In the winter of 2013, my son, Dmitriy, now 26, had a cough that wouldn’t go away. After several rounds of antibiotics failed to halt the persistent problem, a pulmonologist we consulted ordered a chest x-ray, which showed a large tumor lodged between Dmitriy’s lungs. Although the doctor said the tumor was probably benign, he recommended having it surgically removed and ordered additional imaging tests, including a CT scan, which uncovered more tumors in Dmitriy’s liver.
The report suggested benign hemangiomas. But when we met with a surgeon, he took one look at the CT scan and ordered an MRI, which confirmed his and our worst fear. Dmitriy had cancer. A biopsy proved the cancer type was epithelioid hemangioendothelioma (EHE), an extremely rare vascular sarcoma that affects between 100 and 200 people, mostly young adults, each year in the United States.
The cancer is so rare that research funding is scarce and little is known about its natural history. Although localized epithelioid hemangioendothelioma can be surgically resected, there is no effective therapy for systemic disease, and mortality from the cancer ranges between 13% and 18% when confined to soft tissue, but life expectancy in metastatic cases is unpredictable and ranges from a couple of months to 15 to 20 years.
Visits to the top sarcoma specialists in the country only underscored just how little is understood about this cancer and heightened my fear for Dmitriy’s recovery. The surgeon successfully resected the large mediastinal tumor, but several small indolent nodules remain in his lungs. A year later, an experimental procedure called irreversible electroporation (a nonthermal focal ablation technique) was performed on Dmitriy’s liver, killing some tumors and decreasing the size of others.
Today, Dmitriy’s cancer is stable, and it is possible that he will remain that way for many years—possible but not assured. The behavior of epithelioid hemangioendothelioma is totally unpredictable; patients can remain stable for a long time (sometimes decades) or experience rapid disease progression and die.
Clues to Pathogenesis
That said, I needed more certainty about his long-term prognosis than what the few known statistics could provide. More importantly, the fact that epithelioid hemangioendothelioma can remain indolent for a long time indicates that there are some mechanisms that keep it from progressing. This gave me hope that if those mechanisms are uncovered, epithelioid hemangioendothelioma can be controlled. Over the past 2 years, I have been on a quest not to just raise awareness and funding for research in epithelioid hemangioendothelioma, but to gather data on the disease as well, and to hopefully uncover more clues about the pathogenesis of this weird, unpredictable cancer.
An online search for information led me to the epithelioid hemangioendothelioma registry HEARD (Halt EHE through Analysis, Research, and Discovery; heardsupport.org), which was launched by Cynthia Pollak, an Australian, whose son was diagnosed with epithelioid hemangioendothelioma in 2004 and has since died from the disease. Mrs. Pollak was looking for epithelioid hemangioendothelioma patients on Internet cancer chats and reaching out to them; she eventually collected about 300 self-reported stories.
From this repository of patient cases, I learned more about epithelioid hemangioendothelioma than I had gathered from all the sarcoma specialists I had seen. The experience was eye-opening. I extended my search to PubMed, where I found information on more than 700 patient cases. I knew that only by organizing a worldwide network of patients could we produce a foundation for epithelioid hemangioendothelioma research to move forward. I reached out to several patients, and we started discussing our plans.
Two-Database Approach
One of my “EHE mates,” Dawn Scott, decided to create a Facebook page (www.facebook.com/groups/EHEcancer/). Currently, we have nearly 600 members, and that number grows every week. February 26 was the birthday of the EHE Foundation. Our group is pursuing several projects, including the creation of a website and two databases. One database is the continuation of HEARD, containing self-reported patient stories. The other is a computerized questionnaire, which does statistical analysis of the entered data.
Why do we need both of these databases? Epithelioid hemangioendothelioma is so rare and understudied that, very often, relevant facts are overlooked or simply ignored by clinicians. The only way to recognize these facts is to look into stories to find patterns and then to include them in a statistical analysis.
For example, one epithelioid hemangioendothelioma patient complained on our Facebook group’s page about a debilitating rash that would not respond to creams. To my great surprise, many others commented that they had or have a similar problem. All patients mentioned that their doctors did not think the rash could be cancer-related. Looking at the number of people with this rash and the similarity of presentation, I knew this could not be a coincidence.
I started looking on PubMed into cancer-associated rashes and found that they are typical for certain cancers, especially lymphomas. These rashes are not generally reported in sarcomas, which might explain why doctors did not make the connection. I also learned that in many lymphoma cases, the appearance of the rash precedes cancer recurrence, and some authors consider these rashes to be a warning sign. I thought, “What if this were true for EHE? What if the appearance or worsening of the rash could be used as a biomarker for EHE progression?” We will include questions about this rash and its timing in our questionnaire, will get a statistical analysis, and will present the data to the doctors.
Another example: Several female patients from our group reported that their diagnosis was made during or soon after pregnancy. Other patients responded with similar stories. Some indicated that they had a recurrence, progression, or worsening of symtoms during or right after pregnancy. I searched HEARD and PubMed and found other similar cases. I digged further and learned that some types of adult hemangiomas are known to develop or progress during pregnancy.
