by our data, the Memphis VAMC is not a high-volume center for the treatment of RC. However, all our EUS procedures were performed and interpreted by a single operator (C. Ruben Tombazzi) with 18 years of EUS experience. We cannot conclude that no patient was overstaged, as patients receiving a stage of T3N0 or T > N0 received neoadjuvant treatment and were not included. However, we can conclude that no patient was understaged. All patients deemed to be T1 to T2N0 included in our study received accurate staging. Our results are consistent with the high accuracy of EUS reported from other centers with experience in diagnosis and treatment of RC.^1,3-5,17,18

Although EUS is accurate in differentiating T1 from T2 tumors, it cannot reliably differentiate T1 from T0 lesions. In one study, 57.6% of adenomas and 30.7% of carcinomas in situ were staged as T1 on EUS, while almost half of T1 cancers were interpreted as T0.¹⁷ This drawback is a well-known limitation of EUS; although, the misinterpretation does not affect treatment, as both T0 and T1 lesions can be treated successfully by local excision alone, which was the algorithm used for our patients. The choice of the specific procedure for local excision was left to the clinicians and included transanal endoscopic or surgical resections. At a mean follow-up of 32.6 months, none of the 37 patients who underwent endoscopic or surgical transanal resection had evidence of recurrent disease.

A limitation of EUS, or any other imaging modality, is differentiating tumor invasion from peritumoral inflammation. The inflammation can render images of tumor borders ill-defined and irregular, which hinders precise staging. However, the accurate identification of tumors with deep involvement of the submucosa (T1sm3) is of importance, because these tumors are more advanced than the superficial and intermediate T1 lesions (T1sm1 and T1sm2, respectively).

Patients with RC whose lesions are considered T1sm3 are at higher risk of harboring lymph node metastases.¹⁸ Nascimbeni and colleagues had shown that the invasion into the lower third of the submucosa (sm3) was an independent risk factor for lower cancer-free survival among patients with T1 RC.¹⁹We did not measure the distance of the tumor to muscular layer in our study, but we relied on EUS to predict the circumferential tumor margins and guide the surgical resection. Of the 11 patients with T1 rectal adenocarcinomas and the 6 patients with tubular adenoma with high-grade dysplasia, all treated by local excision, none developed a local or distant recurrence during follow-up.

Unlike rectal adenocarcinomas, the prognosis for carcinoid tumors correlates not only with the depth of invasion but also with the size of the tumor. The other adverse prognostic features include poor differentiation, high mitosis index, and lymphovascular invasion.²⁰

EUS had been shown to be highly accurate in determining the precise carcinoid tumor size, depth of invasion, and lymph node metastases.^20,21 In a study of 66 resected rectal carcinoid tumors by Ishii and colleagues, 57 lesions had a diameter of ≤ 10 mm and 9 lesions had a diameter of > 10 mm.²¹ All of the 57 carcinoid tumors with a diameter of ≤ 10 mm were confined to the submucosa. In contrast, 5 of the 9 lesions > 10 mm invaded the muscularis propria, 6 had a lymphovascular invasion, 4 were lymph node metastases, and 1 was a liver metastasis.

In our series, 4 of the 14 carcinoid tumors were > 10 mm but none were > 20 mm. None of the carcinoids with a diameter ≤ 10 mm invaded the muscularis propria. Of the 4 carcinoids > 10 mm, 1 was T2N0 and 3 were T1N0. All carcinoid tumors in our series were low grade and with low proliferation indexes, and all were treated successfully by local excision.

Conclusion

We believe our study shows that EUS can be highly accurate in staging rectal lesions, specifically lesions that are T1-T2N0, be they adenocarcinoma or carcinoid. Although we could not assess overstaging for lesions that were staged > T2 or > N0, we were able to determine no understaging for all of our patients. In experienced hands, EUS remains a highly accurate staging tool for early rectal carcinoma.

Single-agent therapy with either bevacizumab or pemetrexed is efficacious as maintenance therapy for patients with advanced nonsquamous non–small cell lung cancer (NSCLC), but the combination of the two agents offers no survival benefit and is more toxic, results of the randomized ECOG-ACRIN 5508 study show.

Neil Osterweil/MDedge News

For patients with no disease progression after four cycles of induction chemotherapy who were assigned to one of three maintenance therapy strategies, there were no differences in overall survival between those randomized to monotherapy with pemetrexed or bevacizumab or to a combination of the two agents, although progression-free survival (PFS) was better with the combination, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute of Emory University, Atlanta, and colleagues.

The incidence of grade 3 or greater adverse events was also significantly higher with the combination, compared with bevacizumab monotherapy.

Even in the age of immune checkpoint inhibitor therapy in the front line, “[i]t is clear that maintenance therapy will remain an integral part of the treatment approach to advanced nonsquamous NSCLC. The results of ECOG-ACRIN 5508 support the use of either pemetrexed or bevacizumab as a single agent in this setting,” the investigators wrote in the Journal of Clinical Oncology.

Although the combination of bevacizumab and pemetrexed was associated with a significant improvement in PFS in a randomized trial, the three maintenance strategies have never before been directly compared, Dr. Ramalingam and associates noted.

­In ECOG-ACRIN 5508, 1,516 patients with advanced nonsquamous NSCLC who had not received prior systemic therapy were given standard induction chemotherapy, consisting of carboplatin to an area under the curve of 6, paclitaxel 200 mg/m², and bevacizumab 15 mg/kg for up to four cycles.

Patients without progression after four cycles (874) were randomly assigned to maintenance therapy with bevacizumab at 15 mg/kg , pemetrexed 500 mg/m², or a combination of the two agents.

For the primary endpoint of overall survival, with bevacizumab serving as the control group for comparison, the investigators found that, at a median follow-up of 50.6 months, median survival was 15.9 months with pemetrexed, compared with 14.4 months with bevacizumab, a difference that was not statistically significant. Median survival with the combination was 16.4 months and was also not significantly different from bevacizumab.

Median PFS was 4.2 months and 5.1 months for the pemetrexed and bevacizumab groups, respectively, with no significant difference. In contrast, median was 7.5 months with the combination, which was significantly better than controls, with a hazard ratio of 0.67 (P less than .001).

Patients received a median of six maintenance therapy cycles for each of the single agents, and a median of eight for the combinations. The incidence of grade 3-4 toxicity was 29% with bevacizumab, 37% with pemetrexed, and 51% with the combination. The combination was associated with a significantly greater incidence of toxicities, compared with bevacizumab (P less than .001).

The study was supported by grants from the National Cancer Institute. Dr. Ramalingam reported a consulting/advisory role for bevacizumab maker Genentech/Roche and others. Multiple coauthors reported similar disclosures.

SOURCE: Ramalingam SS et al. J Clin Oncol. 2019 Jul 30. doi: 10.1200/JCO.19.01006.

Single-agent therapy with either bevacizumab or pemetrexed is efficacious as maintenance therapy for patients with advanced nonsquamous non–small cell lung cancer (NSCLC), but the combination of the two agents offers no survival benefit and is more toxic, results of the randomized ECOG-ACRIN 5508 study show.

Neil Osterweil/MDedge News

For patients with no disease progression after four cycles of induction chemotherapy who were assigned to one of three maintenance therapy strategies, there were no differences in overall survival between those randomized to monotherapy with pemetrexed or bevacizumab or to a combination of the two agents, although progression-free survival (PFS) was better with the combination, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute of Emory University, Atlanta, and colleagues.

The incidence of grade 3 or greater adverse events was also significantly higher with the combination, compared with bevacizumab monotherapy.

Even in the age of immune checkpoint inhibitor therapy in the front line, “[i]t is clear that maintenance therapy will remain an integral part of the treatment approach to advanced nonsquamous NSCLC. The results of ECOG-ACRIN 5508 support the use of either pemetrexed or bevacizumab as a single agent in this setting,” the investigators wrote in the Journal of Clinical Oncology.

Although the combination of bevacizumab and pemetrexed was associated with a significant improvement in PFS in a randomized trial, the three maintenance strategies have never before been directly compared, Dr. Ramalingam and associates noted.

­In ECOG-ACRIN 5508, 1,516 patients with advanced nonsquamous NSCLC who had not received prior systemic therapy were given standard induction chemotherapy, consisting of carboplatin to an area under the curve of 6, paclitaxel 200 mg/m², and bevacizumab 15 mg/kg for up to four cycles.

Patients without progression after four cycles (874) were randomly assigned to maintenance therapy with bevacizumab at 15 mg/kg , pemetrexed 500 mg/m², or a combination of the two agents.

For the primary endpoint of overall survival, with bevacizumab serving as the control group for comparison, the investigators found that, at a median follow-up of 50.6 months, median survival was 15.9 months with pemetrexed, compared with 14.4 months with bevacizumab, a difference that was not statistically significant. Median survival with the combination was 16.4 months and was also not significantly different from bevacizumab.

Median PFS was 4.2 months and 5.1 months for the pemetrexed and bevacizumab groups, respectively, with no significant difference. In contrast, median was 7.5 months with the combination, which was significantly better than controls, with a hazard ratio of 0.67 (P less than .001).

Patients received a median of six maintenance therapy cycles for each of the single agents, and a median of eight for the combinations. The incidence of grade 3-4 toxicity was 29% with bevacizumab, 37% with pemetrexed, and 51% with the combination. The combination was associated with a significantly greater incidence of toxicities, compared with bevacizumab (P less than .001).

