Cancer prevention is action taken to lower the chance of getting cancer. By preventing cancer, the number of new cases of cancer in a group or population is lowered. Hopefully, this will reduce the burden of cancer and lower the number of deaths caused by cancer.
Cancer is not a single disease but a group of related diseases. Our genes, lifestyle, and the environment around us work together to increase or decrease our risk of getting cancer. Each person’s cancer risk is made up of a combination of these factors.
To prevent new cancers from starting, scientists look at risk factors and protective factors. Anything that increases your chance of developing cancer is called a cancer risk factor; anything that decreases your chance of developing cancer is called a cancer protective factor.
Some risk factors for cancer can be avoided, but many cannot. For example, both smoking and inheriting certain genes are risk factors for some types of cancer, but only smoking can be avoided. Regular exercise and a healthy diet may be protective factors for some types of cancer. Avoiding risk factors and increasing protective factors may lower your risk, but it does not mean that you will not get cancer.
Different ways to prevent cancer are being studied, including:
changing lifestyle or eating habits
avoiding things known to cause cancer
taking medicines to treat a precancerous conditions or to keep cancer from starting
having risk-reducing surgery.
General Information About Breast Cancer
Key Points
Breast cancer is a disease in which malignant (cancer) cells form in the tissues of the breast.
Breast cancer is the second leading cause of death from cancer in American women.
Breast cancer is a disease in which malignant (cancer) cells form in the tissues of the breast.
The breast is made up of lobes and ducts. Each breast has 15 to 20 sections called lobes, which have many smaller sections called lobules. Lobules end in dozens of tiny bulbs that can make milk. The lobes, lobules, and bulbs are linked by thin tubes called ducts.
EnlargeThe female breast contains lobes, lobules, and ducts that produce and transport milk to the nipple. Fatty tissue gives the breast its shape, while muscles and the chest wall provide support. The lymphatic system, including lymph nodes, filter lymph and store white blood cells that help fight infection and disease.
Each breast also has blood vessels and lymph vessels. The lymph vessels carry an almost colorless, watery fluid called lymph. Lymph vessels carry lymph between lymph nodes. Lymph nodes are small, bean-shaped structures that filter lymph and store white blood cells that help fight infection and disease. Groups of lymph nodes are found near the breast in the axilla (under the arm), above the collarbone, and in the chest.
Other PDQ summaries containing information related to breast cancer include:
Breast cancer is the second leading cause of death from cancer in American women.
Women in the United States get breast cancer more than any other type of cancer except for skin cancer. Breast cancer is second to lung cancer as a cause of cancer death in American women. Breast cancer rates in women increased gradually for many years until the early 2000s and then decreased rapidly, coinciding with a drop in postmenopausalhormone therapy use. However, since 2005, there has been a small but steady increase in breast cancer rates in women. Deaths from breast cancer declined by 44% between 1989 and 2022. However, breast cancer deaths in Black women remain about 38% higher than in White women. Breast cancer also occurs in men, but the number of new cases is small.
Breast Cancer Prevention
Key Points
Avoiding risk factors and increasing protective factors may help prevent cancer.
The following are risk factors for breast cancer:
Older age
A personal history of breast cancer or benign (noncancer) breast disease
Inherited risk of breast cancer
Dense breast tissue
Reproductive history resulting in greater exposure to estrogen
Taking hormone therapy for symptoms of menopause
Radiation therapy to the breast or chest
Obesity
Drinking alcohol
The following are protective factors for breast cancer:
Reproductive history resulting in less exposure to estrogen
Taking selective estrogen receptor modulators or aromatase inhibitors and inactivators
Selective estrogen receptor modulators
Aromatase inhibitors and inactivators
Risk-reducing or prophylactic mastectomy
Ovarian ablation
Getting enough exercise
It is not clear whether the following affect the risk of breast cancer:
Hormonal contraceptives
Chemicals in the environment
Studies have shown that some factors have little or no effect on the risk of breast cancer.
Cancer prevention clinical trials are used to study ways to prevent cancer.
New ways to prevent breast cancer are being studied in clinical trials.
Avoiding risk factors and increasing protective factors may help prevent cancer.
Avoiding cancerrisk factors may help prevent certain cancers. Risk factors include smoking, having overweight, and not getting enough exercise. Increasing protective factors such as quitting smoking and exercising may also help prevent some cancers. Talk to your doctor or other health care professional about how you might lower your risk of cancer.
Besides being a woman, older age is the main risk factor for breast cancer. The chance of getting breast cancer increases as a woman gets older. A 30-year-old woman has about a 1 in 175 chance of being diagnosed with breast cancer in the next 10 years, while a 70-year-old woman has a 1 in 9 chance of getting the disease during the same time period.
Women aged 50 to 69 years who have screening mammograms have a lower chance of dying from breast cancer than women who do not have screening mammograms. Screening by mammography decreases breast cancer deaths by identifying cases for treatment at an earlier stage.
A personal history of breast cancer or benign (noncancer) breast disease
Women with any of the following have an increased risk of breast cancer:
Women with a family history of breast cancer in a first-degree relative (mother, sister, or daughter) have an increased risk of breast cancer.
Women who have inherited changes in the BRCA1 or BRCA2gene or in certain other genes have a higher risk of breast cancer. The risk of breast cancer caused by inherited gene changes depends on the type of gene mutation, family history of cancer, and other factors.
Dense breast tissue
Having breast tissue that is dense on a mammogram is a factor in breast cancer risk. The level of risk depends on how dense the breast tissue is. Women with very dense breasts have a higher risk of breast cancer than women with low breast density.
Reproductive history resulting in greater exposure to estrogen
Estrogen is a hormone made by the body. It helps the body develop and maintain female sex characteristics. Being exposed to estrogen over a long time may increase the risk of breast cancer. Estrogen levels are highest during the years a woman is menstruating.
The following factors in a woman’s reproductive history increase the length of time her breast tissue is exposed to estrogen and may increase the risk of breast cancer:
Early menstruation: Beginning to have menstrual periods before age 12 increases the number of years the breast tissue is exposed to estrogen.
