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Malignant Histiocytosis – Ultra rare disease among rare diseases

In March, we focused on Malignant Histiocytosis (MH), to learn more about this rarer form of histio. First, we sat down with Dr. Karen Rech and Dr. Aishu Ravindran to talk about the Pathology of Malignant Histiocytosis (MH); we then spoke with Dr. Gaurav Goyal and Dr. Gordan Ruan about the Clinical aspects of MH.

There were two videos released in April, which we wanted to break down in a more digestible manner in the event watching the full-length discussions are not possible. Please enjoy the summary below of the conversations that took place. I went through the transcripts and combined them to summarize all the aspects of malignant histiocytosis the doctors went through in our conversations. (Some paraphrases may have been made for grammar and readability, but nothing that changed the medical meaning of our discussion).

Me: Thank you for taking time today to sit down today! We’re here to have a discussion about malignant histiocytosis. As I understand t’s actually a regrouping of disorders as well. You were authors on a recent publication on malignant histiocytosis. So, I’d love for you to introduce yourselves.

Dr. Karen Rech: Thank you, Deanna. I’m Dr. Karen Rech, and I’m an Hematopathologist. I work at the Mayo Clinic in Rochester, Minnesota. And here at Mayo Clinic, we have a histiocyte working group that’s multidisciplinary. We all get together and discuss these specific patients, and all of them are very rare. These include Erdheim Chester Disease, Rosai Dorfman Disease, Langerhans Cell histiocytosis [which are more chronic, indolent diseases], and then the more aggressive malignant histiocytosis.

Aishwarya Ravindran

Dr. Aishu Ravindran: Thanks Deanna, for having us here, I’m Aishu Ravindran I am an Assistant Professor of Pathology and a consulting Hematopathologist at University of Alabama at Birmingham. My journey in histiocytosis started when I was a research fellow back at the Mayo Clinic in 2015 under the mentorship of Dr. Ronald Go. Subsequently, when I started my residency over there, I trained with Dr. Rech in histiocytosis and developed a special interest in this area and I continued to do my projects in histiocytosis…including malignant histiocytosis.

Gaurav Goyal

Dr. Gaurav Goyal: Hello, Deanna. Hi, everyone. I am a Hematologist-Oncologist specializing in adult histiocytosis at University of Alabama at Birmingham. And I’ve been working on histiocytic disorder clinical and research aspects for approximately seven years now.

Gordon Ruan, MD, Oncology, Rochester, MN, Mayo Clinic Hospital - Rochester

Dr. Gordan Ruan: My name is Gordon Ruan. I’m a Hematology-Oncology fellow here at Mayo Clinic in Rochester. I’m in my last year of fellowship and I’ve also had an interest in histiocytic disorders. I’ve been working in this space for five years now, working in close collaboration with Dr. Goyal and others.

Me: What is malignant histiocytosis?

Dr. Ruan: Malignant histiocytosis, it’s a very rare histiocytic neoplasm.1

Dr. Rech: So malignant histiocytosis has been a diagnosis that is a last consideration. These cases are very rare, so when we get a biopsy from a patient that shows features that could be malignant histiocytosis there are a lot of other things that are in the differential diagnosis that are much more common. You have to rule out melanoma, carcinoma, sarcoma, lymphomas…then if those are ruled out, the last thing you consider is malignant histiocytosis.

Me: Thank you. What are some of the key takeaways from your publication.

Dr. Ravindran (Pathology Study): We took about 22 cases in our cohort. We went back into single institution studies. We revisited the diagnoses and confirmed that they were in fact malignant histiocytosis. We applied a panel of immuno-stains on the tissue to identify a protein that is expressed by the cells of interest, in this case the malignant cells. Based on the pattern of the immunostaining expression we categorized them into four different groups: Macrophage phenotype, Monocyte macrophage phenotype, dendritic cell phenotype, and Langerhans cell phenotype. We are trying to see how these malignant cells are actually derived or developmentally related to the primary cell of origin, which are…part of your normal immune system. These cells can acquire genetic mutations and they can transform into something cancer-causing or a malignancy.