The study was supported by grants from the National Cancer Institute. Dr. Ramalingam reported a consulting/advisory role for bevacizumab maker Genentech/Roche and others. Multiple coauthors reported similar disclosures.

SOURCE: Ramalingam SS et al. J Clin Oncol. 2019 Jul 30. doi: 10.1200/JCO.19.01006.

Single-agent therapy with either bevacizumab or pemetrexed is efficacious as maintenance therapy for patients with advanced nonsquamous non–small cell lung cancer (NSCLC), but the combination of the two agents offers no survival benefit and is more toxic, results of the randomized ECOG-ACRIN 5508 study show.

Neil Osterweil/MDedge News

For patients with no disease progression after four cycles of induction chemotherapy who were assigned to one of three maintenance therapy strategies, there were no differences in overall survival between those randomized to monotherapy with pemetrexed or bevacizumab or to a combination of the two agents, although progression-free survival (PFS) was better with the combination, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute of Emory University, Atlanta, and colleagues.

The incidence of grade 3 or greater adverse events was also significantly higher with the combination, compared with bevacizumab monotherapy.

Even in the age of immune checkpoint inhibitor therapy in the front line, “[i]t is clear that maintenance therapy will remain an integral part of the treatment approach to advanced nonsquamous NSCLC. The results of ECOG-ACRIN 5508 support the use of either pemetrexed or bevacizumab as a single agent in this setting,” the investigators wrote in the Journal of Clinical Oncology.

Although the combination of bevacizumab and pemetrexed was associated with a significant improvement in PFS in a randomized trial, the three maintenance strategies have never before been directly compared, Dr. Ramalingam and associates noted.

­In ECOG-ACRIN 5508, 1,516 patients with advanced nonsquamous NSCLC who had not received prior systemic therapy were given standard induction chemotherapy, consisting of carboplatin to an area under the curve of 6, paclitaxel 200 mg/m², and bevacizumab 15 mg/kg for up to four cycles.

Patients without progression after four cycles (874) were randomly assigned to maintenance therapy with bevacizumab at 15 mg/kg , pemetrexed 500 mg/m², or a combination of the two agents.

For the primary endpoint of overall survival, with bevacizumab serving as the control group for comparison, the investigators found that, at a median follow-up of 50.6 months, median survival was 15.9 months with pemetrexed, compared with 14.4 months with bevacizumab, a difference that was not statistically significant. Median survival with the combination was 16.4 months and was also not significantly different from bevacizumab.

Median PFS was 4.2 months and 5.1 months for the pemetrexed and bevacizumab groups, respectively, with no significant difference. In contrast, median was 7.5 months with the combination, which was significantly better than controls, with a hazard ratio of 0.67 (P less than .001).

Patients received a median of six maintenance therapy cycles for each of the single agents, and a median of eight for the combinations. The incidence of grade 3-4 toxicity was 29% with bevacizumab, 37% with pemetrexed, and 51% with the combination. The combination was associated with a significantly greater incidence of toxicities, compared with bevacizumab (P less than .001).

The study was supported by grants from the National Cancer Institute. Dr. Ramalingam reported a consulting/advisory role for bevacizumab maker Genentech/Roche and others. Multiple coauthors reported similar disclosures.

SOURCE: Ramalingam SS et al. J Clin Oncol. 2019 Jul 30. doi: 10.1200/JCO.19.01006.

Shared decision making around low-dose computed tomography screening for lung cancer should include risk and benefit information for baseline conditions such as chronic obstructive pulmonary disease (COPD), research suggests.

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Jonathan M. Iaccarino, MD, of the pulmonary center at the Boston University, and coauthors reported the results of a secondary analysis of patient-level outcomes from 75,138 low-dose CT (LDCT) scans in 26,453 participants in the National Lung Screening Trial (Chest 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016).

Currently, LDCT screening is recommended annually for high-risk smokers aged 55-80 years. The National Lung Screening Trial showed that this screening achieved a 20% relative reduction in lung cancer mortality and 6.7% relative reduction in overall mortality in this group. The guidelines stress the importance of shared decision making, with discussion of the risks and benefits of screening.

Dr. Iaccarino and colleagues point out that decision aids for shared decision making need to include important baseline characteristics, such as the presence of COPD, as these can complicate the risk and benefit analysis.

In this study, they found that 14.2% of LDCT scans performed led to a subsequent diagnostic study and 1.5% resulted in an invasive procedure. In addition, 0.3% of scans resulted in a procedure-related complication, and in 89 cases (0.1%), this procedure-related complication was serious.

At the patient level, nearly one-third (30.5%) received a diagnostic study, 4.2% underwent an invasive procedure – 41% of whom ultimately were found not to have lung cancer – 0.9% had a procedure-related complication, and 0.3% had a serious procedure related complication. Furthermore, among those who experienced a serious complication, 12.5% were found not to have lung cancer.

“Our study analyzes cumulative outcomes at the level of the individual patient over the three years of LDCT screening during the NLST, showing higher rates of diagnostic procedures, invasive procedures, complications and serious complications than apparent when data is presented at the level of the individual test,” the authors wrote.

The 4,632 participants with COPD were significantly more likely to undergo diagnostic studies (36.2%), have an invasive procedure (6%), experience a procedure-related complication (1.5%) and experience a serious procedure-related complication (0.6%) than were participants without COPD. However, they also had a significantly higher incidence of lung cancer diagnosis than did participants without COPD (6.1% vs. 3.6%).

“While most decision aids note the risks of screening may be increased in those with COPD, our study helps quantify these increased risks as well as the increased likelihood of a lung cancer diagnosis, a critical advance given that providing personalized (rather than generic) information results in more accurate risk perception and more informed choices among individuals considering screening,” the authors wrote. “With the significant change in the balance of benefits and risks of screening in patients with COPD, it is critical to adjust the shared decision-making discussions accordingly.”

They also noted that other comorbidities, such as heart disease, vascular disease, and other lung diseases, would likely affect the balance of risk and benefit of LDCT screening, and that there was a need for further exploration of screening in these patients.

Noting the study’s limitations, the authors pointed that their analysis focused on outcomes that were not the primary outcomes of the National Lung Screening trial, and that they relied on self-reported COPD diagnoses.

The study was supported by the American Society of Clinical Oncology, the Charles A. King Trust, and Edith Nourse Rogers Memorial Veterans Hospital. No conflicts of interest were declared.

SOURCE: Iaccarino JM et al. CHEST 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016.

Shared decision making around low-dose computed tomography screening for lung cancer should include risk and benefit information for baseline conditions such as chronic obstructive pulmonary disease (COPD), research suggests.

picsfive/Fotolia.com

Jonathan M. Iaccarino, MD, of the pulmonary center at the Boston University, and coauthors reported the results of a secondary analysis of patient-level outcomes from 75,138 low-dose CT (LDCT) scans in 26,453 participants in the National Lung Screening Trial (Chest 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016).

Currently, LDCT screening is recommended annually for high-risk smokers aged 55-80 years. The National Lung Screening Trial showed that this screening achieved a 20% relative reduction in lung cancer mortality and 6.7% relative reduction in overall mortality in this group. The guidelines stress the importance of shared decision making, with discussion of the risks and benefits of screening.

Dr. Iaccarino and colleagues point out that decision aids for shared decision making need to include important baseline characteristics, such as the presence of COPD, as these can complicate the risk and benefit analysis.

In this study, they found that 14.2% of LDCT scans performed led to a subsequent diagnostic study and 1.5% resulted in an invasive procedure. In addition, 0.3% of scans resulted in a procedure-related complication, and in 89 cases (0.1%), this procedure-related complication was serious.

At the patient level, nearly one-third (30.5%) received a diagnostic study, 4.2% underwent an invasive procedure – 41% of whom ultimately were found not to have lung cancer – 0.9% had a procedure-related complication, and 0.3% had a serious procedure related complication. Furthermore, among those who experienced a serious complication, 12.5% were found not to have lung cancer.

“Our study analyzes cumulative outcomes at the level of the individual patient over the three years of LDCT screening during the NLST, showing higher rates of diagnostic procedures, invasive procedures, complications and serious complications than apparent when data is presented at the level of the individual test,” the authors wrote.

The 4,632 participants with COPD were significantly more likely to undergo diagnostic studies (36.2%), have an invasive procedure (6%), experience a procedure-related complication (1.5%) and experience a serious procedure-related complication (0.6%) than were participants without COPD. However, they also had a significantly higher incidence of lung cancer diagnosis than did participants without COPD (6.1% vs. 3.6%).

“While most decision aids note the risks of screening may be increased in those with COPD, our study helps quantify these increased risks as well as the increased likelihood of a lung cancer diagnosis, a critical advance given that providing personalized (rather than generic) information results in more accurate risk perception and more informed choices among individuals considering screening,” the authors wrote. “With the significant change in the balance of benefits and risks of screening in patients with COPD, it is critical to adjust the shared decision-making discussions accordingly.”

They also noted that other comorbidities, such as heart disease, vascular disease, and other lung diseases, would likely affect the balance of risk and benefit of LDCT screening, and that there was a need for further exploration of screening in these patients.

Noting the study’s limitations, the authors pointed that their analysis focused on outcomes that were not the primary outcomes of the National Lung Screening trial, and that they relied on self-reported COPD diagnoses.

The study was supported by the American Society of Clinical Oncology, the Charles A. King Trust, and Edith Nourse Rogers Memorial Veterans Hospital. No conflicts of interest were declared.

