For Newly Diagnosed

This page is intended for people who have just been diagnosed with hemangioendothelioma (HE) and particularly epithelioid hemangioendothelioma (EHE) - the disease this author knows most about. CRAVAT hopes the following information will give you a starting point and basis for understanding EHE so that you can better cope with the diagnosis. Consider it your EHE orientation. I have divided it into an‘Introduction’ and a ‘More Advanced Stuff’ section to accommodate concerns that there is too much information here for the ‘beginner’ who might be overwhelmed. When EHE first came to visit my family, I couldn’t learn enough fast enough; the second section is aimed at like-minded people. Don’t expect to get it all at once. You can come back as often as needed. Continue to seek other resources and sources of information. The more you learn the better. I hope this serves as a good starting point.

Introduction

EHE is a rare disease characterized by tumors that can occur anywhere in the body. These are often very slow-growing and people can live for decades with EHE - there are even a few reports of the disease regressing or disappearing completely over time. Furthermore, it is a very unusual disease because the appearance of tumors in multiple body parts does not necessarily carry a poor outcome or indicate aggressive disease. Therefore, while EHE is usually considered a sarcoma (a form of cancer), it is very different from most cancers.

Now, let’s go back to the beginning The day you learned you or a loved one had EHE was undoubtedly tough - very tough. We know that from personal experience. However, there is much to be optimistic about. First, as mentioned above, EHE is usually slow to grow or spread, so you have time to adjust and plan. Furthermore, recently there have been important advances in understanding the disease – and this is considered the first step to finding an effective treatment.

You probably plan to spend some time learning about HE/EHE and what is currently known about it. However, because EHE is so rare, finding good information can be challenging and most doctors probably won’t be able to tell you very much about it. Unlike the common cancers like breast and prostate, there are few resources about EHE and only a handful of oncologists and surgeons have experience in treating EHE patients. In the US, the doctors with the most experience treating EHE generally practice at large academic medical centers. In countries with smaller populations, such as Australia, these doctors will be more difficult to find and patients are more reliant on word of mouth.

A Movie

A good example of the ways EHE both differs and is similar to other cancers can be found in the movie Crazy Sexy Cancer (crazysexycancer.com). Kris Carr has made a very informative documentary of her entire early experience with EHE, starting with the first trips to the doctor. If you haven’t seen it yet, I recommend this movie to you as another helpful starting point. You will probably recognize many things that you have already experienced. Our family found this an inspirational, funny and poignant film. It was a source of education and emotional support for us at a time of great need. It really hit the spot and I hope it does for you, too.

More Advanced Stuff

The Medical Literature Almost every paper about EHE begins with a statement that reads something like, “EHE is a vascular neoplasm intermediate between hemangioma (benign) and angiosarcoma”.  Although the first part of this description is correct, the second part is not entirely accurate. We call EHE a vascular tumor since it is caused by proliferation (unregulated growth) of endothelial cells – the cells that form the interior lining of blood vessels. However, EHE is entirely distinct from both hemangioma and angiosarcoma. We know this now because a genetic alteration responsible for EHE has recently been identified. It is entirely unique to EHE and is not seen in hemangiomas, angiosarcomas, or other vascular tumors. The overall notion is right though: EHE is neither benign like hemangioma nor is it usually aggressive like angiosarcoma.

Many medical journal papers about EHE describe only a single patient (“case reports”) and are therefore not very useful to you. Moreover, most focus only on surgical approaches to treatment. This is partly because there are no standard non-surgical treatments for EHE and not enough EHE patients to run clinical trials that compare effectiveness of various treatments. We don’t recommend focusing too much on any one given paper that describes only one patient since such reports aren’t usually very helpful in evaluating or comparing treatments or understanding the range of outcomes in EHE. This takes what doctors call a randomized controlled clinical trial (RCT), or more simply, Clinical Trial.

