Diagnosis of Multicentric Castleman's Disease

Corey Casper, MD, MPH:Arriving at a diagnosis of multicentric Castleman’s disease is more challenging than it may initially appear. I think many providers are used to thinking about receiving a classic histopathologic diagnosis from a pathologist in the setting of a constellation of clear clinical symptoms and then making a diagnosis of multicentric Castleman’s disease. But, in reality, it’s not quite that simple. The clinical symptoms of Castleman’s disease can be very diverse and can mimic almost every other condition. So, having fevers, enlarged lymph nodes, and fatigue can be a symptom of the flu, could be a symptom of lymphoma, can be a symptom of almost any inflammatory disease. So, the symptoms can be very diverse. The laboratory abnormalities that are often seen accompanying Castleman’s disease would include things like anemia, thrombocytopenia, elevations in liver function tests, and certainly elevations in inflammatory biomarkers like C-reactive protein or the erythrocyte sedimentation rate. So, these things help to build a case. The symptoms that a patient presents with, the blood tests, and radiographs—usually a CT scan that show enlarged lymph nodes—all can help to bolster support for a diagnosis of Castleman’s disease, which can then be augmented by findings on histopathology.

However, there is no pathognomonic finding on pathology, so while we all may remember Castleman’s disease from our medical textbooks as something that produces these classic looking lymph nodes with onion-skinning or other very extreme and unique histologic appearances, the fact of the matter is that there actually are a number of conditions that can cause that appearance pathologically. Lupus can cause something like that. Syphilis can cause something like that. So, the lymph node appearance under the microscope is not sufficient to make a diagnosis of Castleman’s disease. That becomes much more specific when it’s added to the clinical signs and symptoms that a patient presents with. But even with that constellation of symptoms and the histopathologist doing their best and the hematopathologist doing their best to make a diagnosis, it’s not definitive.

There are certainly things that, in my experience, help to solidify that diagnosis. I would say that in the absence of an elevated inflammatory biomarker, it would be very unusual, regardless of anything else, to have multicentric Castleman’s disease. Beyond that, I would say that oftentimes, clinicians will look for evidence for elevated interleukin-6 in the plasma, and I think that has a very good positive predictive value. If it’s very elevated, then I think chances are likely that you could have Castleman’s disease. But it has a poor negative predictive value. We know that there are patients in whom you can’t detect interleukin-6 in the peripheral blood but still have the disease, so it’s not a perfect test.

And another thing that I think may give evidence toward having a diagnosis of Castleman’s disease is detection of one of the viruses that causes it, human herpesvirus-8. The gold standard would be the detection of human herpesvirus-8 in the lymph node by immunohistochemistry. But there are other ways you can solidify that diagnosis, like quantifying the virus from the plasma in the peripheral blood with a polymerase chain reaction.

Patients with multicentric Castleman’s disease, in my experience, often have a delay in diagnosis from months to years. The most typical presentation that I hear in my patients once they finally arrived at a diagnosis is that for the preceding months—or in one case, up to 20 years—there is a gradual decline in function characterized by increased fatigue, sometimes depression, joint pain, rashes, and sweats. And that is very indolent. It can be very slow and grow slowly year after year after year. So, in extreme cases, that process is so slow that it may take 20 years to make a definitive diagnosis of Castleman’s disease once someone is actually prompted to really go for a full workup and biopsy and whatnot. On the other hand, there are patients who have been completely asymptomatic and present to the emergency department in fulminant multi-organ system failure, seemingly with a new diagnosis of Castleman’s disease. Did those patients have a smoldering course where perhaps they had lymph nodes that were enlarged that they hadn’t noticed them? It’s certainly possible. But I think that, certainly in my experience, there have been patients who have been within the medical system. They’ve been having routine annual physicals totally normal and then one day, just all of a sudden, present with symptoms. It’s very variable in the amount of time that patients can present between initial symptoms and actual diagnosis.

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