What does the patient&rsquo;s initial presentation suggest to you?

This patient&rsquo;s initial presentation suggests an inflammatory syndrome or a malignancy. Of course, in a patient that is this young and with those symptoms, you may be thinking more towards an inflammatory syndrome. Fortunately, some laboratory tests were done that looked at her ANA and looked at other inflammatory markers. Considering the potential downside risk of this being a malignancy, it&rsquo;s really important to evaluate for both autoimmune diseases and malignancies. The FDG uptake on the PET scan SUV max suggests that this is not a high-grade malignancy, but it certainly does not rule out the possibility of it being a malignancy. The fact that the FNA was uninformative is not too surprising, but it&rsquo;s absolutely the right move for this patient to then go on to have an excisional biopsy to determine: does this patient have a malignancy or should they be pursuing more systemic inflammatory disorders.

David Fajgenbaum, MD, MBA, MSc: Findings From Patient's Initial Presentation

What are the relevant findings from her pathology report?

On excisional biopsy, this patient&rsquo;s lymph nodes were found to have atrophic or regressed germinal centers, plasmacytosis, hypervascularization, and occasional hyperplastic germinal centers. This constellation of features is consistent with a disease called Multicentric Castleman Disease. You would call this patient the plasmacytic subtype, and that&rsquo;s because there&rsquo;s sheet-like plasma cells all throughout the lymph node which is really something that you see in Multicentric Castleman Disease and a few other inflammatory disorders.

Now, when you see these features you can&rsquo;t with certainty say that this is definitely Multicentric Castleman Disease because these particular features, this constellation, can also be seen in other diseases. It can be seen in lymphomas. It can also be seen in autoimmune diseases.

Now that you have a lymph node consistent with Multicentric Castleman Disease, there&rsquo;s really 2 important steps. The first is to perform LANA-1 staining to determine if this lymph node, is it HHV-8-positive or HHV-8-negative, what we call idiopathic. That&rsquo;s the first step. The second step, whether it&rsquo;s positive or negative, is you need to make sure to rule out the other diseases that can mimic it. If it&rsquo;s a positive LANA-1 stain, it&rsquo;s less likely that there&rsquo;s something else but if it&rsquo;s a negative LANA-1 stain, you need to do additional stainings to look for Hodgkin&rsquo;s lymphoma. You need to do additional systemic laboratory evaluation for autoimmune diseases.

David Fajgenbaum, MD, MBA, MSc: Pathology Report Findings

What other tests are important in her diagnostic workup?

In this patient, based on the pathology features that were seen, we&rsquo;re thinking that this could be Multicentric Castleman Disease. So the first thing that we need to do is LANA-1 staining. LANA-1 will tell us if this patient is HHV-8-positive. HHV-8 or KSHV is a virus that typically replicates and can cause a systemic inflammatory syndrome which results in Multicentric Castleman Disease. We know that this typically occurs in patients who are immunocompromised, whether it&rsquo;s through the HIV virus or for some other reason. So the first step is to figure out is this patient HHV-8-positive or negative. In HHV-8-positive MCD, we know that the HHV-8 virus typically replicates in B-cells and then secretes cytokines. It causes a cytokine storm in the lymphoproliferation. That is Castleman Disease. It&rsquo;s the viral replication in the virus that&rsquo;s driving the disease.

Now, in HHV-8-negative Multicentric Castleman Disease, there&rsquo;s a very similar cytokine storm and also lymphoproliferation, but we&rsquo;re not sure what&rsquo;s causing the cytokine storms. So that&rsquo;s why we call it HHV-8-negative or idiopathic Multicentric Castleman Disease. So it&rsquo;s really important to do that LANA-1 stain and then if it&rsquo;s LANA-1 negative, you&rsquo;re leaning towards idiopathic Multicentric Castleman Disease. But it&rsquo;s really important to still consider some additional diseases that can overlap or mimic Multicentric Castleman Disease, and that&rsquo;s Hodgkin lymphoma, non-Hodgkin lymphoma. You want to perform a bone marrow biopsy to make sure there&rsquo;s no clonality within the bone marrow. But, at this stage, we&rsquo;re really thinking, based on the previous labs and the lymph node pathology that this is idiopathic Multicentric Castleman Disease of what&rsquo;s called the plasmacytic subtype.

David Fajgenbaum, MD, MBA, MSc: Important Diagnostic Tests

What is the most likely diagnosis for this patient?

Based on the laboratory values and now the pathology report, as well as the clinical featureselevated platelets, a bit of fluid gain, fevers, night sweats, and some cytopenias, anemia included&mdash;and then based on the lymph node pathology, we are really thinking that this is HHV-8-negative idiopathic Multicentric Castleman Disease.

David Fajgenbaum, MD, MBA, MSc: Diagnosis for This Patient

What are potential treatment options for this patient?

Treatment for HHV-8-negative Multicentric Castleman Disease can be one of 4 categories. Corticosteroids are often used, B-cell depletion with a drug called rituximab, cytotoxic chemotherapy with combinations that often include Cytoxan, and finally antiIL-6 therapy. The order that I went in is really the historical order. So corticosteroids were really the earliest options. Cytotoxic chemotherapy certainly came around at a later stage. But as we&rsquo;ve gotten into the age of monoclonal antibodies rituximab is used more commonly, but anti&ndash;IL-6 therapy with siltuximab, which is the only FDA-approved therapy and EMA-approved therapy, is really the gold standard. It&rsquo;s the only drug that has ever been tested in a randomized controlled trial to test the effectiveness against idiopathic or HHV-8-negative Multicentric Castleman Disease. So a patient like this with a very classic MCD scenario with clear systemic inflammatory symptoms with a systemic cytokine storm, like we&rsquo;re seeing, should respond very well to anti&ndash;IL-6 therapy. So that would be the first choice.

Unfortunately, two-thirds of patients with Multicentric Castleman Disease will not respond to siltuximab, to antiIL-6 therapy. For those patients, after trying siltuximab, if that does not work, then physicians should be considering things like rituximab on those targeted B-cells and also cytotoxic chemotherapycytoxan, etoposide, drugs that can eliminate the activated immune cells. At the heart of idiopathic Multicentric Castleman Disease is an activated immune system. We don&rsquo;t yet know which immune cell is driving this cytokine storm, but, until that time, we use cytotoxic chemotherapy in really treatment refractory patients, so that way we can eliminate all immune cells.

But what I should also say is that patients that do respond to antiIL-6 therapy will generally have a pretty quick or brisk response. So that the ones that will respond will usually begin to turn around pretty quickly after the first dose. It&rsquo;s important to give it at least 1 to 2 doses before making a decision of continuing therapy, but it is generally a fairly quick response.

MCD with David Fajgenbaum, MD, MBA, Msc: Case 1

David Fajgenbaum, MD, MBA, MSc: Findings From Patient's Initial Presentation

David Fajgenbaum, MD, MBA, MSc: Pathology Report Findings

David Fajgenbaum, MD, MBA, MSc: Important Diagnostic Tests

David Fajgenbaum, MD, MBA, MSc: Diagnosis for This Patient

David Fajgenbaum, MD, MBA, MSc: Treatment Options