Kaposiform Hemangioendotheliomas (KHEs) are rare vascular tumors formed from endothelial cells that are potentially life threatening. They have both a capillary like component made of narrow elongated “spindle” shaped endothelial cells and a lymphatic vessel like component. They are described to be intermediately malignant, meaning that they tend to be locally aggressive, invading surrounding tissues, and sometimes metastasize (or spread) to close by lymph nodes and organs. While their cause and progression are not fully understood, it is suggested that about 50% of the tumors are formed congenitally and the others are typically formed in the first few years of life. Exceptions have occurred with KHEs forming in adolescents and adults. KHEs are found equally across both sexes and all ethnicities. Mortality resulting from KHEs is often associated with the complications (described further below) and has been shown to range from 7.5% in some studies up to 24% in others. The most common cause of death is due to the development of Kasabach-Merritt Phenomenom, a bleeding and clotting problem highly associated with KHEs. Complications:
Complications associated with KHEs are related to their intermediate malignancy, distinct molecular shapes and patterns, and invasive nature.
Metastasis: Roughly 20% of KHEs metastasize with 80% spreading to local lymph nodes and the other 20% spreading to nearby organs. Metastasis to organs has been shown to lead to organ damage and in some rare cases failure and rupture. The organs that the KHEs metastasize to depends on the location of the KHE. While most KHEs are superficial, meaning closer to the skin, and found on either the extremities (arms/legs) or trunk (torso), some are retroperitoneal or inside the back wall lining of the abdomen. Those that are retroperitoneal are most associated with organ metastasis, and cases have been documented of metastasis to the spleen and pancreas.
Kasabach-Merritt Phenomenom (KMP): KMP is described a rapidly enlarging KHE associated with thrombocytopenia (low platelet count), a consumptive coagulopathy (high rate of turnover of factors needed to form a clot), and sometimes but not always a hemolytic anemia (destruction of red blood cells leading to low red blood cell count). This creates high risk of life threatening hemorrhage or bleeding problems for patients as platelets and coagulation factors are necessary to stop bleeding by forming clots. In some cases, KMP has progressed to Dessiminated Intravascular Coagulation (DIC), a dangerous clotting and bleeding disorder in which many tiny clots develop and break down leading to poor organ and tissue oxygen delivery. This, in conjunction with the high usage rate of platelets puts patients at risk for organ damage and bleeding.
The exact pathogenesis of KMP is not well understood however a couple of hypotheses exist:
The narrow and convoluted capillaries in the KHEs are proposed to have turbulent blood flow that can lead to destruction of red blood cells and activation of the platelets, leading to anemia and thrombocytopenia associated with KMP. The strange endothelium in the KHE tumor activates platelets leading to both platelet and red blood cell trapping as well as consumption of the clotting factors.
Clinical Presentation and Diagnosis:
KHEs that present as bumpy but firm purple vascular lesions, that are poorly defined and and may be quite expansive. They are found typically on the limbs, occasionally on the trunk and rarely in the head and neck region. Diagnosis is best done through a combination of clinical presentation, imaging, and biopsy when possible. MRI is the most effective form of imaging as it can help with diagnosis and describe the extent of the KHE. On MRI, KHEs will reveal a poorly circumscribed vascular lesion, often invading nearby structures, with areas of bleeding and vigorous blood flow. Subsequent biopsies are often performed if possible to confirm diagnosis and reveal diffuse spindle cells, slit-shaped vascular channels, atypical endothelial cells with dark nuclei, and micro thrombi or tiny clots. The cells characteristically stain positive for cellular markers CD31, and CD34. Unfortunately, biopsies are not always possible as some KHEs are deep and others may be too invasively involved in their surroundings to safely sample for biopsy.
Presently there is no consensus on the optimal treatment for KHEs, however an American and Canadian multidisciplinary expert panel has put out a set of guidelines which are followed with physician discretion based on location, extent, and current state of KHE.
If the KHE is both superficial and easy to remove, then surgery is recommended by the expert panel, as surgery has been shown to be the most effective way to treat without residual disease. However, surgery is not always possible as it can be challenging in neonates and young children, and as KHEs tend to be quite infiltrative in nature, it can be very difficult to achieve complete resection. In cases where other forms of management have failed, surgery can be tried as incomplete resection has been shown to improve risks of complications in some patients. However, in patients with KHE associated with KMP, the increased risk of blood loss during surgery often renders surgery too dangerous.
Many different combinations of pharmacologic therapy have been examined either as an initial treatment or an alternative to ineffective surgery. No set regime or standard of medical treatment exists however, current thought seems to be shifting towards the use of corticosteroids and chemotherapy as initial therapy:
1)Corticosteroids: Traditionally corticosteroids have been given to treat KHEs, however they have been shown to be more effective when used in conjunction with other medications.
2)Chemotherapy: Drugs used to prevent endothelial cell division have been used to prevent tumor growth. Most commonly vincristine, a microtubule polymerization inhibitor, which prevents cells from dividing has been used, however recent literature also shows evidence for efficacy of paclitaxel, another chemotherapy drug that works in microtubules.
3)Sirolomus: Sirolomus suppresses the activity of a powerful cellular activity regulator called mTOR. Historically it was used as an immunosuppressive drug, given to transplant patients to prevent transplant rejection, however upon the discovery that mTOR was is seen in high levels in KHEs, Sirolomus was used for treatment of KHEs. It has been shown to be an effective second line treatment. Additional research is currently being done on other mTOR inhibitors and their role in treating KHEs.
4)Interferon Alpha (IFN alpha): IFN alpha is a cell signaling molecule given to patients with KHEs that works to inhibit growth signals to the tumor cells. Most notably IFN alpha inhibits basic fibroblastic growth factor and vascular endothelial growth factor. While IFN alpha has been shown to be effective in some cases, it is used with caution as there are risks of severe side effects including liver and nervous system damage.
For patients with KMP, some anti-platelet drugs are given to prevent disseminated intravascular coagulation including aspirin, clopidogrel, and toclopidine.
Arterial embolization, or the formation of a clot in the blood supply to the tumor has been shown to be effective for small KHEs. Unfortunately KHEs are often fed by tiny vessels that are difficult to target with interventional radiology, and even after the larger vessels are blocked through embolization, the tumor often quickly reforms new vessels. For these reasons, interventional radiology is more commonly used prior to surgery to help minimize blood loss by eliminating
Radiotherapy: Radiation is not often used to treat KHEs as KHEs are most prevalent in young patients and radiation is not desired at a young age due to an increased likelihood of other cancers and complications later in life.