Starting menopause at a later age: The more years a woman menstruates, the longer her breast tissue is exposed to estrogen.
Older age at birth of first child or never having given birth: Pregnancy lowers a woman’s lifetime number of menstrual cycles. Breast tissue is exposed to more estrogen for longer periods of time in women who become pregnant for the first time after age 35 or who never become pregnant.
Taking hormone therapy for symptoms of menopause
Hormones, such as estrogen and progesterone, can be made into a pill form in a laboratory. Estrogen, progestin, or both may be given to replace the estrogen no longer made by the ovaries in postmenopausal women or women who have had their ovaries removed. This is called menopausal hormone therapy (MHT) or hormone replacement therapy (HRT). Estrogen therapy that began close to the time of menopause is associated with an increased risk of developing breast cancer. Estrogen therapy that began at or after menopause is associated with an increased risk of developing endometrial cancer and total cardiovascular disease, especially stroke. The risk of breast cancer does not decrease after women stop taking estrogen.
Combination hormone therapy (HT) is estrogen combined with progestin. This type of HT increases the risk of breast cancer. Studies show that when women stop taking estrogen combined with progestin, the risk of breast cancer decreases.
Radiation therapy to the breast or chest
Radiation therapy to the chest for the treatment of cancer increases the risk of breast cancer, starting 10 years after treatment. The risk of breast cancer depends on the dose of radiation and the age at which it was given. The risk is highest if radiation treatment was used during puberty, when breasts are forming.
Radiation therapy to treat cancer in one breast does not appear to increase the risk of cancer in the other breast.
For women who have inherited changes in the BRCA1 or BRCA2 gene, exposure to radiation, such as that from chest x-rays, may further increase the risk of breast cancer, especially in women who had x-rays before age 20.
Obesity
Obesity increases the risk of breast cancer, especially in postmenopausal women who have not used HT.
Drinking alcohol
Drinking alcohol increases the risk of breast cancer. The level of risk rises as the amount of alcohol consumed rises.
The following are protective factors for breast cancer:
Reproductive history resulting in less exposure to estrogen
A woman’s reproductive history can affect the length of time her breast tissue is exposed to estrogen. Early onset of menstruation, late onset of menopause, later age at first pregnancy, and never having given birth have been linked to an increase in estrogen exposure and breast cancer risk. The following reproductive factors decrease the length of time a woman’s breast tissue is exposed to estrogen and may help prevent breast cancer:
Early pregnancy: Estrogen levels are lower during pregnancy. In one study, women who had a full-term pregnancy before age 20 had a lower risk of breast cancer than women who did not have children or who gave birth to their first child after age 35.
Breast-feeding: Estrogen levels may remain lower while a woman is breast-feeding. Women who breastfed have a lower risk of breast cancer than women who have had children but did not breastfeed.
Taking selective estrogen receptor modulators or aromatase inhibitors and inactivators
Treatment with tamoxifen lowers the risk of estrogen receptor-positive (ER-positive) breast cancer and DCIS in premenopausal and postmenopausal women at high risk. Tamoxifen is also used to treat metastatic breast cancer and to prevent cancer from recurring after surgery to remove breast tumors. Treatment with raloxifene also lowers the risk of breast cancer in postmenopausal women. With either drug, the reduced risk lasts for several years or longer after treatment is stopped. Lower rates of broken bones have been noted in patients taking raloxifene.
Taking tamoxifen increases the risk of hot flashes, endometrial cancer, stroke, cataracts, and blood clots (especially in the lungs and legs). The risk of having these problems increases markedly in women older than 50 years compared with younger women. Premenopausal women who have a high risk of breast cancer may benefit the most from taking a low dose of tamoxifen, which may decrease breast cancer risk while also reducing some side effects of the drug. The risk of endometrial cancer lasts for 5 years after tamoxifen is stopped, but the risk of cataracts or blood clots does not last long. Talk with your doctor about the risks and benefits of taking this drug.
Taking raloxifene increases the risk of blood clots in the lungs and legs but does not appear to increase the risk of endometrial cancer. In postmenopausal women with osteoporosis (decreased bone density), raloxifene lowers the risk of breast cancer for women who have a high or low risk of breast cancer. It is not known if raloxifene would have the same effect in women who do not have osteoporosis. Talk with your doctor about the risks and benefits of taking this drug.
Other SERMs are being studied in clinical trials.
Aromatase inhibitors and inactivators
Aromatase inhibitors (anastrozole, letrozole) and inactivators (exemestane) lower the risk of recurrence and of new breast cancers in women who have a history of breast cancer. Aromatase inhibitors also decrease the risk of breast cancer in women with the following conditions:
postmenopausal women with a personal history of breast cancer
women with no personal history of breast cancer who are 60 years and older, have a history of DCIS with mastectomy, or have a high risk of breast cancer based on the Gail model tool (a tool used to estimate the risk of breast cancer)
In women with an increased risk of breast cancer, taking aromatase inhibitors decreases the amount of estrogen made by the body. Before menopause, estrogen is made by the ovaries and other tissues in a woman’s body, including the brain, fat tissue, and skin. After menopause, the ovaries stop making estrogen, but the other tissues do not. Aromatase inhibitors block the action of an enzyme called aromatase, which is used to make all of the body’s estrogen. Aromatase inactivators stop the enzyme from working.
Possible harms from taking aromatase inhibitors include muscle and joint pain, osteoporosis, hot flashes, and feeling very tired.
Risk-reducing or prophylactic mastectomy
Some women who have a high risk of breast cancer may choose to have a risk-reducing or prophylactic mastectomy (the removal of one or both breasts when there are no signs of cancer). After surgery, the risk of breast cancer becomes much lower in these women, and most feel less anxious about their risk of breast cancer. Some women diagnosed with breast cancer may decide to have a healthy breast removed at the same time the breast with cancer is removed. This is called contralateral prophylactic mastectomy. However, it is very important to have a cancer risk assessment and counseling about the different ways to prevent breast cancer before making any decision about surgery.