Unfortunately there are currently no Clinical Trials comparing treatments for EHE. However, there are two well-designed studies focused on liver transplant (generally very favorable results), though neither has a control group (no transplant) for comparison. Interestingly, outcomes among the transplanted patients are often favorable despite widespread disease . Therefore, the presence of tumors in other parts of the body is not usually considered a contraindication to transplant in EHE as it usually is in other forms of cancer. Finally, the HEARDsupport group in collaboration with physicians at the University of Illinois at Chicago recently published the cumulative clinical experiences of roughly 200 patients with EHE in a recent issue of the journal Chest. They show that information from such an on-line registry can provide potentially helpful insights into the disease.

What Causes EHE? This is an important question since the first step to treating a disease is knowing its cause. Many things have been speculated as potential causes of EHE, including hormonal effects, birth control pills, industrial exposures (vinyl chloride), and trauma among others. None of these associations has been confirmed. Fortunately, significant progress has been made very recently in our understanding of EHE. Two separate research groups published findings in late 2011 indicating a specific  chromosomal translocation that is virtually diagnostic for EHE. This swapping of genetic material between chromosomes 1 and 3 is seen in almost all EHE tumor cells and can be considered ‘disease defining’. This genetic alteration results in the production of a fusion gene and a resulting fusion protein: it  has part of a protein that is normally seen only in endothelial cells and a part that is normally found only in brain. This abnormal fusion protein presumably causes the cells to grow without normal regulation. It is this abnormal system that could theoretically be targeted for therapy. However, to begin testing possible treatments we need to develop laboratory models of of EHE: that is, cells or animals that contain the translocation and resulting fusion protein. CRAVAT Foundation has already funded important research in this area.

A different, less mainstream line of investigation has recently implicated a possible association between EHE and infection by Bartonella bacteria. This bacterium is unique in that it has the ability to cause endothelial cells to proliferate – the underlying biological problem in EHE. Many cancers are thought to result from “two hits” and it is possible that Bartonella infection comprises the other ‘hit’ after the disease defining translocation, possibly by stimulating synthesis of the fusion protein. This is entirely speculative it is good to know there are several possible lines of investigation that could lead to progress in a better understanding of EHE and, possibly a treatment.

Treatment:

Many cases of hemangioendothelioma are asymptomatic and are treated with a ‘wait and see’ approach. It is sometimes considered prudent to wait until the hemangioendothelioma declares its intentions, before starting to fight back. However, there are times when treatment may be indicated.

1) If you have isolated disease, ie a tumor in one place where it can be removed, then surgery to remove the one tumor can be the best chance for a cureand this is almost certainly the way to go. Surgery with wide margins is often the best option when possible.

2) Liver transplantation can be very helpful in controlling disease and symptoms when there are many tumors in the liver. The success with liver transplantation for EHE patients is generally good, however the disease can recur in the new liver in approximately 25-30% of cases.

3) Standard chemotherapy and radiation therapy are not usually very effective in EHE due to its slow growing nature. However, some success has been shown with localised treatments which are still experimental, such as irreversible electroporation (IRE).

4).Newer non-surgical therapies are currently being evaluated including various anti-angiogenics that inhibit formation of new blood vessels. Clinical trials are needed to test the efficacy of anti-angiogenics versus surgery or other treatments like interferon or kinase inhibitors. It might be useful to ask your doctor the exact mechanism of action of any drug he recommends so that you know what category of treatment it falls in.

5) Future treatments:  As the genetic alteration responsible for EHE has now been found, it is now possible to start research to identify the specific molecules that contribute to the growth of EHE. Then the approach, called “targeted therapy” might theoretically be applied to EHE; it has been successfully used to identify useful treatments for other cancers. Obviously, research is the key, including laboratory and clinical research. CRAVAT is currently looking for ways to fund this research through the CRAVAT foundation.  If you would like to contribute financially or if you have suggestions for possible research sponsors please contact CRAVATfoundation.org. Our goal is to fund research that will help lead to a treatment for EHE.