SOURCE: Iaccarino JM et al. CHEST 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016.

Shared decision making around low-dose computed tomography screening for lung cancer should include risk and benefit information for baseline conditions such as chronic obstructive pulmonary disease (COPD), research suggests.

picsfive/Fotolia.com

Jonathan M. Iaccarino, MD, of the pulmonary center at the Boston University, and coauthors reported the results of a secondary analysis of patient-level outcomes from 75,138 low-dose CT (LDCT) scans in 26,453 participants in the National Lung Screening Trial (Chest 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016).

Currently, LDCT screening is recommended annually for high-risk smokers aged 55-80 years. The National Lung Screening Trial showed that this screening achieved a 20% relative reduction in lung cancer mortality and 6.7% relative reduction in overall mortality in this group. The guidelines stress the importance of shared decision making, with discussion of the risks and benefits of screening.

Dr. Iaccarino and colleagues point out that decision aids for shared decision making need to include important baseline characteristics, such as the presence of COPD, as these can complicate the risk and benefit analysis.

In this study, they found that 14.2% of LDCT scans performed led to a subsequent diagnostic study and 1.5% resulted in an invasive procedure. In addition, 0.3% of scans resulted in a procedure-related complication, and in 89 cases (0.1%), this procedure-related complication was serious.

At the patient level, nearly one-third (30.5%) received a diagnostic study, 4.2% underwent an invasive procedure – 41% of whom ultimately were found not to have lung cancer – 0.9% had a procedure-related complication, and 0.3% had a serious procedure related complication. Furthermore, among those who experienced a serious complication, 12.5% were found not to have lung cancer.

“Our study analyzes cumulative outcomes at the level of the individual patient over the three years of LDCT screening during the NLST, showing higher rates of diagnostic procedures, invasive procedures, complications and serious complications than apparent when data is presented at the level of the individual test,” the authors wrote.

The 4,632 participants with COPD were significantly more likely to undergo diagnostic studies (36.2%), have an invasive procedure (6%), experience a procedure-related complication (1.5%) and experience a serious procedure-related complication (0.6%) than were participants without COPD. However, they also had a significantly higher incidence of lung cancer diagnosis than did participants without COPD (6.1% vs. 3.6%).

“While most decision aids note the risks of screening may be increased in those with COPD, our study helps quantify these increased risks as well as the increased likelihood of a lung cancer diagnosis, a critical advance given that providing personalized (rather than generic) information results in more accurate risk perception and more informed choices among individuals considering screening,” the authors wrote. “With the significant change in the balance of benefits and risks of screening in patients with COPD, it is critical to adjust the shared decision-making discussions accordingly.”

They also noted that other comorbidities, such as heart disease, vascular disease, and other lung diseases, would likely affect the balance of risk and benefit of LDCT screening, and that there was a need for further exploration of screening in these patients.

Noting the study’s limitations, the authors pointed that their analysis focused on outcomes that were not the primary outcomes of the National Lung Screening trial, and that they relied on self-reported COPD diagnoses.

The study was supported by the American Society of Clinical Oncology, the Charles A. King Trust, and Edith Nourse Rogers Memorial Veterans Hospital. No conflicts of interest were declared.

SOURCE: Iaccarino JM et al. CHEST 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016.

A significant number of physicians who author practice guidelines are not reporting financial conflicts of interest, a study finds.

Lead author Ramy R. Saleh, MD, of the University of Toronto, and colleagues searched The American Society of Clinical Oncology (ASCO) website to identify all clinical practice guidelines (CPGs) for systemic therapy published between August 2013 and June 2018. Investigators analyzed self-reported author financial conflicts of interest and funding sources and also reviewed The Open Payments database to identify compensation to guideline authors. Researchers categorized conflicts of interest into two groups: research funding (which could include departmental and/or hospital funding) and nonresearch payments (including travel expenses, honoraria, employment, and stock ownership to the individual author).

The initial search identified 121 CPGs published by ASCO between August 2013 and August 2018 of which 26 guidelines were selected because of their focus on systemic treatment. Findings showed that 239 guideline authors who were not exempt from reporting received industry payments, but only 184 (77%) disclosed these payments, according to the study in Cancer. The mean total of all undisclosed payments from 2013 to 2017 received by CPG authors was $187,503 and the median was $30,500. Of the 55 authors with undisclosed conflicts of interest, 34 authors (62%) received more than $1,000 of nonresearch funding, and 19 authors (35%) received more than $5,000 per calendar year.

The majority of the authors with undisclosed conflicts were medical oncologists, the investigators found. Radiation oncologists and surgeons had similar proportions of undisclosed financial conflicts.

The researchers concluded that financial conflicts of interest among authors of ASCO guidelines are common and are not disclosed in a substantial number of cases. The findings indicate that current self-disclosure practices are not adequate for accurately reporting conflicts, they noted.

“Improved transparency of [financial conflicts of interest should become standard practice among CPG authors,” the investigators wrote. “Professional societies and journal editors need to create a mechanism to verify self-reported [financial conflicts of interest].”

Source: Saleh et. al. 2019 July 29 doi: 10.1002/cncr.32408.

A significant number of physicians who author practice guidelines are not reporting financial conflicts of interest, a study finds.

Lead author Ramy R. Saleh, MD, of the University of Toronto, and colleagues searched The American Society of Clinical Oncology (ASCO) website to identify all clinical practice guidelines (CPGs) for systemic therapy published between August 2013 and June 2018. Investigators analyzed self-reported author financial conflicts of interest and funding sources and also reviewed The Open Payments database to identify compensation to guideline authors. Researchers categorized conflicts of interest into two groups: research funding (which could include departmental and/or hospital funding) and nonresearch payments (including travel expenses, honoraria, employment, and stock ownership to the individual author).

The initial search identified 121 CPGs published by ASCO between August 2013 and August 2018 of which 26 guidelines were selected because of their focus on systemic treatment. Findings showed that 239 guideline authors who were not exempt from reporting received industry payments, but only 184 (77%) disclosed these payments, according to the study in Cancer. The mean total of all undisclosed payments from 2013 to 2017 received by CPG authors was $187,503 and the median was $30,500. Of the 55 authors with undisclosed conflicts of interest, 34 authors (62%) received more than $1,000 of nonresearch funding, and 19 authors (35%) received more than $5,000 per calendar year.

The majority of the authors with undisclosed conflicts were medical oncologists, the investigators found. Radiation oncologists and surgeons had similar proportions of undisclosed financial conflicts.

The researchers concluded that financial conflicts of interest among authors of ASCO guidelines are common and are not disclosed in a substantial number of cases. The findings indicate that current self-disclosure practices are not adequate for accurately reporting conflicts, they noted.

“Improved transparency of [financial conflicts of interest should become standard practice among CPG authors,” the investigators wrote. “Professional societies and journal editors need to create a mechanism to verify self-reported [financial conflicts of interest].”

Source: Saleh et. al. 2019 July 29 doi: 10.1002/cncr.32408.

A significant number of physicians who author practice guidelines are not reporting financial conflicts of interest, a study finds.

Lead author Ramy R. Saleh, MD, of the University of Toronto, and colleagues searched The American Society of Clinical Oncology (ASCO) website to identify all clinical practice guidelines (CPGs) for systemic therapy published between August 2013 and June 2018. Investigators analyzed self-reported author financial conflicts of interest and funding sources and also reviewed The Open Payments database to identify compensation to guideline authors. Researchers categorized conflicts of interest into two groups: research funding (which could include departmental and/or hospital funding) and nonresearch payments (including travel expenses, honoraria, employment, and stock ownership to the individual author).

The initial search identified 121 CPGs published by ASCO between August 2013 and August 2018 of which 26 guidelines were selected because of their focus on systemic treatment. Findings showed that 239 guideline authors who were not exempt from reporting received industry payments, but only 184 (77%) disclosed these payments, according to the study in Cancer. The mean total of all undisclosed payments from 2013 to 2017 received by CPG authors was $187,503 and the median was $30,500. Of the 55 authors with undisclosed conflicts of interest, 34 authors (62%) received more than $1,000 of nonresearch funding, and 19 authors (35%) received more than $5,000 per calendar year.

The majority of the authors with undisclosed conflicts were medical oncologists, the investigators found. Radiation oncologists and surgeons had similar proportions of undisclosed financial conflicts.

The researchers concluded that financial conflicts of interest among authors of ASCO guidelines are common and are not disclosed in a substantial number of cases. The findings indicate that current self-disclosure practices are not adequate for accurately reporting conflicts, they noted.

“Improved transparency of [financial conflicts of interest should become standard practice among CPG authors,” the investigators wrote. “Professional societies and journal editors need to create a mechanism to verify self-reported [financial conflicts of interest].”

Source: Saleh et. al. 2019 July 29 doi: 10.1002/cncr.32408.

Over the past few decades, our understanding of the molecular underpinning of primary neoplasms of the central nervous system (CNS) has progressed substantially. Thanks in large part to this expansion in our knowledge base, the World Health Organization (WHO) has recently updated its classification of tumors of the CNS.¹ One of the key elements of this update was the inclusion of molecular diagnostic criteria for the classification of infiltrating gliomas. While the previous classification system was based upon histologic subtypes of the tumor (astrocytoma, oligodendroglioma, and oligoastrocytoma), the revised classification system incorporates molecular testing to establish the genetic characteristics of the tumor to reach a final integrated diagnosis.

