 I want to point out 1 other thing in the small print. Because is the case for many pathologists on that committee, they say “If you don’t do it, you miss some important prognostic information on the presence of fibrosis.” Of course, I don’t know what to do with that prognostic information, so that doesn’t sway me 1 way or the other. How about you?

That’s a good point because the patients always worry about the long-term outcome of the disease. By default, they say it’s benign, but there is a proportion of the patients, about 20% to 25% of patients who, over their life span, may progress to myelofibrosis, and a certain small percentage who will develop leukemia.

Myelofibrosis in particular is the worry because, when you transform officially, the life expectancy can shorten. The bone marrow biopsy can provide some useful information to semi-intelligently prognosticate for the future. This is all relative, but if you have a cytogenetic abnormality, an abnormality of chromosomes, which is very rare but not impossible, that would perhaps prejudice most people to have a high risk of change.

The presence of fibrosis at the time of diagnosis of PV [polycythemia vera] is present in up to 20% of the cases; on a scale from 0 to 3, grade 2 is already seen in up to 20% of the patients. I repeat it because it’s important. These patients with PV are at a higher risk of a change to full-blown myelofibrosis during their life span.

This is the kind of information that we would like to have at the beginning for full understanding not only about diagnosis but also possible prognosis for transformation. Not for the thrombotic risk, which I already mentioned as a primary goal of therapy, but for the future. That needs to be highlighted: the presence of the fibrosis does not mean myelofibrosis by default. Fibrosis can to some degree be seen in PV.

 Thanks, Srdan. Ruben, do you want to add to that?

I just wanted to add an important point that I share with patients, which is that I agree that baseline bone marrow biopsy is helpful. The challenge is if we see a bit of fibrosis and they have that higher risk, we still don’t know what that means in absolute terms. If I compare 2 patients—1 without that fibrosis and 1 with—yes, the patient who has the fibrosis has a higher likelihood of progression through myelofibrosis, but that might be in 10 years compared with the other patient who will never progress during their life span.

As we think about these prognostic factors, it is worse as a population, but it’s always difficult to translate for a patient what that means. Additionally, all of that is in current science. We may well develop therapies, or some of our current therapies might alter that natural history further. So prognostic always has to be taken in appropriate consideration; sometimes patients can become very distressed by some of these prognostic findings as well.

 As everybody said, the bone marrow biopsy may or may not be important. The 1 piece I wanted to add in PV is for patients who may not meet the criteria. Let’s say you have a 

 V617F positivity, and you’re entertaining an MPN [myeloproliferative neoplasm]. Perhaps the hemoglobin isn’t 16.5 or 18.5 g/dL, where you don’t have to do a marrow, but perhaps it’s 13 g/dL. If you did the bone marrow and then you get an iron stain, which I highly recommend on anybody who has a marrow with the suspicion of an MPN, that has 0 iron in it. If you have absent iron stores, then your patient clearly is iron deficient and may have PV, even though the hemoglobin doesn’t necessarily meet the criteria.

In that sense, when the heme parameters do not fit the WHO [World Health Organization classification and diagnostic criteria for myeloproliferative neoplasms] 2016 as opposed to 2017, as it says in the NCCN [National Comprehensive Cancer Network] Guidelines, it has to be performed so that you can characterize the MPN a bit better and pay attention to the iron piece. I often see it done, yet nobody comments on it, and we could improve a lot on the prognostic accuracy of the characteristics of the MPN we’re looking for.

 I agree with that. The iron stain can be helpful in those borderline cases, and I often look for iron deficiency.

Videos

Polycythemia Vera: Bone Marrow Biopsies

 Let’s move on. Srdan, I’d like you to discuss how patients with PV [polycythemia vera] present and what the differential diagnosis of that presentation is.

Although polycythemia vera is the name, it implies that all the cells grow, which is true. 

 means high blood cell count: red blood cells, white blood cells, and lipids. Not everybody has high white cells and high platelets, but everybody does have high red blood cell counts. The cardinal feature of polycythemia vera is a high red blood cell count.

That can be in a setting of blood clots at the time of the presentation in about 20% of the patients, and it’s often associated with the systemic symptoms: itching, night sweating, low-grade fever, fatigue, flushing in the face, not feeling well overall, memory loss, and blurred vision are symptoms related to impaired circulation in the body because there are too many cells in the blood vessels. These are the characteristics of the patients we see, but not every patient who has a high red blood cell count has polycythemia vera.