Ovarian ablation
The ovaries make most of the estrogen that is made by the body. Treatments that stop or lower the amount of estrogen made by the ovaries include surgery to remove the ovaries, radiation therapy, or taking certain drugs. This is called ovarian ablation.
Premenopausal women who have a high risk of breast cancer due to certain changes in the BRCA1 or BRCA2 gene may choose to have a risk-reducing oophorectomy (the removal of both ovaries when there are no signs of cancer). This decreases the amount of estrogen made by the body and lowers the risk of breast cancer. Risk-reducing oophorectomy also lowers the risk of breast cancer in average-risk premenopausal women and in women with an increased risk of breast cancer due to radiation to the chest. However, it is very important to have a cancer risk assessment and counseling before making this decision. The sudden drop in estrogen levels may cause the symptoms of menopause to begin. These include hot flashes, trouble sleeping, anxiety, and depression. Long-term effects include decreased sex drive, vaginal dryness, and decreased bone density.
Getting enough exercise
Women who take part in physical exercise have a lower risk of breast cancer.
It is not clear whether the following affect the risk of breast cancer:
Hormonal contraceptives
Hormonal contraceptives contain estrogen or estrogen and progestin. Some studies have shown that women who are current or recent users of hormonal contraceptives may have a slight increase in breast cancer risk. Other studies have not shown an increased risk of breast cancer in women using hormonal contraceptives.
In one study, the risk of breast cancer slightly increased the longer a woman used hormonal contraceptives. Another study showed that the slight increase in breast cancer risk decreased over time when women stopped using hormonal contraceptives.
More studies are needed to know whether hormonal contraceptives affect a woman’s risk of breast cancer.
Chemicals in the environment
Scientists are studying whether exposure to chemicals in the environment may increase a woman’s risk of breast cancer. Studies of this kind can be difficult to conduct and interpret for many reasons:
It is hard to determine the specific chemicals people have been exposed to in the past. It can take decades after a potential exposure before cancer develops, and a person may not be aware of or remember the past exposure.
Even if a chemical is shown in a laboratory test to cause cancer, this does not necessarily mean it will cause cancer in people exposed to that chemical in the environment. A chemical may cause cancer when tested at high levels in laboratory studies but not at the lower levels seen in the environment.
Individual chemicals are likely to cause only a small increase in risk, and it can be difficult to detect that increase in the context of the other factors that may influence a woman’s risk of breast cancer.
These reasons make it hard to know which chemicals, if any, may increase the risk of breast cancer. More studies are needed to know whether chemicals in the environment affect a woman’s risk of breast cancer. To learn more, visit Environmental Carcinogens and Cancer Risk.
Studies have shown that some factors have little or no effect on the risk of breast cancer.
The following have little or no effect on the risk of breast cancer:
having an abortion
making diet changes such as eating less fat or more fruits and vegetables
changes in your circadian rhythm (physical, mental, and behavioral changes that are mainly affected by darkness and light in 24 hour cycles), which may be affected by working night shifts or the amount of light in your bedroom at night
Cancer prevention clinical trials are used to study ways to prevent cancer.
Cancer prevention clinical trials are used to study ways to lower the risk of developing certain types of cancer. Some cancer prevention trials include healthy people who may or may not have an increased risk of cancer. Other prevention trials include people who have had cancer and are trying to prevent recurrence or a second cancer.
The purpose of some cancer prevention clinical trials is to find out whether actions people take can prevent cancer. These may include eating fruits and vegetables, exercising, quitting smoking, or taking certain medicines, vitamins, minerals, or food supplements.
New ways to prevent breast cancer are being studied in clinical trials.
Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.
PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.
Purpose of This Summary
This PDQ cancer information summary has current information about breast cancer prevention. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
Reviewers and Updates
Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.
The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Screening and Prevention Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
Permission to Use This Summary
PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”
The best way to cite this PDQ summary is:
PDQ® Screening and Prevention Editorial Board. PDQ Breast Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/breast/patient/breast-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389410]
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Soft tissue sarcoma may occur anywhere in the body. In children, the tumors form most often in the arms, legs, chest, or abdomen.
EnlargeSoft tissue sarcoma forms in the soft tissues of the body, including the muscles, tendons, ligaments, cartilage, fat, blood vessels, lymph vessels, nerves, and tissues around joints.
Soft tissue sarcoma occurs in children and adults. Soft tissue sarcoma in children may respond differently to treatment and may have a better prognosis than soft tissue sarcoma in adults. Learn more about soft tissue sarcoma in adults at Soft Tissue Sarcoma Treatment.
Types of soft tissue sarcoma
There are many types of soft tissue sarcoma. They are grouped based on the type of soft tissue cell where they first formed.
This summary is about the following types of soft tissue sarcoma:
Blood vessel tumors
Blood vessel tumors include the following types:
Epithelioid hemangioendothelioma. Epithelioid hemangioendothelioma can occur in children but is most common in adults between 30 and 50 years. It may occur in the liver, lung, bone, skin, or soft tissue. Epithelioid hemangioendothelioma may be fast growing or slow growing. In about a third of patients with a tumor in the soft tissue, the tumor spreads to other parts of the body very quickly. Learn more at Childhood Vascular Tumors.
Angiosarcoma. Angiosarcoma is a fast-growing cancer that forms in the blood vessels or lymph vessels in any part of the body, usually in the soft tissue. Most angiosarcomas are in the skin or in the soft tissue near the skin. Those in deeper soft tissue can form in the liver, spleen, and lung. This cancer is very rare in children. Children sometimes have more than one tumor in the skin, liver, or both. Rarely, infantile hemangioma may become angiosarcoma. Learn more at Childhood Vascular Tumors.
Bone tumors
Extraskeletal osteosarcoma. This type of bone and cartilage cancer is very rare in children and adolescents. It is likely to come back after treatment and may spread to the lungs. Osteosarcoma occurs more often in bone.