In this article, we present 3 cases to highlight some of these recent changes in the WHO diagnostic categories of primary CNS tumors and to illustrate the role of specific molecular tests in reaching a final integrated diagnosis. We then propose a clinical practice guideline for the Veterans Health Administration (VHA) that recommends use of molecular testing for veterans as part of the diagnostic workup of primary CNS neoplasms.

Purpose

In 2013 the VHA National Director of Pathology & Laboratory Medicine Services (P&LMS) chartered a national molecular genetics pathology workgroup (MGPW) that was charged with 4 specific tasks: (1) Provide recommendations about the effective use of molecular genetic testing for veterans; (2) Promote increased quality and availability of molecular testing within the VHA; (3) Encourage internal referral testing; and (4) Create an organizational structure and policies for molecular genetic testing and laboratory developed tests. The workgroup is currently composed of 4 subcommittees: genetic medicine, hematopathology, pharmacogenomics, and molecular oncology. The molecular oncology subcommittee is focused upon molecular genetic testing for solid tumors.

This article is intended to be the first of several publications from the molecular oncology subcommittee of the MGPW that address some of the aforementioned tasks. Similar to the recent publication from the hematopathology subcommittee of the MGPW, this article focuses on CNS neoplasms.²

Scope of Problem

The incidence of tumors of the CNS in the US population varies among age groups. It is the most common solid tumor in children aged < 14 years and represents a significant cause of mortality across all age groups.³ Of CNS tumors, diffuse gliomas comprise about 20% of the tumors and more than 70% of the primary malignant CNS tumors.³ Analysis of the VA Central Cancer Registry data from 2010 to 2014 identified 1,186 veterans (about 237 veterans per year) who were diagnosed with diffuse gliomas. (Lynch, Kulich, Colman, unpublished data, February 2018). While the majority (nearly 80%) of these cases were glioblastomas (GBMs), unfortunately a majority of these cases did not undergo molecular testing (Lynch, Kulich, Colman, unpublished data, February 2018).

Although this low rate of testing may be in part reflective of the period from which these data were gleaned (ie, prior to the WHO release of their updated the classification of tumors of the CNS), it is important to raise VA practitioners’ awareness of these recent changes to ensure that veterans receive the proper diagnosis and treatment for their disease. Thus, while the number of veterans diagnosed with diffuse gliomas within the VHA is relatively small in comparison to other malignancies, such as prostatic adenocarcinomas and lung carcinomas, the majority of diffuse gliomas do not seem to be receiving the molecular testing that would be necessary for (1) appropriate classification under the recently revised WHO recommendations; and (2) making important treatment decisions.

Case Presentations

Case 1. A veteran of the Gulf War presented with a 3-month history of possible narcoleptic events associated with a motor vehicle accident. Magnetic resonance imaging (MRI) revealed a large left frontal mass lesion with minimal surrounding edema without appreciable contrast enhancement (Figures 1A, 1B, and 1C). 

Neither mitotic figures nor endothelial proliferation were identified. Immunohistochemical stains revealed a lack of R132H mutant IDH1 protein expression, a loss of nuclear staining for ATRX protein within a substantial number of cells, and a clonal pattern of p53 protein overexpression (Figures 1E, 1F, and 1G). The lesion demonstrated diffuse glial fibrillary acidic protein (GFAP) immunoreactivity and a low proliferation index (as determined by Ki-67 staining; estimated at less than 5%) (Figures 1H and 1I).

Based upon these results, an initial morphologic diagnosis of diffuse glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. While fluorescence in situ hybridization (FISH) studies were negative for 1p/19q codeletion, pyrosequencing analysis revealed the presence of a c.394C>T (R132C) mutation of the IDH1 gene (Figure 1J). The University of Pittsburgh Medical Center’s GlioSeq targeted next-generation sequence (NGS) analysis confirmed the presence of the c.394C > T mutation in IDH1 gene.⁴ Based upon this additional information, a final integrated morphologic and molecular diagnosis of diffuse astrocytoma, IDH-mutant was rendered.

Case 2. A Vietnam War veteran presented with a 6-week history of new onset falls with associated left lower extremity weakness. A MRI revealed a right frontoparietal mass lesion with surrounding edema without appreciable contrast enhancement (Figures 2A, 2B, and 2C). 

Immunohistochemical stains revealed R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, the lack of a clonal pattern of p53 protein overexpression, diffuse GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 20% (Figures 2E, 2F, 2G, 2H and 2I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were positive for 1p/19q codeletion, and pyrosequencing analysis confirmed the immunohistochemical findings of a c.395G>A (R132H) mutation of the IDH1 gene (Figure 2J). GlioSeq targeted NGS analysis confirmed the presence of the c.395G>A mutation in the IDH1 gene, a mutation in the telomerase reverse transcriptase (TERT) promoter, and possible decreased copy number of the CIC (chromosome 1p) and FUBP1 (chromosome 19q) genes.

A final integrated morphologic and molecular diagnosis of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted was rendered based on the additional information. With this final diagnosis, methylation analysis of the MGMT gene promoter, which was performed for prognostic and predictive purposes, was identified in this case.^5,6

Case 3. A veteran of the Vietnam War presented with a new onset seizure. A MRI revealed a focally contrast-enhancing mass with surrounding edema within the left frontal lobe (Figures 3A, 3B, and 3C). 

Hematoxylin and eosin (H&E) stained sections following formalin fixation and paraffin embedding demonstrated similar findings (Figure 3D), and while mitotic figures were readily identified, areas of necrosis were not identified and endothelial proliferation was not a prominent feature. Immunohistochemical stains revealed no evidence of R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, a clonal pattern of p53 protein overexpression, patchy GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 50% (Figures 3E, 3F, 3G, 3H, and 3I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and the tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were negative for EGFR gene amplification and 1p/19q codeletion, although a gain of the long arm of chromosome 1 was detected. Pyrosequencing analysis for mutations in codon 132 of the IDH1 gene revealed no mutations (Figure 3J). GlioSeq targeted NGS analysis identified mutations within the NF1, TP53, and PIK3CA genes without evidence of mutations in the IDH1, IDH2, ATRX, H3F3A, or EGFR genes or the TERT promoter. Based upon this additional information, a final integrated morphologic and molecular diagnosis of GBM, IDH wild-type was issued. The MGMT gene promoter was negative for methylation, a finding that has prognostic and predictive impact with regard to treatment with temazolamide.^7-9

New Diffuse Glioma Classification

Since the issuance of the previous edition of the WHO classification of CNS tumors in 2007, several sentinel discoveries have been made that have advanced our understanding of the underlying biology of primary CNS neoplasms. Since a detailed review of these findings is beyond the scope and purpose of this manuscript and salient reviews on the topic can be found elsewhere, we will focus on the molecular findings that have been incorporated into the recently revised WHO classification.¹⁰ The importance of providing such information for proper patient management is illustrated by the recent acknowledgement by the American Academy of Neurology that molecular testing of brain tumors is a specific area in which there is a need for quality improvement.¹¹ Therefore, it is critical that these underlying molecular abnormalities are identified to allow for proper classification and treatment of diffuse gliomas in the veteran population.

As noted previously, based on VA cancer registry data, diffuse gliomas are the most commonly encountered primary CNS cancers in the veteran population. Several of the aforementioned seminal discoveries have been incorporated into the updated classification of diffuse gliomas. While the recently updated WHO classification allows for the assignment of “not otherwise specified (NOS)” diagnostic designation, this category must be limited to cases where there is insufficient data to allow for a more precise classification due to sample limitations and not simply due to a failure of VA pathology laboratories to pursue the appropriate diagnostic testing.

Figure 4 presents the recommended diagnostic workflow for the workup of diffuse gliomas. As illustrated in the above cases, a variety of different methodologies, including immunohistochemical, FISH, loss of heterozygosity analysis, traditional and NGS may be applied when elucidating the status of molecular events at critical diagnostic branch points. 

Diagnostic Uses of Molecular Testing

While the case studies in this article demonstrate the use of ancillary testing and provide a suggested strategy for properly subclassifying diffuse gliomas, inherent in this strategy is the assumption that, based upon the initial clinical and pathologic information available, one can accurately categorize the lesion as a diffuse glioma. In reality, such a distinction is not always a straightforward endeavor. It is well recognized that a proportion of low-grade, typically radiologically circumscribed, CNS neoplasms, such as pilocytic astrocytomas and glioneuronal tumors, may infiltrate the surrounding brain parenchyma. In addition, many of these low-grade CNS neoplasms also may have growth patterns that are shared with diffuse gliomas, a diagnostic challenge that often can be further hampered by the inherent limitations involved in obtaining adequate samples for diagnosis from the CNS.

