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 tumor, resection 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.