Centering discussion on the first patient case of BPDCN, expert panelists highlight various assessment tools that may help overcome barriers to an early diagnosis.
Naveen Pemmaraju, MD: This brings us to some cases; we’ve already had a nice discussion. I do want to highlight, I have some questions for both of you about the diagnosis and treatment. So let’s get into this. This is our first case. This is a patient who’s a 71-year-old man. By the way, we should mention, BPDCN [blastic plasmacytoid dendritic cell neoplasm] historically is male predominant. It’s something like 3 or up to 5:1 ratio for various reasons including the incidence of the ZRSR2 slicing factor mutation, which is on the X chromosome. So we have a 71-year-old man who has skin lesions, nobody really knows [what’s going on], he’s going in and out of the primary care clinic, taking antibiotics, steroids, and it’s getting worse. Now he presents to the clinic with circulating blasts, anemia and thrombocytopenia, which is more of a leukemic presentation, fatigue, and sinusitis. The diagnosis is BPDCN. We should say that there was a bone marrow biopsy and a skin biopsy, and as Dr Gru mentioned, a pairing of the 2 in a multidisciplinary format. The ECOG performance status is 1, the heart function is good, the albumin level is good, no major comorbidities for this 71-year-old patient. The question is for both of you, first to Dr Gru. As we talk about diagnostic assessment here, what all do you see as the most beneficial for you at the dermatopathology level and for the clinician? Take us through, and we know there’s no right or wrong answer, we’re all trying to formulate this as we go.
Alejandro Gru, MD: This is an excellent case to go over the multimodality approaches that are done to diagnose BPDCN. You have a patient who has skin lesions, who has peripheral blood cytopenia, and some circulating blasts in the blood. Automatically you can see that this is a patient who has evidence of skin involvement, which you mentioned before is seen in about 80% to 90% of patients with newly diagnosed BPDCN. Then he also has cytopenia, some circulating blasts that essentially suggest that this patient has evidence of peripheral blood and bone marrow involvement. There are multiple diagnostic things that could be done at this point; taking a skin biopsy is a very easy and safe procedure. I also want to emphasize the type of biopsy that is being done. Remember that BPDCN is a malignancy that typically involves the entire dermis and typically the deep subcutis so it is important to have a deep biopsy, preferentially a punch biopsy of the skin. On that skin biopsy we can [check for] a multiplicity of immunohistochemical markers to reach the diagnosis.
You have a patient who has cytopenias and a concern for bone marrow involvement, so this is someone for whom essentially I would likely send peripheral blood for flow cytometry and perform a bone marrow biopsy to send for flow cytometry and additional molecular cytogenetic findings. So this is someone who’s going to get FISH [fluorescence in situ hybridization] done, conventional cytogenetics, and in this era of course they will get a panel of mutational profiling using next-generation sequencing for common myeloid mutated genes.
Immunohistochemistry and immunophenotyping by flow cytometry are 2 very strong techniques that we use to reach the diagnosis. Both of those have similar markers that we can use. CD123, CD4, and CD56 are markers that could be done either by immunohistochemistry or flow cytometry. The antibodies are very good, very robust. The CD123 expression by flow cytometry tends to be pretty intense and bright. Of course you’re going to look at other markers like CD4 and CD56. But as you mentioned, the first thing that is going to come in the differential and perhaps is more common than BPDCN, is a patient who has an acute myeloid leukemia [AML] that has evidence of secondary skin involvement. That’s going to be your critical working diagnosis.
How are we going to separate those two? We’re going to use lineage-defining markers. Myeloperoxidase is the prototype of myeloid antigens that is expressed in acute myeloid leukemias, but we also know that not all acute myeloid leukemias are going to be myeloperoxidase positive. We can use another marker, by immunohistochemistry for example, lysosome. A lysosome is a marker that typically excludes the diagnosis of BPDCN when we use it on the skin. Sometimes you can see aberrant antigenic expression of T-cell markers in BPDCN. So that includes things like CD2 or CD7, sometimes we see that. We need to have an exclusion of a T-cell lineage-defining marker like CD3, and we’re going to do the same thing with B-cell lineage-defining markers like CD20, CD10, and CD19.
Naveen Pemmaraju, MD: That’s awesome. I could listen to you all day because I think about these rare diseases a lot, but you underline with your enthusiasm and passion how important it is to get it right for the patient. You have a rare disease, you’re trying to distinguish between several modalities, and it brings me to this question for Dr McCloskey, which is exactly what you’re hitting on. Here we are as 3 experts, we have academic resources, but what does someone do when they’re not in an academic center? They’re in a community setting or a hybrid setting. There are some barriers here to even getting a diagnosis, much less medical care. I was hoping you could comment on that, James.
James McCloskey, MD: I think the first thing is having this on your radar. What we’re talking about now is really important. New therapies that have come into this space have heightened people’s awareness, but I think that depending on how you even define academic, there are places where I still talk to folks and they say, “We’ve never seen this.” You sort of know that can’t be true, right? There had to be 1 case in the last 10 years there. So I think first is having it on your radar, having a clinical suspicion, and then chasing the diagnosis, biopsying.
In our experience probably half of the cases that we see were not initially diagnosed as BPDCN. There was always something that didn’t fit. There was something that pathologists struggled with that didn’t feel quite right, but in an effort to arrive at a final diagnosis they shoved it in a box it didn’t belong in. I think the first thing is to do a thorough work-up and biopsy your skin lesions. Also go ahead and biopsy lymph nodes because a lot of these people do have lymphadenopathy as well.
Lastly, I think the biggest thing is that in AML, until the last few years, there’s always been a huge rush and desire to treat patients immediately. I think that persists in the community, and that often means that we might jump to the wrong diagnosis before all the results come back. For everyone listening, [it’s important] to remember that, especially for your older patients, we know that it’s appropriate to wait for some of those tests to come back. Complete the work-up if the patient is stable and otherwise not suffering complications from the disease itself because we might arrive at a different answer if we give time for some of these results to come back.
Naveen Pemmaraju, MD: That’s a great discussion gentlemen.
Transcript edited for clarity.