Although there are limitations and caveats, molecular diagnostic testing may be invaluable in properly classifying CNS tumors in such situations. The finding of mutations in the IDH1 or IDH2 genes has been shown to be very valuable in distinguishing low-grade diffuse glioma from both nonneoplastic and low-grade circumscribed neuroepithelial neoplasms that may exhibit growth patterns that can mimic those of diffuse gliomas.^15-17 Conversely, finding abnormalities in the BRAF gene in a brain neoplasm that has a low-grade morphology suggests that the lesion may represent one of these low-grade lesions such as a pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or mixed neuronal-glial tumor as opposed to a diffuse glioma.^18,19

Depending upon the environment in which one practices, small biopsy specimens may be prevalent, and unfortunately, it is not uncommon to obtain a biopsy that exhibits a histologic growth pattern that is discordant from what one would predict based on the clinical context and imaging findings. Molecular testing may be useful in resolving discordances in such situations. If a biopsy of a ring-enhancing lesion demonstrates a diffuse glioma that doesn’t meet WHO grade IV criteria, applying methodologies that look for genetic features commonly encountered in high-grade astrocytomas may identify genetic abnormalities that suggest a more aggressive lesion than is indicated by the histologic findings. The presence of genetic abnormalities such as homozygous deletion of the CDKN2A gene, TERT promoter mutation, loss of heterozygosity of chromosome 10q and/or phosphatase and tensin homolog (PTEN) mutations, EGFR gene amplification or the presence of the EGFR variant III are a few findings that would suggest the aforementioned sample may represent an undersampling of a higher grade diffuse astrocytoma, which would be important information to convey to the treating clinicians.^20-26

Testing In the VA

The goals of the MPWG include promoting increased quality and availability of genetic testing within the VHA as well as encouraging internal referral testing. An informal survey of the chiefs of VA Pathology and Laboratory Medicine Services was conducted in November of 2017 in an attempt to identify internal VA pathology laboratories currently conducting testing that may be of use in the workup of diffuse gliomas (Table 1). 

The VA currently offers NGS panels for patients with advanced-stage malignancies under the auspices of the Precision Oncology Program, whose reports provide both (1) mutational analyses for genes such as TP53, ATRX, NF1, BRAF, PTEN, TERT IDH1, and IDH2 that may be useful in the proper classifying of high-grade diffuse gliomas; and (2) information regarding clinical trials for which the veteran may be eligible for based on their glioma’s mutational profile. Interested VA providers should visit tinyurl.com/precisiononcology/ for more information about this program. Finally, although internal testing within VA laboratories is recommended to allow for the development of more cost-effective testing, testing may be performed through many nationally contracted reference laboratories.

Conclusion

In light of the recent progress made in our understanding of the molecular events of gliomagenesis, the way we diagnose diffuse gliomas within the CNS has undergone a major paradigm shift. While histology still plays a critical role in the process, we believe that additional ancillary testing is a requirement for all diffuse gliomas diagnosed within VA pathology laboratories. In the context of recently encountered cases, we have provided a recommended workflow highlighting the testing that can be performed to allow for the proper diagnosis of our veterans with diffuse gliomas (Figure 4).

Unless limited by the amount of tissue available for such tests, ancillary testing must be performed on all diffuse gliomas diagnosed within the VA system to ensure proper diagnosis and treatment of our veterans with diffuse gliomas. 

Acknowledgments
The authors thank Dr. Craig M. Horbinski (Feinberg School of Medicine, Northwestern University) and Dr. Geoffrey H. Murdoch (University of Pittsburgh) for their constructive criticism of the manuscript. We also thank the following individuals for past service as members of the molecular oncology subcommittee of the MGPW: Dr. George Ansstas (Washington University School of Medicine), Dr. Osssama Hemadeh (Bay Pines VA Health Care System), Dr. James Herman (VA Pittsburgh Healthcare System), and Dr. Ryan Phan (formerly of the VA Greater Los Angeles Healthcare System) as well as the members of the Veterans Administration pathology and laboratory medicine service molecular genetics pathology workgroup.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Dr. Kulich is the Acting Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System and member of the Division of Neuropathology at University of Pittsburgh Department of Pathology, Dr. Duvvuri is an Otolaryngologist at VA Pittsburgh Healthcare System, and Dr. Passero is the Section Chief of Hematology\Oncology at VA Pittsburgh Healthcare System in Pennsylvania. Dr. Becker is an Oncologist at VA-New York Harbor Healthcare System. Dr. Dacic is a Pathologist at University of Pittsburgh Department of Pathology in Pennsylvania. Dr. Ehsan is Chief of Pathology and Laboratory Medicine Services at the South Texas Veterans Healthcare System in San Antonio. Dr. Gutkin is the former Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System. Dr. Hou is a Pathologist at St. Louis VA Medical Center in Missouri. Dr. Icardi is the VA National Director of Pathology and Laboratory Medicine Services. Dr. Lyle is a Pathologist at Bay Pine Health Care System in Florida. Dr. Lynch is an Investigator at VA Salt Lake Health Care System Informatics and Computing Infrastructure. Dr. Montgomery is an Oncologist at VA Puget Sound Health Care System, in Seattle, Washington. Dr. Przygodzki is the Director of Genomic Medicine Implementation and Associate Director of Genomic Medicine for the VA. Dr. Colman is a Neuro-Oncologist at George E. Wahlen VA Medical Center and the Director of Medical Neuro-Oncology at the Huntsman Cancer Institute, Salt Lake City, Utah.

Correspondence: Dr. Kulich ([email protected])

Over the past few decades, our understanding of the molecular underpinning of primary neoplasms of the central nervous system (CNS) has progressed substantially. Thanks in large part to this expansion in our knowledge base, the World Health Organization (WHO) has recently updated its classification of tumors of the CNS.¹ One of the key elements of this update was the inclusion of molecular diagnostic criteria for the classification of infiltrating gliomas. While the previous classification system was based upon histologic subtypes of the tumor (astrocytoma, oligodendroglioma, and oligoastrocytoma), the revised classification system incorporates molecular testing to establish the genetic characteristics of the tumor to reach a final integrated diagnosis.

In this article, we present 3 cases to highlight some of these recent changes in the WHO diagnostic categories of primary CNS tumors and to illustrate the role of specific molecular tests in reaching a final integrated diagnosis. We then propose a clinical practice guideline for the Veterans Health Administration (VHA) that recommends use of molecular testing for veterans as part of the diagnostic workup of primary CNS neoplasms.

Purpose

In 2013 the VHA National Director of Pathology & Laboratory Medicine Services (P&LMS) chartered a national molecular genetics pathology workgroup (MGPW) that was charged with 4 specific tasks: (1) Provide recommendations about the effective use of molecular genetic testing for veterans; (2) Promote increased quality and availability of molecular testing within the VHA; (3) Encourage internal referral testing; and (4) Create an organizational structure and policies for molecular genetic testing and laboratory developed tests. The workgroup is currently composed of 4 subcommittees: genetic medicine, hematopathology, pharmacogenomics, and molecular oncology. The molecular oncology subcommittee is focused upon molecular genetic testing for solid tumors.

This article is intended to be the first of several publications from the molecular oncology subcommittee of the MGPW that address some of the aforementioned tasks. Similar to the recent publication from the hematopathology subcommittee of the MGPW, this article focuses on CNS neoplasms.²

Scope of Problem

The incidence of tumors of the CNS in the US population varies among age groups. It is the most common solid tumor in children aged < 14 years and represents a significant cause of mortality across all age groups.³ Of CNS tumors, diffuse gliomas comprise about 20% of the tumors and more than 70% of the primary malignant CNS tumors.³ Analysis of the VA Central Cancer Registry data from 2010 to 2014 identified 1,186 veterans (about 237 veterans per year) who were diagnosed with diffuse gliomas. (Lynch, Kulich, Colman, unpublished data, February 2018). While the majority (nearly 80%) of these cases were glioblastomas (GBMs), unfortunately a majority of these cases did not undergo molecular testing (Lynch, Kulich, Colman, unpublished data, February 2018).

Although this low rate of testing may be in part reflective of the period from which these data were gleaned (ie, prior to the WHO release of their updated the classification of tumors of the CNS), it is important to raise VA practitioners’ awareness of these recent changes to ensure that veterans receive the proper diagnosis and treatment for their disease. Thus, while the number of veterans diagnosed with diffuse gliomas within the VHA is relatively small in comparison to other malignancies, such as prostatic adenocarcinomas and lung carcinomas, the majority of diffuse gliomas do not seem to be receiving the molecular testing that would be necessary for (1) appropriate classification under the recently revised WHO recommendations; and (2) making important treatment decisions.

Case Presentations

Case 1. A veteran of the Gulf War presented with a 3-month history of possible narcoleptic events associated with a motor vehicle accident. Magnetic resonance imaging (MRI) revealed a large left frontal mass lesion with minimal surrounding edema without appreciable contrast enhancement (Figures 1A, 1B, and 1C). 

Neither mitotic figures nor endothelial proliferation were identified. Immunohistochemical stains revealed a lack of R132H mutant IDH1 protein expression, a loss of nuclear staining for ATRX protein within a substantial number of cells, and a clonal pattern of p53 protein overexpression (Figures 1E, 1F, and 1G). The lesion demonstrated diffuse glial fibrillary acidic protein (GFAP) immunoreactivity and a low proliferation index (as determined by Ki-67 staining; estimated at less than 5%) (Figures 1H and 1I).

Based upon these results, an initial morphologic diagnosis of diffuse glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. While fluorescence in situ hybridization (FISH) studies were negative for 1p/19q codeletion, pyrosequencing analysis revealed the presence of a c.394C>T (R132C) mutation of the IDH1 gene (Figure 1J). The University of Pittsburgh Medical Center’s GlioSeq targeted next-generation sequence (NGS) analysis confirmed the presence of the c.394C > T mutation in IDH1 gene.⁴ Based upon this additional information, a final integrated morphologic and molecular diagnosis of diffuse astrocytoma, IDH-mutant was rendered.