Cartilage tumors
Extraskeletal mesenchymal chondrosarcoma. This type of cartilage cancer often affects young adults and occurs in the head and neck. It is usually high grade (likely to grow quickly) and may spread to other parts of the body. It may also come back many years after treatment.
Fat tissue tumors
Liposarcoma. This is a cancer of the fat cells. Liposarcoma usually forms in the fat layer just under the skin. In children and adolescents, liposarcoma is often low grade (likely to grow and spread slowly). Liposarcoma may spread to the lungs and rarely to the lymph nodes. There are several different types of liposarcoma, including:
Myxoid pleomorphic liposarcoma. This is a rare cancer that most often forms in the middle of the chest in children, adolescents, and young adults. This cancer is high grade and can grow quickly and spread to other areas in the body.
Pleomorphic liposarcoma. This is usually a high-grade cancer that is less likely to respond well to treatment. Pleomorphic liposarcoma often forms in older adults.
Dermatofibrosarcoma protuberans. This is a cancer of the deep layers of the skin that most often forms in the trunk, arms, or legs. Dermatofibrosarcoma protuberans usually does not spread to the lymph nodes or other parts of the body.
Some cancers have cells with a certain genetic change called a translocation (part of one chromosome switches places with part of another chromosome). In dermatofibrosarcoma protuberans, an abnormal gene is formed when the COL1A1 gene switches places with part of the PDGFRB gene. To diagnose dermatofibrosarcoma protuberans, the cancer cells are checked for this genetic change.
Fibrosarcoma. There are two types of fibrosarcoma in children and adolescents:
Infantile fibrosarcoma (also called congenital fibrosarcoma). This type of fibrosarcoma usually occurs in children 1 year and younger and may be seen in a prenatal ultrasound exam. This cancer is fast growing and is often large at diagnosis. It rarely spreads to distant parts of the body.
Some cancers have cells with a certain genetic change called a translocation (part of one chromosome switches places with part of another chromosome). In infantile fibrosarcoma, an abnormal gene is formed when the ETV6 gene on chromosome 12 switches places with the NTRK3 gene on another chromosome. To diagnose infantile fibrosarcoma, the cancer cells are checked for this genetic change. A similar tumor has been seen in older children, but it does not have the translocation that is often seen in younger children. Other abnormal genes involved in infantile fibrosarcoma are BRAF, ALK, RAF1, GOLGA4, LRRFIP2, and CLIP1.
Adult-type fibrosarcoma. This is the same fibrosarcoma found in adults. The cells of this cancer do not have the genetic change found in infantile fibrosarcoma. Learn more about soft tissue sarcoma in adults at Soft Tissue Sarcoma Treatment.
Myxofibrosarcoma. This is a rare fibrous tissue cancer that occurs less often in children than in adults.
Low-grade fibromyxoid sarcoma. This is a slow-growing cancer that forms deep in the arms or legs and mostly affects young and middle-aged adults. The cancer may come back many years after treatment and spread to the lungs and the lining of the chest wall. Lifelong follow-up is needed.
Pericytic tumors form in cells that wrap around blood vessels. There are different types of pericytic tumors, including:
Myopericytoma. Infantile hemangiopericytoma is a type of myopericytoma. Children younger than 1 year at the time of diagnosis may have a better prognosis. In children older than 1 year, infantile hemangiopericytoma is more likely to spread to other parts of the body, including the lymph nodes and lungs.
Plexiform fibrohistiocytic tumor. This is a rare tumor that usually affects children and young adults. The tumor usually starts as a painless growth on or just under the skin on the arm, hand, or wrist. It may rarely spread to nearby lymph nodes or to the lungs.
Tumors of unknown cell origin
Tumors of unknown cell origin (the type of cell the tumor first formed in is not known) have many subtypes, including:
Myxoma. Myxoma is a tumor that can occur in the heart or skin. This tumor is frequently seen in children with Carney complex. Carney complex is a rare condition marked by spots on the skin, and tumors in the heart, endocrine glands, skin, and nerves. Carney complex may be linked to gene changes in the PRKAR1A gene.
Synovial sarcoma. Synovial sarcoma is a common type of soft tissue sarcoma in children and adolescents. Learn about Synovial Sarcoma.
Epithelioid sarcoma. This is a rare sarcoma that usually starts deep in soft tissue as a slow growing, firm lump and may spread to the lymph nodes. If cancer formed in the arms, legs, or buttocks, a sentinel lymph node biopsy may be done to check for cancer in the lymph nodes. Epithelioid sarcoma is linked to a change in a tumor suppressor gene called SMARCB1. This type of gene makes a protein that helps control cell growth.
Extraskeletal myxoid chondrosarcoma. This type of soft tissue sarcoma may occur in children and adolescents. Over time, it tends to spread to other parts of the body, including the lymph nodes and lungs. The tumor may come back many years after treatment.
Undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma). This type of soft tissue tumor may form in parts of the body where people have received radiation therapy in the past, or as a second cancer in children with retinoblastoma. The cancer usually forms in the arms or legs and may spread to other parts of the body. Learn more about Osteosarcoma Treatment.
Intracranialmesenchymal tumor. This type of malignant tumor forms in the brain of children, adolescents, and young adults.
Causes and risk factors for childhood soft tissue sarcoma
Childhood soft tissue sarcoma is caused by certain changes to the way soft tissue cells function, especially how they grow and divide into new cells. Often, the exact cause of these changes is unknown. Learn more about how cancer develops at What Is Cancer?
A risk factor is anything that increases the chance of getting a disease. Not every child with one or more of these risk factors will develop a soft tissue sarcoma. And it will develop in some children who don’t have a known risk factor.
The risk of soft tissue sarcoma may be increased if your child has one of the following inheriteddisorders:
Talk with your child’s doctor if you think your child may be at risk.
Symptoms of childhood soft tissue sarcoma
Soft tissue sarcoma may appear as a painless lump under the skin, often on an arm, a leg, the chest, or the abdomen. There may be no other symptoms at first. As the sarcoma gets bigger and presses on nearby organs, nerves, muscles, or blood vessels, it may cause symptoms, such as pain or weakness. Fever, weight loss, night sweats, and low or high blood sugar levels are rare symptoms.