As you alluded in your impression, there are other conditions that may resemble these kinds of presentations. Particularly in the setting of younger people, we need to be cautious when we look at the erythrocytosis associated with the use of certain medications like testosterone. Erythrocytosis is associated with problems with lung function—people who had sleep apnea, for example. There are also problems related to certain cancers—kidney cancer, for example.

Not everybody who has high a red blood cell count has polycythemia vera. The first goal is to make sure we are talking about the bone marrow neoplasm and not reactivated erythrocytosis, because the approach is different. With the disease, we have not only the number of cells increasing but also their activity. They are sticky, and that is the problem: too many cells that are sticking together, and that increases the risk of thrombosis. Therefore, the approach there is to decrease the thrombotic risk in polycythemia vera patients.

To go back to the diagnostic process, once we roll out the secondary diseases that would increase blood cell counts, which are usually benign, you would look at lung functions, medications, and other possible causes. You would focus specifically on the criteria for PV that, in 2016, has been simplified and modified to quite a significant degree. We now have 3 major criteria to fulfill, or you can fill at least 2 of them, and I’ll give you a brief summary of those.

The cardinal picture is high red blood cell count. We are talking about decreased hematocrit or hemoglobin, as is routine when you do CBC [complete blood count]. That should be associated with the testing you can do in blood for the presence of 

 V617F mutation, which is present in about 95% of the patients, or in those who don’t have that 1, testing for 

That will cover almost everybody: either of the 2 mutations, and there is still a possibility of having anecdotal cases of patients who do not have any of these, which may be a matter of the sensitivity of the test, or they have something else that can link mutation for which we cannot test.

 mutation, and then the question of the bone marrow biopsy: Do you need to have it done? In the synopsis for the diagnostic criteria it says No. 1, high red blood cell count; No. 2, bone marrow biopsy; and No. 3, the 

 mutation. If you have all 3, you have PV, no question about it, but there is a minor criterion there which is suboptimal serum erythropoietin level, meaning low erythropoietin level.

It’s in case you cannot do genetic testing. The purpose of genetic testing is to fulfill diagnostic criteria, but sometimes you may not have it, or the testing is not available. You can use the high red blood cell count, the bone marrow, and the suboptimal erythropoietin as a combination for making diagnosis. This is the standard practice.

Many ask the question: Do we need to do a bone marrow biopsy in every single case? If you read the guidance on how the diagnosis process needs to be done, it clearly says in the small print—and that’s the problem, it’s very small—that you don’t need to do it every single time. If you have an above-normal red blood cell count, a 

 mutation, and a suboptimal erythropoietin level, there is no other disease than polycythemia vera that can cause this trifecta of findings.

In that case, with very high red blood cell count above normal, 

 mutation on blood protein, and a low erythropoietin level, that’s PV. I don’t do the bone marrow biopsies, and the small print in the guidance says not to do it.

I hope I simplified for you what needs to be done to get the diagnosis of PV.

Polycythemia Vera: Diagnostic Work-up

®, titled “Updates in the Management of Myeloproliferative Neoplasms.” I am Dr Harry Erba from Duke Cancer Institute. Joining me today in this virtual discussion are my colleagues Dr Krisstina Gowin from the University of Arizona Cancer Center; Dr Ruben Mesa from the University of Texas Health San Antonio MD Anderson Cancer Center; Dr Jamile Shammo from Rush University Medical Center; and Dr Srdan Verstovsek from The University of Texas MD Anderson Cancer Center.

Today we are going to discuss a number of topics pertaining to the management of myeloproliferative neoplasms, including practical information for community oncologists. Let’s get started on our first topic. I’m going to turn to you, Dr Gowin, if you don’t mind. Krisstina, can you provide an overview of the myeloproliferative neoplasms?

Absolutely. Good morning. Myeloproliferative neoplasms are a type of chronic myeloid malignancy that are characterized by overproduction of mature blood cells. They are characterized by a 

 nipple or other clonal mutations. They are also characterized, and this recently been described more eloquently over the last decade, by a very heterogenous symptom burden.