Case 2. A Vietnam War veteran presented with a 6-week history of new onset falls with associated left lower extremity weakness. A MRI revealed a right frontoparietal mass lesion with surrounding edema without appreciable contrast enhancement (Figures 2A, 2B, and 2C). 

Immunohistochemical stains revealed R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, the lack of a clonal pattern of p53 protein overexpression, diffuse GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 20% (Figures 2E, 2F, 2G, 2H and 2I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were positive for 1p/19q codeletion, and pyrosequencing analysis confirmed the immunohistochemical findings of a c.395G>A (R132H) mutation of the IDH1 gene (Figure 2J). GlioSeq targeted NGS analysis confirmed the presence of the c.395G>A mutation in the IDH1 gene, a mutation in the telomerase reverse transcriptase (TERT) promoter, and possible decreased copy number of the CIC (chromosome 1p) and FUBP1 (chromosome 19q) genes.

A final integrated morphologic and molecular diagnosis of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted was rendered based on the additional information. With this final diagnosis, methylation analysis of the MGMT gene promoter, which was performed for prognostic and predictive purposes, was identified in this case.^5,6

Case 3. A veteran of the Vietnam War presented with a new onset seizure. A MRI revealed a focally contrast-enhancing mass with surrounding edema within the left frontal lobe (Figures 3A, 3B, and 3C). 

Hematoxylin and eosin (H&E) stained sections following formalin fixation and paraffin embedding demonstrated similar findings (Figure 3D), and while mitotic figures were readily identified, areas of necrosis were not identified and endothelial proliferation was not a prominent feature. Immunohistochemical stains revealed no evidence of R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, a clonal pattern of p53 protein overexpression, patchy GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 50% (Figures 3E, 3F, 3G, 3H, and 3I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and the tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were negative for EGFR gene amplification and 1p/19q codeletion, although a gain of the long arm of chromosome 1 was detected. Pyrosequencing analysis for mutations in codon 132 of the IDH1 gene revealed no mutations (Figure 3J). GlioSeq targeted NGS analysis identified mutations within the NF1, TP53, and PIK3CA genes without evidence of mutations in the IDH1, IDH2, ATRX, H3F3A, or EGFR genes or the TERT promoter. Based upon this additional information, a final integrated morphologic and molecular diagnosis of GBM, IDH wild-type was issued. The MGMT gene promoter was negative for methylation, a finding that has prognostic and predictive impact with regard to treatment with temazolamide.^7-9

New Diffuse Glioma Classification

Since the issuance of the previous edition of the WHO classification of CNS tumors in 2007, several sentinel discoveries have been made that have advanced our understanding of the underlying biology of primary CNS neoplasms. Since a detailed review of these findings is beyond the scope and purpose of this manuscript and salient reviews on the topic can be found elsewhere, we will focus on the molecular findings that have been incorporated into the recently revised WHO classification.¹⁰ The importance of providing such information for proper patient management is illustrated by the recent acknowledgement by the American Academy of Neurology that molecular testing of brain tumors is a specific area in which there is a need for quality improvement.¹¹ Therefore, it is critical that these underlying molecular abnormalities are identified to allow for proper classification and treatment of diffuse gliomas in the veteran population.

As noted previously, based on VA cancer registry data, diffuse gliomas are the most commonly encountered primary CNS cancers in the veteran population. Several of the aforementioned seminal discoveries have been incorporated into the updated classification of diffuse gliomas. While the recently updated WHO classification allows for the assignment of “not otherwise specified (NOS)” diagnostic designation, this category must be limited to cases where there is insufficient data to allow for a more precise classification due to sample limitations and not simply due to a failure of VA pathology laboratories to pursue the appropriate diagnostic testing.

Figure 4 presents the recommended diagnostic workflow for the workup of diffuse gliomas. As illustrated in the above cases, a variety of different methodologies, including immunohistochemical, FISH, loss of heterozygosity analysis, traditional and NGS may be applied when elucidating the status of molecular events at critical diagnostic branch points. 

Diagnostic Uses of Molecular Testing

While the case studies in this article demonstrate the use of ancillary testing and provide a suggested strategy for properly subclassifying diffuse gliomas, inherent in this strategy is the assumption that, based upon the initial clinical and pathologic information available, one can accurately categorize the lesion as a diffuse glioma. In reality, such a distinction is not always a straightforward endeavor. It is well recognized that a proportion of low-grade, typically radiologically circumscribed, CNS neoplasms, such as pilocytic astrocytomas and glioneuronal tumors, may infiltrate the surrounding brain parenchyma. In addition, many of these low-grade CNS neoplasms also may have growth patterns that are shared with diffuse gliomas, a diagnostic challenge that often can be further hampered by the inherent limitations involved in obtaining adequate samples for diagnosis from the CNS.

Although there are limitations and caveats, molecular diagnostic testing may be invaluable in properly classifying CNS tumors in such situations. The finding of mutations in the IDH1 or IDH2 genes has been shown to be very valuable in distinguishing low-grade diffuse glioma from both nonneoplastic and low-grade circumscribed neuroepithelial neoplasms that may exhibit growth patterns that can mimic those of diffuse gliomas.^15-17 Conversely, finding abnormalities in the BRAF gene in a brain neoplasm that has a low-grade morphology suggests that the lesion may represent one of these low-grade lesions such as a pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or mixed neuronal-glial tumor as opposed to a diffuse glioma.^18,19

Depending upon the environment in which one practices, small biopsy specimens may be prevalent, and unfortunately, it is not uncommon to obtain a biopsy that exhibits a histologic growth pattern that is discordant from what one would predict based on the clinical context and imaging findings. Molecular testing may be useful in resolving discordances in such situations. If a biopsy of a ring-enhancing lesion demonstrates a diffuse glioma that doesn’t meet WHO grade IV criteria, applying methodologies that look for genetic features commonly encountered in high-grade astrocytomas may identify genetic abnormalities that suggest a more aggressive lesion than is indicated by the histologic findings. The presence of genetic abnormalities such as homozygous deletion of the CDKN2A gene, TERT promoter mutation, loss of heterozygosity of chromosome 10q and/or phosphatase and tensin homolog (PTEN) mutations, EGFR gene amplification or the presence of the EGFR variant III are a few findings that would suggest the aforementioned sample may represent an undersampling of a higher grade diffuse astrocytoma, which would be important information to convey to the treating clinicians.^20-26

Testing In the VA

The goals of the MPWG include promoting increased quality and availability of genetic testing within the VHA as well as encouraging internal referral testing. An informal survey of the chiefs of VA Pathology and Laboratory Medicine Services was conducted in November of 2017 in an attempt to identify internal VA pathology laboratories currently conducting testing that may be of use in the workup of diffuse gliomas (Table 1). 

The VA currently offers NGS panels for patients with advanced-stage malignancies under the auspices of the Precision Oncology Program, whose reports provide both (1) mutational analyses for genes such as TP53, ATRX, NF1, BRAF, PTEN, TERT IDH1, and IDH2 that may be useful in the proper classifying of high-grade diffuse gliomas; and (2) information regarding clinical trials for which the veteran may be eligible for based on their glioma’s mutational profile. Interested VA providers should visit tinyurl.com/precisiononcology/ for more information about this program. Finally, although internal testing within VA laboratories is recommended to allow for the development of more cost-effective testing, testing may be performed through many nationally contracted reference laboratories.

Conclusion

In light of the recent progress made in our understanding of the molecular events of gliomagenesis, the way we diagnose diffuse gliomas within the CNS has undergone a major paradigm shift. While histology still plays a critical role in the process, we believe that additional ancillary testing is a requirement for all diffuse gliomas diagnosed within VA pathology laboratories. In the context of recently encountered cases, we have provided a recommended workflow highlighting the testing that can be performed to allow for the proper diagnosis of our veterans with diffuse gliomas (Figure 4).

Unless limited by the amount of tissue available for such tests, ancillary testing must be performed on all diffuse gliomas diagnosed within the VA system to ensure proper diagnosis and treatment of our veterans with diffuse gliomas. 

Acknowledgments
The authors thank Dr. Craig M. Horbinski (Feinberg School of Medicine, Northwestern University) and Dr. Geoffrey H. Murdoch (University of Pittsburgh) for their constructive criticism of the manuscript. We also thank the following individuals for past service as members of the molecular oncology subcommittee of the MGPW: Dr. George Ansstas (Washington University School of Medicine), Dr. Osssama Hemadeh (Bay Pines VA Health Care System), Dr. James Herman (VA Pittsburgh Healthcare System), and Dr. Ryan Phan (formerly of the VA Greater Los Angeles Healthcare System) as well as the members of the Veterans Administration pathology and laboratory medicine service molecular genetics pathology workgroup.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Dr. Kulich is the Acting Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System and member of the Division of Neuropathology at University of Pittsburgh Department of Pathology, Dr. Duvvuri is an Otolaryngologist at VA Pittsburgh Healthcare System, and Dr. Passero is the Section Chief of Hematology\Oncology at VA Pittsburgh Healthcare System in Pennsylvania. Dr. Becker is an Oncologist at VA-New York Harbor Healthcare System. Dr. Dacic is a Pathologist at University of Pittsburgh Department of Pathology in Pennsylvania. Dr. Ehsan is Chief of Pathology and Laboratory Medicine Services at the South Texas Veterans Healthcare System in San Antonio. Dr. Gutkin is the former Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System. Dr. Hou is a Pathologist at St. Louis VA Medical Center in Missouri. Dr. Icardi is the VA National Director of Pathology and Laboratory Medicine Services. Dr. Lyle is a Pathologist at Bay Pine Health Care System in Florida. Dr. Lynch is an Investigator at VA Salt Lake Health Care System Informatics and Computing Infrastructure. Dr. Montgomery is an Oncologist at VA Puget Sound Health Care System, in Seattle, Washington. Dr. Przygodzki is the Director of Genomic Medicine Implementation and Associate Director of Genomic Medicine for the VA. Dr. Colman is a Neuro-Oncologist at George E. Wahlen VA Medical Center and the Director of Medical Neuro-Oncology at the Huntsman Cancer Institute, Salt Lake City, Utah.