Other conditions may cause the same symptoms. Check with your child’s doctor if your child has any of these problems.
Tests to diagnose childhood soft tissue sarcoma
If your child has symptoms that suggest a soft tissue sarcoma, the doctor will need to find out if these are due to cancer or another problem. The doctor will ask when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family medical history and do a physical exam. Depending on these results, they may recommend tests to find out if your child has a soft tissue sarcoma, and if so, its extent (stage).
The following tests may be used to diagnose soft tissue sarcomas. The results of these tests will also help you and your child’s doctor plan treatment.
X-ray
X-ray is a type of radiation that can go through the body and make pictures of areas inside the body.
Magnetic resonance imaging (MRI)
MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas in the body, such as the chest, abdomen, arms, or legs. This procedure is also called nuclear magnetic resonance imaging (NMRI).
EnlargeMagnetic resonance imaging (MRI) scan. The child lies on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body. The positioning of the child on the table depends on the part of the body being imaged.
CT scan
CT scan (CAT scan) uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body, such as the chest or abdomen. The pictures are taken from different angles and are used to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. Learn more about Computed Tomography (CT) Scans and Cancer.
EnlargeComputed tomography (CT) scan. The child lies on a table that slides through the CT scanner, which takes a series of detailed x-ray pictures of areas inside the body.
Ultrasound
Ultrasound uses high-energy sound waves (ultrasound) that bounce off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
Biopsy
Biopsy is the removal of a sample of cells or tissue from the tumor so that a pathologist can view it under a microscope to check for cancer. The type of biopsy depends, in part, on the size of the mass and whether it is close to the surface of the skin or deeper in the tissue. The following types of biopsies may be used to check for soft tissue sarcoma:
Core needle biopsy removes tissue using a wide needle. Multiple tissue samples are taken. This procedure may be guided using ultrasound, CT scan, or MRI.
Incisional biopsy removes part of a lump or a sample of tissue.
Excisional biopsy removes an entire lump or area of tissue that doesn’t look normal. A pathologist views the tissue under a microscope to look for cancer cells. An excisional biopsy may be used to completely remove smaller tumors that are near the surface of the skin. This type of biopsy is rarely used because cancer cells may remain after the biopsy. If cancer cells remain, the cancer may come back, or it may spread to other parts of the body.
An MRI of the tumor is done before the excisional biopsy. This is done to make a picture of where the original tumor formed and may be used to guide future surgery or radiation therapy.
If possible, it is important to have the same surgeon perform the biopsy and the surgery to remove the tumor. The placement of needles or incisions for the biopsy can affect whether the tumor can be completely removed during a future surgery.
To plan the best treatment, the sample of tissue removed during the biopsy must be large enough to find out the type of soft tissue sarcoma and do other laboratory tests. Tissue samples will be taken from the primary tumor, lymph nodes, and other areas that may have cancer cells. A pathologist views the tissue under a microscope to look for cancer cells and to find out the type and grade of the tumor. The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the cells are dividing. High-grade and mid-grade tumors usually grow and spread more quickly than low-grade tumors.
One or more of the following laboratory tests may be done to study the tissue samples:
Light and electron microscopy checks cells in a sample of tissue under regular and high-powered microscopes to look for certain changes.
Immunocytochemistry uses antibodies to check for certain antigens (markers) in a sample of a patient’s cells or tissues. The antibodies are usually linked to an enzyme or fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test may be used to tell one type of soft tissue sarcoma from another type.
Reverse transcription–polymerase chain reaction (RT-PCR) is a laboratory method used to make many copies of a specific genetic sequence for analysis. It may be used to look for certain changes in a gene or chromosome or for activation of certain genes, which may help diagnose a disease, such as cancer.
Cytogenetic analysis checks the chromosomes of cells in a sample of tumor tissue for broken, missing, rearranged, or extra chromosomes. Changes in certain chromosomes may be a sign of cancer. Cytogenetic analysis is used to help diagnose cancer, plan treatment, or find out how well treatment is working. Fluorescence in situ hybridization (FISH) is a type of cytogenetic analysis.
Molecular test checks for certain genes, proteins, or other molecules in a sample of tissue, blood, or bone marrow. Molecular tests also check for certain changes in a gene or chromosome that may cause or affect the chance of developing soft tissue sarcoma. A molecular test will often help determine the type of soft tissue sarcoma.
The Molecular Characterization Initiative offers free molecular testing to children, adolescents, and young adults with certain types of newly diagnosed cancer. The program is offered through NCI’s Childhood Cancer Data Initiative. To learn more, visit About the Molecular Characterization Initiative.
The following tests may be used to find out if cancer has spread:
Sentinel lymph node biopsy
Sentinel lymph node biopsy removes the sentinel lymph node during surgery. The sentinel lymph node is the first lymph node in a group of lymph nodes to receive lymphatic drainage from the primary tumor. It is therefore the first lymph node the cancer is likely to spread to from the primary tumor. To identify the sentinel lymph node, a radioactive substance, blue dye, or both is injected near the tumor. The substance or dye flows through the lymph ducts to the lymph nodes. The first lymph node to receive the substance or dye is removed. A pathologist views the tissue under a microscope to look for cancer cells. If cancer cells are found, more lymph nodes will be removed through a separate incision (cut). This is called a lymph node dissection. Sometimes, a sentinel lymph node is found in more than one group of nodes. This procedure is used for epithelioid sarcoma.
For the PET scan, a small amount of radioactive sugar (also called radioactive glucose) is injected into a vein. The PET scanner rotates around the body and makes pictures of where sugar is being used in the body. Cancer cells show up brighter in the picture because they are more active and take up more sugar than normal cells do.
For the CT scan (CAT scan), a series of detailed x-ray pictures are taken from different angles and are used to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. Learn more about Computed Tomography (CT) Scans and Cancer.
Getting a second opinion
You may want to get a second opinion to confirm your child’s cancer diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the genetic test results, pathology report, slides, and scans. This doctor may agree with the first doctor, suggest changes or another approach, or provide more information about your child’s tumor.