Epithelioid hemangioendothelioma is a vascular cancer. Endothelial cells are known to be a target of estrogen. I remembered that epithelioid hemangioendothelioma happens predominantly in women and that many of our female patients have either had breast cancer themselves or have a family history of breast cancer. Maybe epithelioid hemangioendothelioma development/progression has a hormonal component? After digging further on PubMed, I found a few “old” articles about epithelioid hemangioendothelioma suggesting a hormonal influence on its development. We are collecting more data, and once we get the statistics, we will bring the information to researchers.
Hope on the Horizon
Although I have a full-time job, I spend at least 40 additional hours per week researching information about epithelioid hemangioendothelioma and everything that can be related to it. I pass on what I learn to patients on our Facebook page and to specialists studying this cancer. This communication between patients with rare cancer and the medical community is an incredible bridge, one that transforms data into clinical and research decisions.
Several patients in our group have shown good long-term responses to mTOR inhibitors. I found several publications confirming that mTOR inhibitors have some efficacy in epithelioid hemangioendothelioma. I saw that this should be investigated further as a possible treatment for certain types of EHE patients. So I reached out to physicians who I knew had used mTOR inhibitors to treat epithelioid hemangioendothelioma and informed them about these additional successful cases. There is now ongoing communication between those doctors about publishing a retrospective analysis of mTOR inhibition in epithelioid hemangioendothelioma patients. It is extremely difficult to find funds for a clinical trial, but I hope that once the anecdotal stories lead to peer-reviewed publication, we will have a better chance.
Nothing gives me more satisfaction than to see my endless efforts bearing fruit. As a result of the information I collected and the resulting discussion we had online about mTOR inhibitors, one of our patients was put on sirolimus and has had disease stabilization, after the failure of several other regimens.
In addition, there is exciting research news on the horizon. The leading investigator in epithelioid hemangioendothelioma is Brian P. Rubin, MD, PhD, Professor and Vice-Chair of Pathology, Director of Soft Tissue Pathology, and Director of the Bone and Soft Tissue Pathology Fellowship Program at Robert J. Tomsich Pathology & Laboratory Medicine Institute and Department of Medicine Genetics at the Cleveland Clinic and Lerner Research Institute. Dr. Rubin and his colleagues discovered that a genetic translocation involving chromosomes 1 and 3 results in the fusion of the WWTR1 (or TAZ) gene to the CAMTA1 gene and is found in nearly all epithelioid hemangioendothelioma tumors. That discovery is leading to greater understanding of the molecular pathways in the cancer and potential therapies. (Editor’s note: See “Unraveling the Mysteries of Epithelioid Hemangioendothelioma: A Conversation With Brian P. Rubin, MD, PhD,” in the February 10, 2015, issue of The ASCO Post.)
Dr. Rubin is also investigating a MEK inhibitor, trametinib (Mekinist), which is showing efficacy in his laboratory studies. He is currently working on the clinical trial that all epithelioid hemangioendothelioma patients have been waiting for. We are hopeful that it will show that trametinib can be an effective targeted therapy for epithelioid hemangioendothelioma.
Next Steps
I am organizing an epithelioid hemangioendothelioma meeting to be held during the 2015 ASCO Annual Meeting. We will have 14 doctors from around the world discussing the latest developments in epithelioid hemangioendothelioma research and treatment strategies. I will present some data that I learned from our patients and from my research on PubMed.
I am also almost done with structuring the PubMed data into a user-friendly EHE library, with open access to anybody who would like to find the most useful information on epithelioid hemangioendothelioma. I organized files using axes such as location, pathologic correlations, radiologic correlations, successful treatment, most-informative studies, and so on. Once I am done, I will ask our patients to share the library access with their doctors, and I will send the library to major sarcoma clinics.
The patient registry is an ongoing project. We already have many stories collected. The next step is to translate these stories into a format that will be most useful to researchers and patients alike. We believe this will help aid progress in epithelioid hemangioendothelioma research. To that end, I need your help.
If you have epithelioid hemangioendothelioma patients, tell them about our Facebook group. If you have any resources on epithelioid hemangioendothelioma that you would like to share with us, and/or if I can provide you with the data that I have collected, please e-mail me at jgutkovich@
gmail.com or theehefoundation@gmail.com.
I know it is possible to defeat this disease—maybe not to cure it but to make it a chronic condition like diabetes or coronary artery disease, well known and well controlled. My goal is to ensure that my son and the thousands of other epithelioid hemangioendothelioma survivors won’t have to die from this cancer, maybe just with it. ■
Disclosure: Ms. Gutkovich reported no potential financial conflicts of interest. Her research is uncompensated.
Jane Gutkovich is the manager of a nuclear stress lab at CardioVascular Medical Associates in Garden City, New York. She lives in Forest Hills, New York.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.