Correspondence: Dr. Kulich ([email protected])

Over the past few decades, our understanding of the molecular underpinning of primary neoplasms of the central nervous system (CNS) has progressed substantially. Thanks in large part to this expansion in our knowledge base, the World Health Organization (WHO) has recently updated its classification of tumors of the CNS.¹ One of the key elements of this update was the inclusion of molecular diagnostic criteria for the classification of infiltrating gliomas. While the previous classification system was based upon histologic subtypes of the tumor (astrocytoma, oligodendroglioma, and oligoastrocytoma), the revised classification system incorporates molecular testing to establish the genetic characteristics of the tumor to reach a final integrated diagnosis.

In this article, we present 3 cases to highlight some of these recent changes in the WHO diagnostic categories of primary CNS tumors and to illustrate the role of specific molecular tests in reaching a final integrated diagnosis. We then propose a clinical practice guideline for the Veterans Health Administration (VHA) that recommends use of molecular testing for veterans as part of the diagnostic workup of primary CNS neoplasms.

Purpose

In 2013 the VHA National Director of Pathology & Laboratory Medicine Services (P&LMS) chartered a national molecular genetics pathology workgroup (MGPW) that was charged with 4 specific tasks: (1) Provide recommendations about the effective use of molecular genetic testing for veterans; (2) Promote increased quality and availability of molecular testing within the VHA; (3) Encourage internal referral testing; and (4) Create an organizational structure and policies for molecular genetic testing and laboratory developed tests. The workgroup is currently composed of 4 subcommittees: genetic medicine, hematopathology, pharmacogenomics, and molecular oncology. The molecular oncology subcommittee is focused upon molecular genetic testing for solid tumors.

This article is intended to be the first of several publications from the molecular oncology subcommittee of the MGPW that address some of the aforementioned tasks. Similar to the recent publication from the hematopathology subcommittee of the MGPW, this article focuses on CNS neoplasms.²

Scope of Problem

The incidence of tumors of the CNS in the US population varies among age groups. It is the most common solid tumor in children aged < 14 years and represents a significant cause of mortality across all age groups.³ Of CNS tumors, diffuse gliomas comprise about 20% of the tumors and more than 70% of the primary malignant CNS tumors.³ Analysis of the VA Central Cancer Registry data from 2010 to 2014 identified 1,186 veterans (about 237 veterans per year) who were diagnosed with diffuse gliomas. (Lynch, Kulich, Colman, unpublished data, February 2018). While the majority (nearly 80%) of these cases were glioblastomas (GBMs), unfortunately a majority of these cases did not undergo molecular testing (Lynch, Kulich, Colman, unpublished data, February 2018).

Although this low rate of testing may be in part reflective of the period from which these data were gleaned (ie, prior to the WHO release of their updated the classification of tumors of the CNS), it is important to raise VA practitioners’ awareness of these recent changes to ensure that veterans receive the proper diagnosis and treatment for their disease. Thus, while the number of veterans diagnosed with diffuse gliomas within the VHA is relatively small in comparison to other malignancies, such as prostatic adenocarcinomas and lung carcinomas, the majority of diffuse gliomas do not seem to be receiving the molecular testing that would be necessary for (1) appropriate classification under the recently revised WHO recommendations; and (2) making important treatment decisions.

Case Presentations

Case 1. A veteran of the Gulf War presented with a 3-month history of possible narcoleptic events associated with a motor vehicle accident. Magnetic resonance imaging (MRI) revealed a large left frontal mass lesion with minimal surrounding edema without appreciable contrast enhancement (Figures 1A, 1B, and 1C). 

Neither mitotic figures nor endothelial proliferation were identified. Immunohistochemical stains revealed a lack of R132H mutant IDH1 protein expression, a loss of nuclear staining for ATRX protein within a substantial number of cells, and a clonal pattern of p53 protein overexpression (Figures 1E, 1F, and 1G). The lesion demonstrated diffuse glial fibrillary acidic protein (GFAP) immunoreactivity and a low proliferation index (as determined by Ki-67 staining; estimated at less than 5%) (Figures 1H and 1I).

Based upon these results, an initial morphologic diagnosis of diffuse glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. While fluorescence in situ hybridization (FISH) studies were negative for 1p/19q codeletion, pyrosequencing analysis revealed the presence of a c.394C>T (R132C) mutation of the IDH1 gene (Figure 1J). The University of Pittsburgh Medical Center’s GlioSeq targeted next-generation sequence (NGS) analysis confirmed the presence of the c.394C > T mutation in IDH1 gene.⁴ Based upon this additional information, a final integrated morphologic and molecular diagnosis of diffuse astrocytoma, IDH-mutant was rendered.

Case 2. A Vietnam War veteran presented with a 6-week history of new onset falls with associated left lower extremity weakness. A MRI revealed a right frontoparietal mass lesion with surrounding edema without appreciable contrast enhancement (Figures 2A, 2B, and 2C). 

Immunohistochemical stains revealed R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, the lack of a clonal pattern of p53 protein overexpression, diffuse GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 20% (Figures 2E, 2F, 2G, 2H and 2I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were positive for 1p/19q codeletion, and pyrosequencing analysis confirmed the immunohistochemical findings of a c.395G>A (R132H) mutation of the IDH1 gene (Figure 2J). GlioSeq targeted NGS analysis confirmed the presence of the c.395G>A mutation in the IDH1 gene, a mutation in the telomerase reverse transcriptase (TERT) promoter, and possible decreased copy number of the CIC (chromosome 1p) and FUBP1 (chromosome 19q) genes.

A final integrated morphologic and molecular diagnosis of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted was rendered based on the additional information. With this final diagnosis, methylation analysis of the MGMT gene promoter, which was performed for prognostic and predictive purposes, was identified in this case.^5,6

Case 3. A veteran of the Vietnam War presented with a new onset seizure. A MRI revealed a focally contrast-enhancing mass with surrounding edema within the left frontal lobe (Figures 3A, 3B, and 3C). 

Hematoxylin and eosin (H&E) stained sections following formalin fixation and paraffin embedding demonstrated similar findings (Figure 3D), and while mitotic figures were readily identified, areas of necrosis were not identified and endothelial proliferation was not a prominent feature. Immunohistochemical stains revealed no evidence of R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, a clonal pattern of p53 protein overexpression, patchy GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 50% (Figures 3E, 3F, 3G, 3H, and 3I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and the tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were negative for EGFR gene amplification and 1p/19q codeletion, although a gain of the long arm of chromosome 1 was detected. Pyrosequencing analysis for mutations in codon 132 of the IDH1 gene revealed no mutations (Figure 3J). GlioSeq targeted NGS analysis identified mutations within the NF1, TP53, and PIK3CA genes without evidence of mutations in the IDH1, IDH2, ATRX, H3F3A, or EGFR genes or the TERT promoter. Based upon this additional information, a final integrated morphologic and molecular diagnosis of GBM, IDH wild-type was issued. The MGMT gene promoter was negative for methylation, a finding that has prognostic and predictive impact with regard to treatment with temazolamide.^7-9

New Diffuse Glioma Classification

Since the issuance of the previous edition of the WHO classification of CNS tumors in 2007, several sentinel discoveries have been made that have advanced our understanding of the underlying biology of primary CNS neoplasms. Since a detailed review of these findings is beyond the scope and purpose of this manuscript and salient reviews on the topic can be found elsewhere, we will focus on the molecular findings that have been incorporated into the recently revised WHO classification.¹⁰ The importance of providing such information for proper patient management is illustrated by the recent acknowledgement by the American Academy of Neurology that molecular testing of brain tumors is a specific area in which there is a need for quality improvement.¹¹ Therefore, it is critical that these underlying molecular abnormalities are identified to allow for proper classification and treatment of diffuse gliomas in the veteran population.

As noted previously, based on VA cancer registry data, diffuse gliomas are the most commonly encountered primary CNS cancers in the veteran population. Several of the aforementioned seminal discoveries have been incorporated into the updated classification of diffuse gliomas. While the recently updated WHO classification allows for the assignment of “not otherwise specified (NOS)” diagnostic designation, this category must be limited to cases where there is insufficient data to allow for a more precise classification due to sample limitations and not simply due to a failure of VA pathology laboratories to pursue the appropriate diagnostic testing.

Figure 4 presents the recommended diagnostic workflow for the workup of diffuse gliomas. As illustrated in the above cases, a variety of different methodologies, including immunohistochemical, FISH, loss of heterozygosity analysis, traditional and NGS may be applied when elucidating the status of molecular events at critical diagnostic branch points. 