To learn more about choosing a doctor and getting a second opinion, visit Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor or hospital that can provide a second opinion. For questions you might want to ask at your appointments, visit Questions to Ask Your Doctor about Cancer.
Types of treatment for childhood soft tissue sarcoma
Who treats children with soft tissue sarcoma?
A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment for soft tissue sarcoma. The pediatric oncologist works with other health care providers who are experts in treating children with soft tissue sarcoma and who specialize in certain areas of medicine. These may include a pediatric surgeon with special training in the removal of soft tissue sarcomas. Other specialists may include:
There are different types of treatment for children and adolescents with soft tissue sarcoma. You and your child’s cancer care team will work together to decide treatment. Often, the treatments depend on the type of soft tissue sarcoma. Many other factors will be considered, such as your child’s overall health and whether the cancer is newly diagnosed or has come back.
Your child’s treatment plan will include information about the cancer, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s cancer care team before treatment begins about what to expect. For help every step of the way, visit our booklet, Children with Cancer: A Guide for Parents.
Types of treatment your child might have include:
Surgery
Surgery to completely remove the soft tissue sarcoma is done when possible. If the tumor is very large, radiation therapy or chemotherapy may be given first, to make the tumor smaller and decrease the amount of tissue that needs to be removed during surgery. This is called neoadjuvant (preoperative) therapy.
The following types of surgery may be used:
Wide local excision removes the tumor along with some normal tissue around it.
Amputation removes all or part of the arm or leg with cancer.
Mohs surgery is used to treat cancer in the skin. Individual layers of cancer tissue are removed and checked under a microscope one at a time until all cancer tissue has been removed. This type of surgery is used to treat dermatofibrosarcoma protuberans. It is also called Mohs micrographic surgery.
check the area around where the tumor was removed for cancer cells and then remove more tissue, if needed
After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are different types of radiation therapy:
External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Certain ways of giving radiation therapy can help keep radiation from damaging nearby healthy tissue. This type of radiation therapy may include:
Stereotactic body radiation therapy uses special equipment to place the patient in the same position for each radiation treatment. Once a day for several days, a radiation machine aims a larger than usual dose of radiation directly at the tumor. By having the patient in the same position for each treatment, there is less damage to nearby healthy tissue. This procedure is also called stereotactic external-beam radiation therapy and stereotaxic radiation therapy.
Conformal radiation therapy uses a computer to make a 3-dimensional (3-D) picture of the tumor and shapes the radiation beams to fit the tumor. This allows a high dose of radiation to reach the tumor and causes less damage to nearby healthy tissue.
Intensity-modulated radiation therapy (IMRT) is a type of 3-D radiation therapy that uses a computer to make pictures of the size and shape of the tumor. Thin beams of radiation of different intensities (strengths) are aimed at the tumor from many angles. This type of external radiation therapy causes less damage to nearby healthy tissue.
Proton beam radiation therapy is a type of high-energy, external radiation therapy that uses streams of protons (tiny particles with a positive charge) to kill tumor cells. This type of treatment can lower the amount of radiation damage to healthy tissue near a tumor.
The way radiation therapy is given depends on the type and stage of the cancer being treated, if any cancer cells remain after surgery, and the expected side effects of treatment. External and internal radiation therapy are used to treat childhood soft tissue sarcoma.
Chemotherapy (also called chemo) uses drugs to stop the growth of cancer cells. Chemotherapy either kills the cancer cells or stops them from dividing. Chemotherapy may be given alone or with other types of treatment, such as radiation therapy.
For children with soft tissue sarcoma, chemotherapy is taken by mouth or injected into a vein. When given this way, the drugs enter the bloodstream to reach cancer cells throughout the body.
The way the chemotherapy is given depends on the type of soft tissue sarcoma being treated. Some types of soft tissue sarcoma may respond to treatment with chemotherapy.
Chemotherapy that may be used alone or in combination includes:
Other chemotherapy drugs not listed here may also be used.
Learn more about how chemotherapy works, how it is given, common side effects, and more at Chemotherapy to Treat Cancer.
Observation
Observation is closely monitoring a person’s condition without giving any treatment until signs or symptoms appear or change. Observation may be done when:
complete removal of the tumor is not possible
no other treatments are available
the tumor is not likely to damage any vital organs
Targeted therapy uses drugs or other substances to block the action of specific enzymes, proteins, and other molecules involved in the growth and spread of cancer cells. Targeted therapies used to treat soft tissue sarcoma include:
Atezolizumab is used to treat children older than 2 years with alveolar soft part sarcoma that can’t be removed with surgery or has spread to other places in the body.
Larotrectinib is used to treat infantile fibrosarcoma.
Immunotherapy is a treatment that uses the person’s immune system to fight cancer. Pembrolizumab may be used to treat undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma) and progressive and recurrent soft tissue sarcoma.
For some children, joining a clinical trial may be an option. There are different types of clinical trials for childhood cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.
You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your child’s age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Treatment of newly diagnosed undifferentiated pleomorphic sarcoma may include surgery. Treatment of recurrent or refractory undifferentiated pleomorphic sarcoma may include immunotherapy (pembrolizumab).
Treatment of childhood soft tissue sarcoma that has spread to other parts of the body at diagnosis is chemotherapy and radiation therapy. Surgery may be done to remove tumors that have spread to the lung.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of progressive or recurrent childhood soft tissue sarcoma
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Side effects and late effects of treatment
Cancer treatments can cause side effects. Which side effects your child might have depends on the type of treatment they receive, the dose, and how their body reacts. Talk with your child’s treatment team about which side effects to look for and ways to manage them.
To learn more about side effects that begin during treatment for cancer, visit Side Effects.
Problems from cancer treatment that begin 6 months or later after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include:
physical problems
changes in mood, feelings, thinking, learning, or memory
second cancers (new types of cancer)
Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the effects cancer treatment can have on your child. Learn more about Late Effects of Treatment for Childhood Cancer.