The Work Ahead

Most cancers are of epithelial origin. They are collectively called carcinomas and derive from cells that are from either ectoderm (the outer cell lining of the developing fetus; eg skin) or endoderm (the inner cell lining; e.g., colon cells). This does not mean cancers begin during fetal development, it’s merely a way of differentiating the cell-types of various cancers. Cancers that derive from cells of mesodermal origin (the middle layer of tissue in between the ectoderm and endoderm; e.g., muscle, blood vessels, bone) are called sarcomas and EHE falls into this group.  Sarcomas make up roughly 10% of all cancers.  However, almost all available research funding goes to study carcinomas, especially breast, prostate, lung and colon. Unfortunately sarcoma research is the poor cousin of cancer research and receives only a tiny amount of research funding, far less than the 10% it is entitled to.

It’s time for the community of sarcoma patients, their families and friends to raise a banner and be heard. It’s time for money for research to be spent proportionately. Sarcomas might be individually rare, but are common as a group and they are important scientifically as well. Understanding the biology of sarcomas has provided and will continue to provide important insights into the nature and possible treatment of all types of cancer. Let’s work together to improve the visibility of sarcomas and the need to support research in the field. If you want to help, contribute to fund research on EHE or other sarcomas. If you want the government to help, we must have our voices heard together. Your input and ideas are appreciated. We will probably need to launch a campaign to make politicians aware of these funding discrepancies and the importance of rectifying them.

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             And Now, back to some basics: 

 

WHAT IS HEMANGIOENDOTHELIOMA (HE)

Hemangioendothelioma (HE) is the term used to describe a diverse group of vascular cancers. It can be broken down as follows:  

Hem = blood

Angio  = blood vessel

Endo = inside

thelia = cellular layer or surface

endothelium = interior lining of a (blood) vessel

Oma  = tumor

The term is descriptive, indicating that the predominant proliferating cell is related to an endothelial cell (the cell that lines the inside of blood vessels). EHE specifically refers to a variety where the cells take on an 'epithelial' appearance. However, it is distinct, both histologically and pathologically and in its cause from the common hemangiomas of infancy. It is generally considered a low grade malignancy based on its histological features.

HE tumors can involve soft tissue, bone, skin, liver, lymph node and/or lung, but there are clear patterns of clinical presentation. For example EHE is most common in the liver, commonly occurs at multiple sites at the same time (metachronous growth), and does not cause coagulopathy. Kaposiform Hemangioendothelioma (KHE) typically occurs on the trunk, remains very local and is commonly associated with coagulopathy. In contrast,  pattern of progression of these tumors varies greatly and is distinctly different from its benign counterpart, the hemangioma. While in rare cases spontaneous regressions have been reported, these tumors are generally slow and indolent.  However, in some cases it can progress to devastating disease. The tumors are often locally invasive and destroy surrounding tissue. Vascular cancers (ie, cancers pertaining to vessels, particularly blood vessels) are very rare, accounting for only a fraction of 1% of all cancers. Due to it's rarity, it is crucial for patients to seek a sarcoma specialist for the treatment of any hemangioendothelioma. 

CLASSIFICATIONS OF HEMANGIOENDOTHELIOMA

The term "hemangioendothelioma" has been used to designate various groups of vascular tumors. There are many different subtypes:

  • epithelioid hemangioendothelioma (EHE), having epithelial-like cells lining the vascular channels and can occur simultaneously at multiple sites
  • retiform (RKE) - retiform pattern of proliferating vessels with intraluminal papillae and hyaline cores. Histologically similar to those seen in Dabska tumor.
  • spindle cell hemangioendothlioma (SCHE), has spindle cells,smooth muscle cells normally supporting the vessels.
  • kaposiform hemangioendothelioma (KHE) which is a locally invasive tumor, occuring in young children and having no capacity to metastasize.
  • angiolymphoid
  • malignant endovascular papillary angioendothelioma, also known as a Dabska tumor, a. low-grade angiosarcoma that can affect the skin of children.

Each of these clinical entities has its own typical pattern of progression and of associated symptoms, and it is unclear whether they represent a different disease or a spectrum of related disorders. Unfortunately, the term hemagioendothelioma is often used erroneously, and the multiplicity of terms may be reflective of the great confusion that exists about the terminology.  Other forms of hemangioendotheliomas have recently been noted, eg, Composite and Polymorphous. Sometimes, it may be hard to make a correct distinction between these and other rare vascular conditions.