Dr. Goyal (Clinical Study): When we did a study using our SEER database, which captures 30 % of all cancer diagnosis in the US; we were only able to find approximately 150 cases of histiocytic sarcoma nationally. So, it’s an ultra-rare disease among rare diseases.

In our series of 46 cases…histiocytic sarcoma was the most common one with 26 cases. Nine were interdigitating dendritic cell sarcoma and eight were Langerhans cell sarcoma. And the most common organ involvement was lymph node involvement, which we found half of the cases to have. And approximately 10 out of the 43 had single-site disease, and the rest were multi-site disease.

Dr. Ruan: Based on the work that we did, we studied three subtypes specifically, histiocytic sarcoma, Langerhans cell sarcoma, and then interdigitating dendritic cell sarcoma. Historically, the data in this space has really been kind of driven by case series or registry-based data.

Me: To have this information is amazing, for malignant histiocytosis. I’m learning so much more about it every day and we are interacting with more people who are being diagnosed…so to be able to recognize these different subtypes is incredible.

What’s the impact this can potential have on treatment?

Dr. Ruan: We know that for patients who had limited disease involvement, so if it was, let’s say, just involving one site of the body, if they underwent surgery and that was able to completely remove everything, then those patients had overall much better outcomes compared to patients where if there was disease more spread out -multifocal is what we refer to in the paper. So, we know that actually the higher risk patients are folks who have liver, bone marrow, spleen involvement.

In terms of the treatments though, a lot of it’s based on chemotherapy, or immunotherapy. For patients who had chemotherapy, for the most part, again, this would be if the disease was more widespread. And while chemotherapy would be able to provide a response, typically the response would not be durable. So, there’d have to be a change in the treatment plan at some point in time.

What’s really interesting in our study is, based on the mutational profile, historically in ECD, LCH and even RDD, that based on the mutational profile, we can use targeted inhibitors. But based on our report, you know, with the MH, they have so many mutations. From what we’ve seen in our report, it may not be driven by just one mutation, in which case, the targeted therapies were not as effective.

Using something like chemotherapy, if these patients had to go for stem cell transplant to try and consolidate that response, or for immunotherapy, those patients may have had a better shot at a response compared to just targeted therapy alone.

Immunotherapy is still something that we’re actively researching and trying to learn more about in MH because historically in blood cancers, immunotherapy doesn’t have as much of a role, but certainly that paradigm is shifting in other diseases too, like Hodgkin lymphoma.

Dr. Goyal: The other important thing to note about malignant histiocytosis, is that they can also occur as primary, meaning that’s the only cancer that’s affecting an individual, versus secondary, where the histiocytic tumor cell or the cancer cell is arising from another cancer. In fact, in our study, we did a series of tests. In about 7 out of those 11 cases that we were able to do tests on, we found that the histiocytic tumor cell was actually clonally linked, meaning they were originating from the same cell that was driving the original lymphoma or leukemia.

So, it is very important when somebody with lymphoma or leukemia develops a new tumor to try and assess if it is associated with the lymphoma or leukemia because the treatments may be different.

Me: There are so many amazing takeaways from your work and your studies, and through your work, we are learning so much. With malignant histiocytosis, there was a lot of ground to make up in learning about the basic science, diagnostics, and treatment options for the diseases so this feels like it’s very groundbreaking and will lead to a lot of very important additional discoveries.

Thank you to the dedicated doctors-scientists who passionately research histiocytic disorders. If you would like to view the webinars, you can find them here: MH Pathology and MH Clinical.

  1. The average age at diagnosis is around 60 years, although malignant histiocytosis (MH) has been diagnosed in children as well as elderly. MH can involve any organ system of the body, with most common organs involved being lymph nodes, bone, lung, skin, bone marrow, and central nervous system. ↩︎