Ensuring an Accurate Diagnosis

Amy DeZern, MD, MHS: From your perspective, Dr Komrokji, what do community physicians need to look out for in terms of recognizing some of these symptoms and making sure we bring a patient to their accurate diagnosis?

Rami Komrokji, MD: As you mentioned, the symptoms are nonspecific in MDS [myelodysplastic syndrome], and that’s always the challenge. When we see those low counts, the differential diagnosis could be wide, from nonhematologic conditions to hematologic conditions. There are so many things that can resemble MDS. For primary care physician doctors, as you mentioned, when I see some of those patients, I see that they, for example, have some macrocytosis that was present a year or 2 before. From my point of view, I would say that whenever you see bicytopenias, with more than 1 cell line affected, that’s probably a red flag or a trigger to have a little more thorough evaluation and to look at the bone marrow and presence of circulating blasts. Obviously, it’s a very good practice to exclude things that resemble MDS or the basic stuff, like nutrition deficiencies, B12, folate, and iron deficiency. There is no doubt that these cytopenias can be caused by other things. It’s important to keep in mind that MDS is not that uncommon actually, and if you think of older patients, it’s probably 1 of the top 5 causes of anemia. It should be on our mind when we are seeing those patients.

That probably leads me to ask you, when you see those patients, what’s the diagnostic work-up that you do?

Amy DeZern, MD, MHS: I do always have it at the forefront of my mind because just like you, the majority of patients in my clinic carry this diagnosis. I like to give them the benefit of the doubt and make sure they’ve had a thorough internal medicine work-up to make sure we aren’t missing what I think of as the masqueraders of MDS. You alluded to the cytopenias. Certainly, I always check peripheral blood counts, and that does include a complete blood count with differential. The differential is quite important. I also always check reticulocyte count. Sometimes that can lead you down a different path if it’s a more hyperproliferative procedure.

I do tend to get iron studies with a focus on the ferritin for iron storage. Folate levels are something that, when I trained, we were taught to always check—and red blood cell folate as opposed to serum. But this is really falling out of favor as the majority of people, at least in the United States, are not folate deficient. I check this less now. I do check a vitamin B12; this certainly can be a masquerader in some. I personally always also check a baseline erythropoietin level as well as a comprehensive metabolic panel because, occasionally, you’ll pick up some quite significant renal insufficiency that could be leading to the anemia or hepatitis that had been previously undiagnosed.

One of my favorite diagnostic tests to send is a copper level. Every once in a while, you get a truly copper-deficient patient that does not have MDS. Last but certainly not least, it’s very important to me that we get a very good bone marrow evaluation, which includes an aspirate. We send flow cytometry on that aspirate. We also do an iron stain at diagnosis, a reticulin stain, and conventional cytogenetics, as well as molecular testing. This is how I tend to approach it, but I’d be very interested to hear if you always do molecular and genetic testing or agree with the work-up that I suggested.

Rami Komrokji, MD: Definitely I agree, and it sounds sometimes that we are talking about simple things. To put this in perspective, just a couple of anecdotes. I had a younger patient who presented—originally on the outside they called it acute myeloid leukemia, and he was transferred to another place and sent to start intensive chemotherapy. They get the bone marrow at the other institution, and the blast percentage was 15%. They started on azacitidine for 6 months, and he was pancytopenic. We see the patient, and it was actually megaloblastoid changes. The patient had a severe vitamin B12 deficiency, that the megaloblastoids were resembling myeloblasts, and with vitamin B12 treatment, he improved. To your favorite copper level, I also had seen a patient last year that was 1 year on azacitidine, labeled as MDS ring sideroblasts, but had neutropenia, thrombocytopenia, and some neurological changes. It was severe copper deficiency. For example, in MDS ring sideroblasts, whenever I don’t see SF3B1 mutation, which is very common, I would not treat a patient without checking a copper level. Although what you went through sounds simple and everybody does it, we’ve seen real cases where it really makes a big difference.

Moving on, when we get the patients, most of the time this has been done. Obviously we get the bone marrow, the aspirate biopsy, and currently we do standardly get a next-generation sequencing on those patients. It’s very helpful. It’s not part of the diagnostic criteria, but it definitely can help you make a new diagnosis. It has some prognostic implications, no doubt, and we are moving now that we are incorporating that in how we manage patients, so we do get molecular testing. In the past, we used to go a little bit more, even sophisticated, checking LDH [lactate dehydrogenase] and flow cytometry on every lower-risk MDS patient. In my experience, the need for that is pretty low, but if I see a high large LGH, low hemoglobin, I may get it because this subset of patients that will have it, most of the time they are minute clones and we don’t have to do anything about them. Then we also used to check for LGL [granular lymphocytic] in almost every patient. Around 20% of these patients will have a small LGL clone, but most of the time it’s not significant. However, there are some cases where LGL would resemble MDS, and the diagnosis will be LGL.

We do get a bone marrow aspirate biopsy. We get a molecular profile. In select cases we may look for LGL, paroxysmal nocturnal hemoglobinuria, and the basic stuff you mentioned. It’s really crucial to get those levels of B12, looking at the retic count, some aspect of hemolysis, and so forth. It’s very important. Making a diagnosis is an important step. There is 1 paper that I know about, from The University of Texas MD Anderson Cancer Center, looking at its experience reviewing outside bone marrows. In 20% of the cases, the diagnosis was changed. Sometimes it’s just a subtle difference between the blast percentage, but in some cases it’s extreme, like the ones we talked about. It was copper deficiency and stuff like that.

Transcript Edited for Clarity