Prognostic factors for childhood soft tissue sarcoma
If your child has been diagnosed with a soft tissue sarcoma, you may have questions about how serious the cancer is and your child’s chances of survival. The likely outcome or course of a disease is called prognosis. The prognosis depends on:
the part of the body where the tumor first formed
the size and grade of the tumor
the type of soft tissue sarcoma
how deep the tumor is under the skin
whether the tumor has spread to other places in the body and where it has spread
the amount of tumor remaining after surgery to remove it
whether radiation therapy was used to treat the tumor
whether the cancer has just been diagnosed or has recurred (come back)
No two people are alike, and responses to treatment can vary greatly. Your child’s cancer care team is in the best position to talk with you about your child’s prognosis.
Follow-up care
As your child goes through treatment, they will have follow-up tests or check-ups. Some of the tests that were done to diagnose the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your child’s condition has changed or if the cancer has recurred (come back).
When your child has cancer, every member of the family needs support. Taking care of yourself during this difficult time is important. Reach out to your child’s treatment team and to people in your family and community for support. To learn more, visit Support for Families: Childhood Cancer and the booklet Children with Cancer: A Guide for Parents.
Related resources
For more childhood cancer information and other general cancer resources, visit:
Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.
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Vulvar cancer is a rare cancer that starts in the tissues of the vulva.
Having vulvar intraepithelial neoplasia or HPV infection can increase the risk of vulvar cancer.
Signs of vulvar cancer include bleeding or itching in the vulvar area.
Tests that examine the vulva are used to diagnose vulvar cancer.
Certain factors affect prognosis (chance of recovery) and treatment options.
Vulvar cancer is a rare cancer that starts in the tissues of the vulva.
Vulvar cancer forms in a woman’s external genitalia, called the vulva. It occurs when cells in the vulva start to grow out of control. The vulva includes:
the mons pubis (the rounded area in front of the pubic bones that becomes covered with hair at puberty)
EnlargeAnatomy of the vulva. The vulva includes the mons pubis, clitoris, inner and outer lips of the vagina, and the openings of the urethra and vagina.
Vulvar cancer most often affects the outer vaginal lips. Less often, cancer affects the inner vaginal lips, clitoris, or vaginal glands.
Vulvar cancer usually forms slowly over many years. Abnormal cells can grow on the surface of the vulvar skin for a long time. This condition is called vulvar intraepithelial neoplasia (VIN). Because it is possible for VIN to become vulvar cancer, it is important to get treatment.
Having vulvar intraepithelial neoplasia or HPV infection can increase the risk of vulvar cancer.
Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop vulvar cancer, and it will develop in some people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk. Risk factors for vulvar cancer include:
having a history of abnormal Pap tests (Pap smears)
Signs of vulvar cancer include bleeding or itching in the vulvar area.
Vulvar cancer often does not cause early signs or symptoms. Signs and symptoms may be caused by vulvar cancer or by other conditions. Check with your doctor if you have any of the following:
a lump or growth on the vulva that looks like a wart or ulcer
Pelvic exam: An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. A speculum is inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test of the cervix is usually done. The doctor or nurse also inserts one or two lubricated, gloved fingers of one hand into the vagina and places the other hand over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas. EnlargePelvic exam. A doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and presses on the lower abdomen with the other hand. This is done to feel the size, shape, and position of the uterus and ovaries. The vagina, cervix, fallopian tubes, and rectum are also checked.
Pap test: A procedure to collect cells from the surface of the cervix and vagina. A piece of cotton, a brush, or a small wooden stick is used to gently scrape cells from the cervix and vagina. The cells are viewed under a microscope to find out if they are abnormal.
Human papillomavirus (HPV) test: A laboratory test used to check DNA or RNA for certain types of HPV infection. Cells are collected from the vulva and DNA or RNA from the cells is checked to find out if an infection is caused by a type of human papillomavirus that is linked to vulvar cancer. This test may be done using the sample of cells removed during a Pap test. This test may also be done if the results of a Pap test show certain abnormal vulvar cells.
Biopsy: The removal of cells or tissues from the vulva so they can be viewed under a microscope by a pathologist to check for signs of cancer.
Colposcopy: A procedure in which a colposcope (a lighted, magnifying instrument) is used to check the vagina and cervix for abnormal areas. Tissue samples may be taken using a curette (spoon-shaped instrument) or a brush and checked under a microscope for signs of disease.
MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
PET scan (positron emission tomography scan): A procedure to find malignanttumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
Certain factors affect prognosis (chance of recovery) and treatment options.
whether the cancer has just been diagnosed or has recurred (come back)
Stages of Vulvar Cancer
Key Points
After vulvar cancer has been diagnosed, tests are done to find out if cancer cells have spread within the vulva or to other parts of the body.
There are three ways that cancer spreads in the body.
Cancer may spread from where it began to other parts of the body.
In vulvar intraepithelial neoplasia (VIN), abnormal cells are found on the surface of the vulvar skin.
The following stages are used for vulvar cancer:
Stage I
Stage II
Stage III
Stage IV
Vulvar cancer can recur (come back) after it has been treated.
After vulvar cancer has been diagnosed, tests are done to find out if cancer cells have spread within the vulva or to other parts of the body.
The process used to find out if cancer has spread within the vulva or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment. The following tests and procedures may be used in the staging process:
Cystoscopy: A procedure to look inside the bladder and urethra to check for abnormal areas. A cystoscope is inserted through the urethra into the bladder. A cystoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.
Proctoscopy: A procedure to look inside the rectum and anus to check for abnormal areas, using a proctoscope. A proctoscope is a thin, tube-like instrument with a light and a lens for viewing the inside of the rectum and anus. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.
Chest x-ray: An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body. To stage vulvar cancer, x-rays may be taken of the organs and bones inside the chest.
Intravenous pyelogram (IVP): A series of x-rays of the kidneys, ureters, and bladder to find out if cancer has spread to these organs. A contrast dye is injected into a vein. As the contrast dye moves through the kidneys, ureters and bladder, x-rays are taken to see if there are any blockages. This procedure is also called intravenous urography.