Below is an extract from an article which refers to the importance of a rare disease registry in general and specifically for EHE:

The Importance of Clinical Registries for Pulmonary Epithelioid Hemangioendothelioma Written by Kpodonu, Jacques MD; Tshibaka, Cimenga MD; Massad, Malek G. MD, FCCP, The University of Illinois at Chicago, Chicago, IL (Included here with permission from the American College of Chest Physicians.) ......

"Due to the rarity of this disease, double-blind randomized controlled studies investigating at various management strategies will not be possible. Clinical registries such as the Armed Forces Institute of Pathology Registry and the InternationalHemangioendothelioma, Epithelioid Hemangioendothelioma and Vascular Disorders Registry are places where physicians as well as patients and their families can share their symptoms and treatments, along with response rates and relapses. Such registries may help both patients and physicians alike in following the natural history of the disease and its response to different therapeutic regimens."

What causes Epithelioid Hemangioendothelioma (EHE)? Until recently, there was no known cause for this disease. However, two laboratories recently identified independently atranslocation (swapping of genetic material) between chromosomes 1 and 3 in the tumor cells of ~90% of EHE patients but not in any controls or other types of vascular tumors. This translocation results in the fusion of two genes (WWTR1 which is normally expressed in endothelial cells and CAMTA1 which is normally expressed in brain cells) into a new fusion gene. This abnormal gene produces a fusion protein containing parts of the two proteins normally synthesized under the direction of WWTR1 and CAMTA1. It is highly probable that the presence of this new fusion protein results in the abnormal endothelial growth of EHE.  Previously, there had been speculation on a number of causes – the contraceptive pill, exposure to vinyl chloride, an infection, a connection with hypothyroidism, and the inhalation of paints, chemicals or pesticides have all been considered. However, these most recent studies indicate that the WWTR/CAMTA translocation is highly specific and sensitive for EHE and therefore can be considered ‘disease-defining’ for this disease. Another speculative idea is based on a possible but unproven  association between infection with the Bartonella bacterium and EHE. It  is hypothesized by some that infection with Bartonella, a bacterium known to induce endothelial growth, could contribute to the growth of cells where the translocation has occurred. This entirely hypothetical notion is consistent with the ‘two hit’ hypothesis of cancer. More studies are needed to determine if this association is real.

PROGRESSION OF HEMANGIOENDOTHELIOMA

Often, hemangioendotheliomas are made up of cells that are inactive and so the tumor grows very slowly. However, sometimes the tumors are made up of cells that are more active (atypical or malignant). These cells look different when examined under the microscope and may be more likely to spread to other sites of the body (metastasize). Therefore, the clinical course is unpredictable and different treatment modalities are offered depending on the patient’s condition.

Therefore, the clinical course is somewhat unpredictable and different treatment modalities should be offered depending on the patient’s condition. The lack of predictability is especially true for EHE. In cases of multifocal EHE (many of sites that are simultaneously affected) some of the lesions may disappear (at least by imaging) and re-occur later. Others may grow and later spontaneously regress. Importantly, some cases remain totally asymptomatic (no adverse symptoms), for more that 15 or 20 years – although routine monitoring should be performed as a precaution in case the indolent tumors become active.

After a surgical intervention, particularly when the tumor could not be fully resected, hemangioendotheliomas can recur at the original site, or in close proximity. However, whenever a total resection is possible, such as may be the case with EHE confined to a limb, or one part ofthe liver, then tumor recurrence is much less common. Almost a third of epithelioid hemangioendotheliomas has multiple affected sites in lymph nodes, lungs, liver or bones. Notably, some cases of EHE have been known to go into spontaneous remission.

TREATMENTS FOR HEMANGIOENDOTHELIOMA

Treatment depends on a number of factors such as the location of the tumor, the speed at which the tumor is growing and its appearance under a microscope (grade) and whether it has spread to other parts of the body (stage). A person’s general health and symptoms are also taken into account.

Upon diagnosis, your specialist may tell you one of two things:

    • Treatment is required, be it medication, surgery, radiation therapy or something else. This could all be very new to you, and very scary.

