Characteristics of Castleman's Disease

Corey Casper, MD, MPH: It’s been roughly 50 years since Castleman’s disease was first recognized, and the thing that I would say characterizes Castleman’s disease most is how diverse it can be. It can range from a disease where people have enlarged lymph nodes but no symptoms to one where patients present with fulminant multi-organ failure and require mechanical ventilation and support in an intensive care unit. One of the hallmarks of Castleman’s disease is really how diverse it can present and the many different clinical manifestations that accompany it.

I would say that the most common presentation for Castleman’s disease is a patient who has an enlarged lymph node, usually symptomatic. I think the reason that is the case is because those are the patients that come for medical attention. There may be many additional patients who have enlarged lymph nodes but no symptoms, but we don’t see them. The patients who are referred to physicians or to the medical system typically have enlarged lymph nodes, and generally the patients will have some associated symptoms. Either the lymph node is having symptoms locally because it expands and compresses something important in a nearby area or there are associated symptoms that are signs of systemic inflammatory illnesses. Those are things like fevers, fatigue, night sweats, joint pain, and sometimes rashes. These are the most common clinical manifestations that we see with Castleman’s disease.

It’s hard to estimate the actual prevalence and incidence of Castleman’s disease because, for many years, we had no way of tracking it. The way that we generally know about how common a disease is in the population is either that it’s tracked in a registry or sometimes we can use billing data if there are diagnostic codes. Until very recently, there actually was no ICD-9 diagnostic code for Castleman’s disease, so it was very hard to know in the medical system how many patients were actually being seen with the disease. There have been at least two studies that evaluated how common the disease is and they’ve used different clever methodologies. One looked at the fraction of patients that presented to a major referral center with a diagnosis of enlarged lymph nodes because that actually is an ICD-9 code. And they looked at what fraction of those patients wound up having a diagnosis of Castleman’s disease and then used that to extrapolate to the broader population across the United States.

A second study took two major referral centers in the United States and tried to estimate the proportion of patients within a catchment area that were referred to those two referral centers, then looked at how many Castleman’s patients they saw, and again, then extrapolated that to the larger population. Neither of those are optimal methods, and both would only provide rough estimates. I would say that using those estimates, there could be anywhere from as few as 500 to as many as 30,000 cases of Castleman’s disease in the United States that are currently diagnosed now. I think that’s underestimated because, obviously, first of all, the majority of patients with Castleman’s disease may never actually come to a diagnosis if they have no symptoms and an enlarged lymph node that they don’t know about. I would also say that there’s underdiagnosis by providers. I think that providers are not familiar with this rare disease. They may have seen it in medical school or in their training, but it’s not usually top of mind. And the way that most physicians will come to a diagnosis of Castleman’s disease is when a biopsy is performed and a pathologist sees something that’s unusual, and it reports Castleman’s disease from a pathologic diagnosis.

So, because of those reasons, I think it’s probably underestimated, and we only know about a fraction of the patients that have the disease. But, that being said, I still think it’s fair to say it’s a rare disease and probably no more than 30,000 cases in the United States. How many new cases occur each year or what’s the incidence of Castleman’s disease is incredibly difficult to estimate. I would say that based on the number of referrals that I see, which may range between 20 and 50 new cases a year, that some of the statistics that point to 500 or 1000 new cases a year is probably an underestimate. I guess I would say that it certainly is a rare disease. It certainly is the case where most providers will not have seen a case of the disease, and most patients certainly won’t have heard about it when you diagnose them. But exact numbers are hard to come by.

Castleman’s disease is a fascinating disease with a number of different things that we think can lead to its genesis. The pathogenesis of the disease is interesting and probably accounts for the diverse clinical manifestations. The way I think about Castleman’s disease is that the central property of the disease is that you have an overexpression of interleukin-6 (IL-6). Interleukin-6 is a cytokine that has a number of different effects, but it certainly calls for the recruitment and expansion of B-cells and plasma cells, the enlargement of lymph nodes, and a series of constitutional symptoms when interleukin-6 is overexpressed. That is a central feature of all forms of Castleman’s disease. Now, what causes the interleukin-6 to be elevated has many different potential sources.

One source that we clearly understand is that there is a virus, a virus known as human herpesvirus 8. This virus makes an analog to interleukin-6 that is called viral interleukin-6. It shares about 40% homology with the protein, and, indeed, the overexpression of that viral interleukin-6 causes also an overexpression of human interleukin-6. Together they cause the symptoms of Castleman’s disease. There may well be other viruses that have a similar mechanism, but that hasn’t been elucidated. So, for right now, we know that that’s one mechanism of Castleman’s disease.

For the other cases of Castleman’s disease that are not related to the virus, we tend to call those idiopathic multicentric Castleman’s disease or disease that we don’t really know what the etiology is. For those, there’s an increasing understanding of some of the factors that may contribute. For instance, we know that there are promoter polymorphisms for the IL-6 gene that lead to constitutive overexpression of IL-6 protein. Patients have either constant production of IL-6 or an exaggerated response to producing IL-6 when they should only produce a little bit of it. So, that again is an overproduction of IL-6 from a genetic polymorphism. Whether you’re born with that or that accumulates over the course of your life, we don’t know. There haven’t really been families or kindreds where Castleman’s disease runs in the family, but there are suggestions that there are families that have a higher prevalence of autoimmune diseases, lymphomas, and other inflammatory diseases, even cases like multiple sclerosis where they will also have histories of Castleman’s disease.

So, I guess, in my mind, I think about cases where IL6 is overexpressed because of a virus and we know that’s human herpesvirus-8, but there may be others. We know that there are genetic polymorphisms that lead to too much IL-6 production, and I would imagine that as we learn more about this disease and learn more about the IL-6 pathway, there may be other factors downstream of the receptor signaling within cell signaling pathways that could be mutated and lead to the same phenotype of IL-6 overexpression.

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