 That’s great. There are various types. Those are similarities; how do we distinguish these?

What’s interesting about myeloproliferative neoplasms is that it’s truly a spectrum of disorders. There’s a dynamic nature within the different umbrella of myeloproliferative neoplasms.

When we’re looking at these patients, we’re first asking if this is a classical myeloproliferative neoplasm or is there a Philadelphia chromosome involved, and that would be more diagnostic and a CML [chronic myelogenous leukemia]–type of picture. Within the classical myeloproliferative neoplasms, there are 3 different entities: polycythemia vera, myelofibrosis, and essential thrombocythemia. Polycythemia vera is classified based on a tri-lineage hematopoiesis, a very symptomatic splenomegaly, and a diffuse, heterogenous symptom burden.

Myelofibrosis, in contrast, is more of a fibrosis: scarring of the bone marrow that can lead to more of a cytopenic phase, rather than the hyperproliferative phase that we see with polycythemia. You can get this cyto-proliferation, this high burden of both white blood cells and platelets within myelofibrosis, as well. They tend to be more symptomatic and have a worse associated prognosis.

Finally, essential thrombocythemia is characterized by increased thrombocytosis as well as a very significant symptom burden. The treatment goals are different within these categories in that, for both polycythemia vera and essential thrombocythemia, it’s looking at the thrombotic and hemorrhagic complications of the disease; in myelofibrosis, we’re focusing more on spleen reduction and symptom burden.

Characterization of Myeloproliferative Neoplasms

As fellows in oncology, we are constantly required to assimilate data, interpret diagnostic tests, decide on appropriate treatment regimens, and employ compassionate care in an increasingly truncated allotment of time. We must simultaneously juggle these responsibilities with each patient, and as we progress in our training, we hardly even notice we have 12 balls in the air at once.

Our thought processes undoubtedly become somewhat automated as we develop our thinking algorithms and we rely more and more on our gestalt assessments of patients. We are trained to treat patients based on evidence-based medicine, a term defined as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.”

Yet, delivery of better medical care requires more from us. It requires a higher level of thinking. In fact, to be the best requires thinking about our thinking. Here, I share 3 cases that exhibit physician errors in cognition and how questioning our thinking may lead to the delivery of better care.

Recently, a 56-year-old male came to me for consultation regarding his newly diagnosed metastatic prostate cancer. He was an anxious marketing associate from the East Coast who presented to his primary care physician with increased urinary frequency, particularly at night. His prostate-specific antigen (PSA) level was found to be elevated at 4.0. He was referred to his local urologist, who recommended a transrectal ultrasound with biopsy, and shortly thereafter the patient was diagnosed with Gleason grade 6 prostate cancer. Prior to starting therapy, he was staged with a positron emission tomography—computed tomography (PET-CT) scan; although not supported by National Comprehensive Cancer Network guidelines, this is a common practice in the community.

The patient was found to have “numerous fluorodeoxyglucose—avid lesions within his osseous skeleton consistent with metastatic prostate cancer.” He presented to my office with the pathology slides, imaging report, and records from another physician noting his diagnosis of metastatic prostate adenocarcinoma. It was a busy day in the clinic, and I was behind schedule. Two patients were already anxiously awaiting their appointments. Initially, I was relieved by what seemed to be an easy consult. It was a cut-and-dried case of prostate cancer. My plan was to start androgen deprivation therapy and move on to the next patient. However, something seemed amiss. He was only 56 years old. He only had Gleason grade 6 prostate cancer. He had no family history of cancer. And yet he presents with widely metastatic disease?

I promptly called the radiologist to review the images. Interestingly, all of his “lesions” were in joint spaces and more typical of degenerative joint disease. This was only arthritis! My instinct had been correct and this patient was misdiagnosed initially. I was able to change his terminal diagnosis of metastatic prostate cancer to a case of local and potentially curable prostate cancer. The patient and his family were ecstatic, but wisely inquired, “How could this have happened?” Where had the medical decision-making gone wrong?

The difficulty in providing an explanation lies, in part, in that no true medical error occurred. It was an error in medical thinking. The radiologist viewed the images under the clinical premise that the patient was recently diagnosed with prostate cancer. He was looking for evidence of prostate cancer and he believed he found it. The radiologist had made an error in medical cognition, namely an “attribution” error. He saw lesions in the skeleton and wrongly attributed them to prostate cancer because he did not question the diagnosis and think, “What else could this be?”