OR

    • Treatment is not required, but the tumors will be monitored and checked again in six months time. To a newly diagnosed patient, this advice can be even scarier, thinking that you have cancer and the doctor doesn’t think it warrants any treatment!

Many cases of hemangioendothelioma are asymptomatic and are treated with a ‘wait and see’ approach. It is sometimes considered prudent to wait until the hemangioendothelioma declares it’s intentions, before starting to fight back. If hemangioendothelioma is active and causing problems, treatment options have to be considered.

First, a change in lifestyle might be required for some people who are over-stressed, inactive, and don’t eat a sensible diet. These changes, as well as a healthy dose of optimism are all a step in the right direction towards beating, or coping with this cancer.

It must be noted that there is no standard treatment for hemangioendothelioma, and almost ALL treatments are relatively unproven and somewhat experimental. Because of the rarity of the disease, the usual manner in which therapies are tested is just not possible. None of these treatments have been tried on a large number of patients, as the numbers are just not there. There has been a degree of success with some treatments, but the success is inconsistent – what works for one patient, does not necessarily work for the next.

The degree of success may be caused by the variability of the growth of the tumor. The confusion about the pattern of growth, the “best time to treat” and the low number of patients to study makes if difficult to recommend a single therapeutic modality. Thus, because of the rarity of the disease, many centres use therapies that are “generally” applicable to other soft tissue tumors, and with which the oncologists are more familiar. This may not be the best therapies for this type of tumor.

Conventional (or Western medicine) treatments

Surgery Where possible, for a single tumorresection with wide margins may be suitable.

Medications Traditional chemotherapeutic regimens, which target cells that are growing (cells in cycle) do not play an active part in the treatment of hemangioendothelioma. The rate of growth with hemangioendotheliomas is variable. Some tumors can grow very fast from the beginning; some can change from fast-growing to slow-growing, or vice-versa. Some chemotherapy regimes have been used with varying degrees of success.

There are also several newer approaches,which are being used to treat HE. These include anti-angiogenetic drugs, which restrict the growth of the tumor by restricting its blood supply. Examples of these are Thalidomide (or the newer Revilimid), Celebrex, Interferon and Avastin.

Radiation treatment (Radiotherapy) Radiotherapy may be prescribed for some cases to try to shrink the tumor and/or as a form of pain relief for the patient. However, there have not been many cases indicating efficacy of radiotherapy for EHE.

Transplant Transplant surgery might be provided for those with hepatic hemangioendothelioma, Interestingly, it is often still a possibility when the patient has additional tumorsoutside the liver. This is one of the few diseases where evidence of multiorgan involvement does not preclude transplant.

Other conventional approaches Radiofrequency treatment, electroporation, vascular embolization and fractionated stereotactic radiosurgery have also been used with success in some cases.

A reminder - This is not a medical document – please discuss treatment options with your own medical team.

THE FUTURE FOR PEOPLE WITH HEMANGIOENDOTHELIOMA

Doctors are looking into a variety of methods to control the growth and spread of HE tumors. One very promising theoretical approach is to identify links in the WWTR/CAMTA directed cell-signaling system that could be targeted by specific inhibitors. This approach of ‘targeted therapy has been used successfully in other types of cancer. Impressive scientific progress is being made in this field and CRAVAT has contributed money to support such important research. In the meantime, many of the currently available drugs are managing to restrain the tumors, providing vital time until other treatments are discovered....AND it is incumbent on the EHE community to support each other, continue seeking funds for needed research, and educating clinicians, scientists, friends and family as well as politicians and others with political leverage about the importance of supporting EHE research.

DISCLAIMER

This information herein is for information only. The author has used all reasonable care and skill but makes no warranty as to the accuracy of any information herein, and cannot accept liability for any errors or omissions. The information provided is not intended nor implied to be a substitute for professional medical advice nor is it intended to be for medical diagnosis or treatment. If you are reading this, you have possibly been diagnosed already and are under medical instruction. DO NOT take the word of this brochure over that of your medical team.