Diagnostic Uses of Molecular Testing

While the case studies in this article demonstrate the use of ancillary testing and provide a suggested strategy for properly subclassifying diffuse gliomas, inherent in this strategy is the assumption that, based upon the initial clinical and pathologic information available, one can accurately categorize the lesion as a diffuse glioma. In reality, such a distinction is not always a straightforward endeavor. It is well recognized that a proportion of low-grade, typically radiologically circumscribed, CNS neoplasms, such as pilocytic astrocytomas and glioneuronal tumors, may infiltrate the surrounding brain parenchyma. In addition, many of these low-grade CNS neoplasms also may have growth patterns that are shared with diffuse gliomas, a diagnostic challenge that often can be further hampered by the inherent limitations involved in obtaining adequate samples for diagnosis from the CNS.

Although there are limitations and caveats, molecular diagnostic testing may be invaluable in properly classifying CNS tumors in such situations. The finding of mutations in the IDH1 or IDH2 genes has been shown to be very valuable in distinguishing low-grade diffuse glioma from both nonneoplastic and low-grade circumscribed neuroepithelial neoplasms that may exhibit growth patterns that can mimic those of diffuse gliomas.^15-17 Conversely, finding abnormalities in the BRAF gene in a brain neoplasm that has a low-grade morphology suggests that the lesion may represent one of these low-grade lesions such as a pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or mixed neuronal-glial tumor as opposed to a diffuse glioma.^18,19

Depending upon the environment in which one practices, small biopsy specimens may be prevalent, and unfortunately, it is not uncommon to obtain a biopsy that exhibits a histologic growth pattern that is discordant from what one would predict based on the clinical context and imaging findings. Molecular testing may be useful in resolving discordances in such situations. If a biopsy of a ring-enhancing lesion demonstrates a diffuse glioma that doesn’t meet WHO grade IV criteria, applying methodologies that look for genetic features commonly encountered in high-grade astrocytomas may identify genetic abnormalities that suggest a more aggressive lesion than is indicated by the histologic findings. The presence of genetic abnormalities such as homozygous deletion of the CDKN2A gene, TERT promoter mutation, loss of heterozygosity of chromosome 10q and/or phosphatase and tensin homolog (PTEN) mutations, EGFR gene amplification or the presence of the EGFR variant III are a few findings that would suggest the aforementioned sample may represent an undersampling of a higher grade diffuse astrocytoma, which would be important information to convey to the treating clinicians.^20-26

Testing In the VA

The goals of the MPWG include promoting increased quality and availability of genetic testing within the VHA as well as encouraging internal referral testing. An informal survey of the chiefs of VA Pathology and Laboratory Medicine Services was conducted in November of 2017 in an attempt to identify internal VA pathology laboratories currently conducting testing that may be of use in the workup of diffuse gliomas (Table 1). 

The VA currently offers NGS panels for patients with advanced-stage malignancies under the auspices of the Precision Oncology Program, whose reports provide both (1) mutational analyses for genes such as TP53, ATRX, NF1, BRAF, PTEN, TERT IDH1, and IDH2 that may be useful in the proper classifying of high-grade diffuse gliomas; and (2) information regarding clinical trials for which the veteran may be eligible for based on their glioma’s mutational profile. Interested VA providers should visit tinyurl.com/precisiononcology/ for more information about this program. Finally, although internal testing within VA laboratories is recommended to allow for the development of more cost-effective testing, testing may be performed through many nationally contracted reference laboratories.

Conclusion

In light of the recent progress made in our understanding of the molecular events of gliomagenesis, the way we diagnose diffuse gliomas within the CNS has undergone a major paradigm shift. While histology still plays a critical role in the process, we believe that additional ancillary testing is a requirement for all diffuse gliomas diagnosed within VA pathology laboratories. In the context of recently encountered cases, we have provided a recommended workflow highlighting the testing that can be performed to allow for the proper diagnosis of our veterans with diffuse gliomas (Figure 4).

Unless limited by the amount of tissue available for such tests, ancillary testing must be performed on all diffuse gliomas diagnosed within the VA system to ensure proper diagnosis and treatment of our veterans with diffuse gliomas. 

Acknowledgments
The authors thank Dr. Craig M. Horbinski (Feinberg School of Medicine, Northwestern University) and Dr. Geoffrey H. Murdoch (University of Pittsburgh) for their constructive criticism of the manuscript. We also thank the following individuals for past service as members of the molecular oncology subcommittee of the MGPW: Dr. George Ansstas (Washington University School of Medicine), Dr. Osssama Hemadeh (Bay Pines VA Health Care System), Dr. James Herman (VA Pittsburgh Healthcare System), and Dr. Ryan Phan (formerly of the VA Greater Los Angeles Healthcare System) as well as the members of the Veterans Administration pathology and laboratory medicine service molecular genetics pathology workgroup.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Dr. Kulich is the Acting Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System and member of the Division of Neuropathology at University of Pittsburgh Department of Pathology, Dr. Duvvuri is an Otolaryngologist at VA Pittsburgh Healthcare System, and Dr. Passero is the Section Chief of Hematology\Oncology at VA Pittsburgh Healthcare System in Pennsylvania. Dr. Becker is an Oncologist at VA-New York Harbor Healthcare System. Dr. Dacic is a Pathologist at University of Pittsburgh Department of Pathology in Pennsylvania. Dr. Ehsan is Chief of Pathology and Laboratory Medicine Services at the South Texas Veterans Healthcare System in San Antonio. Dr. Gutkin is the former Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System. Dr. Hou is a Pathologist at St. Louis VA Medical Center in Missouri. Dr. Icardi is the VA National Director of Pathology and Laboratory Medicine Services. Dr. Lyle is a Pathologist at Bay Pine Health Care System in Florida. Dr. Lynch is an Investigator at VA Salt Lake Health Care System Informatics and Computing Infrastructure. Dr. Montgomery is an Oncologist at VA Puget Sound Health Care System, in Seattle, Washington. Dr. Przygodzki is the Director of Genomic Medicine Implementation and Associate Director of Genomic Medicine for the VA. Dr. Colman is a Neuro-Oncologist at George E. Wahlen VA Medical Center and the Director of Medical Neuro-Oncology at the Huntsman Cancer Institute, Salt Lake City, Utah.

Correspondence: Dr. Kulich ([email protected])

The Food and Drug Administration has approved darolutamide for nonmetastatic, castration-resistant prostate cancer.

Olivier Le Moal/Getty Images

The approval was based on improved metastasis-free survival (MFS) in the randomized ARAMIS trial of 1,509 patients with nonmetastatic, castration-resistant prostate cancer.

Median MFS was 40.4 months (95% confidence interval, 34.3 months to not reached) for patients treated with darolutamide, compared with 18.4 months (95% CI, 15.5-22.3 months) for those receiving placebo (hazard ratio, 0.41; 95% CI, 0.34-0.50; P less than .0001), according to the FDA.

MFS is defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.

In ARAMIS, patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554). All patients received a gonadotropin-releasing hormone analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

Overall survival data is not yet mature, the FDA said.

The most common adverse reactions in patients who received darolutamide were fatigue, extremity pain, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm, while seizure incidence was similar in the two arms (0.2%).

The recommended darolutamide dose is 600 mg (two 300-mg tablets) administered orally twice daily with food. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy, the FDA said.

Darolutamide is marketed as Nubeqa by Bayer HealthCare Pharmaceuticals.

 

The Food and Drug Administration has approved darolutamide for nonmetastatic, castration-resistant prostate cancer.

Olivier Le Moal/Getty Images

The approval was based on improved metastasis-free survival (MFS) in the randomized ARAMIS trial of 1,509 patients with nonmetastatic, castration-resistant prostate cancer.

Median MFS was 40.4 months (95% confidence interval, 34.3 months to not reached) for patients treated with darolutamide, compared with 18.4 months (95% CI, 15.5-22.3 months) for those receiving placebo (hazard ratio, 0.41; 95% CI, 0.34-0.50; P less than .0001), according to the FDA.

MFS is defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.

In ARAMIS, patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554). All patients received a gonadotropin-releasing hormone analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

Overall survival data is not yet mature, the FDA said.

The most common adverse reactions in patients who received darolutamide were fatigue, extremity pain, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm, while seizure incidence was similar in the two arms (0.2%).

The recommended darolutamide dose is 600 mg (two 300-mg tablets) administered orally twice daily with food. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy, the FDA said.

Darolutamide is marketed as Nubeqa by Bayer HealthCare Pharmaceuticals.

 

The Food and Drug Administration has approved darolutamide for nonmetastatic, castration-resistant prostate cancer.

Olivier Le Moal/Getty Images

The approval was based on improved metastasis-free survival (MFS) in the randomized ARAMIS trial of 1,509 patients with nonmetastatic, castration-resistant prostate cancer.

Median MFS was 40.4 months (95% confidence interval, 34.3 months to not reached) for patients treated with darolutamide, compared with 18.4 months (95% CI, 15.5-22.3 months) for those receiving placebo (hazard ratio, 0.41; 95% CI, 0.34-0.50; P less than .0001), according to the FDA.

MFS is defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.

In ARAMIS, patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554). All patients received a gonadotropin-releasing hormone analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

Overall survival data is not yet mature, the FDA said.

The most common adverse reactions in patients who received darolutamide were fatigue, extremity pain, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm, while seizure incidence was similar in the two arms (0.2%).

The recommended darolutamide dose is 600 mg (two 300-mg tablets) administered orally twice daily with food. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy, the FDA said.

Darolutamide is marketed as Nubeqa by Bayer HealthCare Pharmaceuticals.