In another case, an 80-year-old grandfather came to me for a consult on the biochemical recurrence of his prostate cancer. He had been diagnosed 5 years earlier and had been successfully treated with brachytherapy. His urologist had trended his PSA and after a long period of being undetectable, it had increased over the preceding 4 months with a doubling time of only 2 months. A CT scan of his abdomen revealed diffuse lymphadenopathy, particularly within the obturator nodes, a pattern typical of metastatic prostate cancer. He was referred to me for treatment of his metastatic disease.

Upon my evaluation, I noted that a serum protein electrophoresis performed 2 years prior showed a mild monoclonal gammopathy that had not been addressed. I diligently performed my evaluation, including work-up of his monoclonal gammopathy, and given the questionable diagnosis of metastatic prostate cancer, elected to refer him for excisional lymph node biopsy. Several days later I was paged by the hematopathologist, who relayed the diagnosis of lymphoplasmacytic lymphoma, or Waldenström’s macroglobulinemia. When the news had been communicated to him, the patient questioned, “How could I be mislabeled as having stage 4 cancer?” How could his trusted urologist make such a mistake?

Our 80-year-old grandfather’s urologist fell into the cognitive error of “anchoring,” or latching on to an already established diagnosis. The urologist opened our patient’s medical record and immediately read the first line of the last note entitled “prostate cancer follow-up.” When his PSA was elevated in the presence of CT-demonstrated lymphadenopathy, his first thought was prostate cancer. “Of course!” the urologist thought. He failed to challenge his own thinking and consider an alternate diagnosis.

A final case demonstrates an “availability” error, when an unusual case creates a sharp bias in medical decisionmaking. A 60-year-old female with newly diagnosed diffuse large B-cell lymphoma underwent routine outpatient chemotherapy utilizing the well-known regimen of R-CHOP (rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, and prednisone). On day 4 of her chemotherapy, she developed tumor lysis syndrome, acute renal failure, and arrhythmias. She died in the intensive care unit later that day.

The attending physician, extremely distraught by the outcome of this patient, subsequently developed a new policy requiring that all of his patients undergoing initial chemotherapy with R-CHOP be admitted to the hospital. He is acutely aware of the lack of evidence to drive his decision and the additional cost, inconvenience, and potential risk of hospital-acquired infections to the patient. His personal experience has driven him to develop a sharp bias in the treatment of his patients. His poignant past experience is cognitively available to cloud future decisions.

These 3 cases demonstrate how cognitive errors can affect medical practice. As Atul Gawande, MD, MPH, writes, “There is science in what we do, yes, but also habit, intuition, and sometimes plain old guessing.” We are human, and by definition, imperfect in our nature. The acceptance of imperfection is our first step toward avoidance of the cognitive error traps. We must constantly be on guard. We must question our conclusions and thought processes. We must continually evaluate our emotions and contemplate how they may affect our assessments.

The errors of attribution, anchoring, and availability are only as strong as our negligence of them. The recognition of the potential for error and resilience to a cavalier mindset is our only insurance. To be better doctors now, and many years from now, we must continue to think about how we think.

			Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. 

Articles

As fellows in oncology, we are constantly required to assimilate data, interpret diagnostic tests, decide on appropriate treatment regimens, and employ compassionate care in an increasingly truncated allotment of time.

The Cognitive Error Paradigm

 Fighting cancer is much like fighting a war. As Sun Tzu states in Art of War, understanding yourself and the enemy will greatly increase the chance for victory. As a fellow in oncology, I have been uniquely primed for the war on cancer. I know the enemy well. However, when a loved one was diagnosed with end-stage cancer, I found I still had much to learn.

Acting as a primary caregiver, and taking a stance from the patient’s angle, taught me more about treating patients with cancer than all of my combined years of medical training.

Despite my medical knowledge and dedication, we ultimately lost our battle, but the war on cancer remains. I hope to take my lessons forward for the benefit of my patients and their families. Having gained perspective from the patient’s point of view, I am now a different doctor.

It is of the utmost importance when fighting cancer that patients have an understanding of their disease and undergo self-reflection while still maintaining a positive mental attitude. We cannot always prevent death, but we may prepare our patients so they are equipped to face it without fear.

