Multicentric Castleman's Disease

Corey Casper, MD, MPH:Multicentric Castleman’s disease (MCD) is a fascinating clinical presentation. It’s a disease that can be incredibly diverse, ranging from very minimal symptoms related to either detection radiographically or clinically of enlarged lymph nodes to a fulminant case of multi-organ system failure requiring intensive care support. We don’t understand the reasons for the diverse clinical manifestations of multicentric Castleman’s disease, but we know they exist. There are some who have thought that the plasma cell variant of multicentric Castleman’s disease is more aggressive, it presents more fulminantly. There are others who’ve also seen that presentation with the hyaline vascular variant. So, I don’t think the histologic variant itself is the only factor that governs the severity of multicentric Castleman’s disease. I think there are other factors that we clearly don’t understand.

The symptoms of multicentric Castleman’s disease can all be attributable to the overproduction of interleukin-6 (IL-6). So, certainly, the enlarged lymph nodes are a consequence of the increased IL-6 production. But also in the more severe cases of the disease, you tend to see things like respiratory failure, and that often occurs in the setting of interleukin-6 causing a capillary leak syndrome, where, again, fluid and whatnot is spaced into the lungs through the capillaries. That same mechanism, we think, can occur in the kidney and lead to renal failure, and there are a number of associated kidney diseases that can be seen largely due to interleukin-6 overexpression in the kidney causing renal failure. And, similarly, patients can present with a tremendous amount of ascites or third spacing of fluid from these leaky capillaries as a consequence of overexpression of interleukin-6. The recurrent high fevers, night sweats, sky-high inflammatory markers—like C-reactive protein or erythrocyte sedimentation rate—are attributable to IL-6 overexpression.

What’s interesting is that there’s not a direct correlation even between measuring interleukin-6 in the plasma and the severity of clinical symptoms, and we don’t understand why that is. There are some patients who will have a near-normal interleukin-6 level but yet have clear signs of interleukin-6 overexpression, where there are other patients that have levels which aren’t very high. There may be many reasons for that. One might be that interleukin-6 may only be produced locally, for instance, in the lymph node or in the lung and, therefore, is not measurable in the plasma. We also know that there are other important cytokines that are also playing a role, things like VEGF that play a role and are improperly regulated in the setting of Castleman’s disease. Again, a wide clinical variety of manifestations in multicentric disease ranging from, and usually including, enlarged lymph nodes and constitutional symptoms, but sometimes including more severe symptoms like renal failure, respiratory failure, and massive ascites because of overexpression of interleukin-6.

The prevalence of multicentric Castleman’s disease is difficult to estimate as up until recently, there were no routine coding systems that captured the frequency of multicentric Castleman’s disease. There have been some estimates about the total frequency of Castleman’s disease in the population, and those estimates are imprecise but range from approximately 1000 to 30,000 patients across the United States. We think that multicentric disease represents roughly 30% of all of Castleman’s cases, so it’s the minority. But, again, if you apply those numbers of 30% to anywhere between 1000 and 30,000, it’s a pretty rare disease. One would think that really no more than 10,000 cases are prevalent in the United States. And, in terms of incidence, it’s very hard to measure that, but probably in the order of several hundred cases per year.

The complications of Castleman’s disease, especially the multicentric version, can be, again, very diverse but very significant. I would say the most severe complication of multicentric Castleman’s disease can be multi-organ system failure. I’ve had a number of patients present to the emergency department with fevers, enlarged lymph nodes, and within hours under observation, they progressed to multi-organ system failure. These complications are, again, mediated by interleukin-6 overexpression and are caused by capillary leak leading to respiratory failure, renal failure, and oftentimes massive ascites. So that’s, I would say, the most severe complication of multicentric Castleman’s disease. That’s an immediate complication.

Longer term, there are other severe complications of multicentric Castleman’s disease. One severe complication in the long term is that there is evidence to support some degree of immunosuppression, and patients succumb to overwhelming bacterial and viral infections more commonly than patients without multicentric Castleman’s disease. Finally, I would say that in a small proportion of multicentric Castleman’s disease patients, there is the risk for progression to lymphoma. This has been most well described for the HIV-associated human herpesvirus-8—associated multicentric Castleman’s disease. Under those circumstances, when the disease has not been treated, some prospective studies would suggest that up to 25% of patients every 2 years will progress to an aggressive diffuse large B-cell lymphoma. Whether this remains true of the other multicentric Castleman’s disease variants, we don’t know, but we certainly know that a severe long-term sequelae of HIV, human herpesvirus-8–associated Castleman’s disease, is the development of lymphoma.

I would say that those are the most common and most severe long-term sequelae, but there are other complications of multicentric Castleman’s disease. In my experience, patients experience debilitating fatigue, oftentimes leading them to be disabled, not able to work, not able to enjoy their activities of daily living and being with their families. At the same time, I would say that in addition to that debilitating fatigue, there can be a tremendous amount of pain and discomfort, pain in joints. Long-term joint pain is something that’s often suffered by patients with Castleman’s disease. And in addition to that, there are the night sweats and the other constitutional symptoms associated with Castleman’s disease that can have severe long-term effects on individuals. I’ve seen cases of very severe depression accompanying Castleman’s disease. I had previously thought that these were just the consequences of a long, chronic illness. But there is now some emerging evidence that interleukin-6 plays a role in mediating some of the signs of depression.

I think as we learn more about the disease, we may learn about some of the associated symptoms, but on the least-severe side, I would say some of the complications of the disease include fatigue that can be disabling, chronic battling with sweats and night sweats, and more severely, multi-organ system failure and progression to lymphoma.

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