Diagnosis of Castleman's Disease

Corey Casper, MD, MPH:A diagnosis of Castleman’s disease really begins first with suspecting it. It’s a hard disease to keep at the front of your mind for most providers because it is so rare. There’s a classic expression in medicine, when you hear hoof beats, you should think horses not zebras. And most providers on the frontline, when they see a patient who has enlarged lymph nodes or constitutional symptoms, are not thinking about Castleman’s disease. That’s clearly the zebra in the herd, not the horse. So, the first challenge is really knowing when you should suspect it.

In my mind, there are certain risk groups who definitely need to be considered as more likely to develop Castleman’s disease. First, and foremost, those are patients with HIV infection. Patients with HIV infection who are co-infected with human herpesvirus-8 are at a higher risk for developing Castleman’s disease, still not a high risk but significantly higher than the general population. In those patients, I would say anyone who presents with enlarged lymph nodes, constitutional symptoms, unexplained causes of anemia and thrombocytopenia, or high inflammatory markers, you really have to consider a diagnosis of Castleman’s disease.

Really, unfortunately, the only other risk group that, in my mind, I keep at the forefront is patients who do have a family history of autoimmune inflammatory diseases or hematologic malignancies, like lymphoma. And, for patients like that, I also would keep in the forefront of my mind that there may be some predisposition within those individuals for a higher risk of Castleman’s disease. Apart from that, it’s hard to identify someone as having a higher risk for Castleman’s disease just based on what they look like. There’s a relatively equal distribution of men and women. It can be seen in all ethnicities and all ages, as well.

It’s hard to have in your mind a portrait of what you think someone should look like, and that’s really what we do in medicine. We sort of profile people and think about what they are at risk for, and it’s hard to do that with Castleman’s disease. But, certainly, the diagnosis starts by suspecting it and I think that, certainly, anyone who’s had persistent symptoms of fever, night sweats, enlarged lymph nodes, other constitutional symptoms, especially in the setting of having any abnormalities in their blood counts and high inflammatory markers, those are patients that you need to suspect Castleman’s disease in.

One way that we can facilitate providers making a prompter and accurate diagnosis of Castleman’s disease is to incorporate the disease itself in guidelines that are given to physicians for the management of many different conditions. At present, there really aren’t a whole lot of guidelines and recommendations around the treatment of Castleman’s disease, mostly because it is so rare. But, the National Comprehensive Cancer Network has included Castleman’s disease in their diagnostic criteria and does have a series of algorithms for both the suspicion and management. I think that it’s important to think about these things, and guidelines are really a great way to familiarize clinicians, especially with these rare diseases and how to try and standardize the management of them.

But, I think that the thing that is challenging about the NCCN recommendations around diagnosis of Castleman’s disease is that all of the NCCN Guidelines start with a box essentially. It’s a flow diagram, and it starts with a box with when you might suspect the disease. And, if you look at the criteria that the NCCN uses for suspecting a case of Castleman’s disease, it’s a very broad swath of the population. It basically is anyone with a persistence of constitutional symptoms and some associated laboratory abnormalities. And, unfortunately, I think that that applies to many more patients than actually will ever be diagnosed with Castleman’s disease. Is it useful to have a broad set of criteria and have it in national guidelines that providers think about? Of course. On the other hand, I think that it also highlights to me the challenges in trying to standardize or protocolize the thinking about a very rare disease that can have very heterogeneous manifestations.

Two other important tools in making a diagnosis for Castleman’s disease are getting a piece of the involved tissue of the lymph node to make a pathologic diagnosis, and also radiography to show the extent of disease. In my experience, a CT scan with contrast and one applied broadly— neck, chest, abdomen, pelvis–is sufficient to both make a diagnosis and also quantify the extent of disease. Some providers find that it’s useful to get additional information with a PET scan or a PET/CT. The thinking there is that the degree of heat or “hotness” of the lymph node may help to differentiate between infection, Castleman’s disease, and lymphoma. But, in my experience, actually, there can be such overlap and such a heterogeneity in the avidity on a PET scan with Castleman’s disease that I personally don’t find a PET scan to be very helpful in guiding treatment or making a diagnosis. So, certainly a CT scan with contrast applied broadly because, again, [understanding that] lymph nodes can really be anywhere in this disease is essential. Pursuing a biopsy is also essential. Many pathologists will tell you that it’s better to have an excisional biopsy as opposed to a fine-needle aspirate. The reason for that is that the architecture of the lymph node is very important, and, from my perspective, I would say that it certainly is critical.

My first step in making a diagnosis of Castleman’s disease is ruling out lymphoma because there’s an overlap between those two diagnoses, and lymphoma has much more severe consequences and needs to be treated much differently. First in my workup is making sure they don’t have lymphoma, and typically that’s an excisional biopsy of the lymph node and looking for clonality or evidence of restriction of light chains. These are things that I think are critical in making the diagnosis of Castleman’s disease but also ruling out other conditions. For my money, an excisional lymph node biopsy is much preferred to a fine-needle aspirate, even though, obviously, from ease of obtaining the tissue, a fine-needle aspirate may be preferred. But, I think an excisional lymph node biopsy and a CT of the neck, chest, abdomen, and pelvis are really important tests in working up and diagnosing Castleman’s disease.

Corey Casper, MD, provides information on the diagnosis and treatment of patients with Castleman Disease (CD).