Perhaps the most profound lesson learned from my experience was the importance of instilling hope. It is a difficult challenge balancing this essential element with the medical statistics or “realities” of cancer. We must be aware of the truth, but also understand that each case is different.

Fear can be destructive to a patient’s healing process, and can be overwhelming to the patient’s family. In any survival situation, it is vital for a person to have hope. The balance of educating the patient about their opponent, while simultaneously laying the foundation for hope, is a delicate one. Even the masters seem to struggle from time to time. It is now clear to me that this is where the true art of oncology lies.

Every doctor will approach the challenge in a different way, and unfortunately this is an area of discussion that is lacking in medical education. During our medical training, we must take it upon ourselves to master some of the difficult psychosocial challenges as well as the educational ones.

Healthcare is so much bigger than any particular disease. The average person does not interact with healthcare providers enough to consider it a familiar part of life. The simple act of going to see a doctor can be somewhat unnerving and even the best healthcare systems are often frustrating in some way.

We must remember that the patient has more to deal with than just treatment. Many long-term disabilities force patients to also learn a very complex healthcare program, and system inefficiencies add greatly to the stress of patients and their families. It is essential for all healthcare providers, including doctors, nurses, pharmacists, and social workers, to coordinate their efforts in empowering the patient. The healthcare environment must facilitate efficiency and communication.

Many aspects of healing are overwhelming to patients, and one that certainly tops the list is medication. With just about every prescribed medication having a laundry list of side effects, a patient can easily shy away from a medication, or take it improperly, if he or she does not understand how it fits into the larger plan of healing.

As with training a person on anything new, a cycle which includes education, reinforcement, and additional education will serve the patient well and lead to better symptom control, fewer hospital admissions, and better overall outcomes. For example, a high school math teacher is not evaluated on how well he or she knows math, but how well he or she is able to empower students to learn it. In comparison, our ultimate goal is to have the patient leave the facility with a full understanding of treatment techniques and engage in the prescribed method. This is a very large task, evolving emotional coaching as well as education.

There are times when a disease progresses regardless of treatment, or evolves at an unanticipated rate. Patients can easily experience out-of-control type feelings and seek new ways to establish order in their lives. Feelings of helplessness often set in and this can manifest in small acts of defiance. Refusing to eat as suggested, or refusal to take medications, may be the only factor a patient feels he or she can still control. Although the patient may still truly want to do their best to heal, the need to have some control overtakes rational thought. Frustration from the family or medical staff is futile. We must avoid trying to make the patient do what is prescribed, and instead enable them to be a part of the decisionmaking process. There is an art to the gentle empowerment of a patient, and a practitioner who masters this art serves his or her patient well.

Caregivers and practitioners often have their own idea of how the patient’s story will unfold. It should be recognized that the patient is the ultimate director of this. Each patient will have his or her own unique course, and this is particularly apparent when an end-of-life situation is nearing. The process of dying is as individual as we are from one another. Communication and recognition of non-verbal cues are essential during this time. It is important to identify agendas that may be caregiver driven and not reflective of a patient’s goals. End-of-life care requires guidance and skill in listening to the patient fully and allowing them to largely guide the transition.

In conclusion, a vast knowledge of both your opponent and oneself is essential in the battle of cancer. As medical oncologists, we must be intelligent and stealthy in our attack while arming our patients with education and empowerment to heal. However, we must not lose sight of the fundamental element of survival, hope. We will be called upon to fight utilizing tools of our minds, but most importantly, our hearts. Inspiring the patient to live courageously or die gracefully is an undeniable aspect of our field. As future oncologists, we will be faced with many challenges in patient care, and tailoring our art will undoubtedly require a lifetime. To be victorious, we must work to know our enemy, as well as ourselves.

Fighting cancer is much like fighting a war. As Sun Tzu states in Art of War, understanding yourself and the enemy will greatly increase the chance for victory.

Krisstina Gowin, DO, University of Arizona Cancer Center

Articles

Polycythemia Vera: Bone Marrow Biopsies

Polycythemia Vera: Diagnostic Work-up

Characterization of Myeloproliferative Neoplasms

The Cognitive Error Paradigm

Lessons on Treating Cancer: A Caregiver's Perspective