Biopsy: The removal of cells or tissues from the bladder or rectum so they can be viewed under a microscope by a pathologist to check for signs of cancer, if it is suspected that cancer has spread there.
There are three ways that cancer spreads in the body.
Tissue. The cancer spreads from where it began by growing into nearby areas.
Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.
Cancer may spread from where it began to other parts of the body.
When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.
Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.
The metastatic tumor is the same type of cancer as the primary tumor. For example, if vulvar cancer spreads to the lung, the cancer cells in the lung are actually vulvar cancer cells. The disease is metastatic vulvar cancer, not lung cancer.
Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.
In vulvar intraepithelial neoplasia (VIN), abnormal cells are found on the surface of the vulvar skin.
In stage I, cancer has formed. The tumor is found only in the vulva. Stage I is divided into stages IA and IB.
EnlargeTumor sizes are often measured in centimeters (cm) or inches. Common food items that can be used to show tumor size in cm include: a pea (1 cm), a peanut (2 cm), a grape (3 cm), a walnut (4 cm), a lime (5 cm or 2 inches), an egg (6 cm), a peach (7 cm), and a grapefruit (10 cm or 4 inches).
In stage IA, the tumor is 2 centimeters or smaller and has spread 1 millimeter or less into the tissue of the vulva. Cancer has not spread to the lymph nodes.
In stage IB, the tumor is larger than 2 centimeters or has spread more than 1 millimeter into the tissue of the vulva. Cancer has not spread to the lymph nodes. EnlargeMillimeters (mm). A sharp pencil point is about 1 mm, a new crayon point is about 2 mm, and a new pencil eraser is about 5 mm.
Stage II
In stage II, the tumor is any size and has spread to the lower one-third of the urethra, the lower one-third of the vagina, or the lower one-third of the anus. Cancer has not spread to the lymph nodes.
Stage III
In stage III, the tumor is any size and has spread to the upper two-thirds of the urethra, the upper two-thirds of the vagina, the inner lining of the bladder or rectum, or to any number of lymph nodes. Stage III is divided into stages IIIA, IIIB, and IIIC.
In stage IIIA, cancer is found in lymph nodes in the groin that are not larger than 5 millimeters.
In stage IIIB, cancer is found in lymph nodes in the groin that are larger than 5 millimeters.
In stage IIIC, cancer is found in lymph nodes in the groin and has extended through the outer covering of the lymph nodes.
Stage IV
In stage IV, the tumor is any size and has become attached to the bone, or cancer has spread to lymph nodes that are not movable or have become ulcerated, or there is distant spread. Stage IV is divided into stages IVA and IVB.
In stage IVA, the cancer is attached to the pelvic bone or has spread to lymph nodes in the groin that are not movable or have become ulcerated.
In stage IVB, the cancer has spread beyond the pelvis to distant parts of the body.
Vulvar cancer can recur (come back) after it has been treated.
The cancer may come back in the vulva or in other parts of the body.
Treatment Option Overview
Key Points
There are different types of treatment for patients with vulvar cancer.
The following types of treatment are used:
Surgery
Radiation therapy
Chemotherapy
Immunotherapy
New types of treatment are being tested in clinical trials.
Treatment for vulvar cancer may cause side effects.
Patients may want to think about taking part in a clinical trial.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Follow-up tests may be needed.
There are different types of treatment for patients with vulvar cancer.
Different types of treatments are available for patients with vulvar cancer. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
One of the following types of surgery may be done to treat VIN:
Separate excision of a lesion: A surgical procedure to remove a lesion of concern.
Wide local excision: A surgical procedure to remove the area of skin affected by VIN and some of the normal tissue around it.
Laser surgery: A surgical procedure that uses a laser beam (a narrow beam of intense light) as a knife to make bloodless cuts in tissue or to remove a surface lesion such as a tumor.
Ultrasound surgical aspiration: A surgical procedure to break the tumor up into small pieces using very fine vibrations. The small pieces of tumor are washed away and removed by suction. This procedure causes less damage to nearby tissue.
Skinning vulvectomy: The top layer of vulvar skin where the VIN is found is removed. Skin grafts from other parts of the body may be needed to cover the area where the skin was removed.
The goal of surgery for vulvar cancer is to remove all the cancer without any loss of the woman’s sexual function. One of the following types of surgery may be done to treat vulvar cancer:
Wide local excision: A surgical procedure to remove the cancer and some of the normal tissue around the cancer.
Radical local excision: A surgical procedure to remove the cancer and a large amount of normal tissue around it. Nearby lymph nodes in the groin may also be removed.
Vulvectomy: A surgical procedure to remove part or all of the vulva:
Radical vulvectomy: Surgery to remove the entire vulva. Nearby lymph nodes are also removed.
Pelvic exenteration: A surgical procedure to remove the lower colon, rectum, and bladder. The cervix, vagina, ovaries, and nearby lymph nodes are also removed. Artificial openings (stoma) are made for urine and stool to flow from the body into a collection bag.
After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy and/or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.
Radiation therapy
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward area of the body with cancer.
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). Topical chemotherapy for vulvar cancer may be applied to the skin in a cream or lotion. The way the chemotherapy is given depends on the type and stage of the cancer being treated.
Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer.
Patients may want to think about taking part in a clinical trial.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Follow-up tests may be needed.
As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
radiation therapy or chemotherapy and radiation therapy followed by surgery
radiation therapy with or without chemotherapy
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
radiation therapy or chemotherapy and radiation therapy followed by surgery
radiation therapy with or without chemotherapy
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
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Purpose of This Summary
This PDQ cancer information summary has current information about the treatment of vulvar cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
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Clinical Trial Information
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The best way to cite this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Vulvar Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/vulvar/patient/vulvar-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389324]
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This summary addresses squamous cell cancer of the vulva and vulvar intraepithelial neoplasia (VIN). VIN may be a precursor to invasive squamous cell cancer.
About 50% of vulvar carcinomas arise in the labia majora, the most common site. The labia minora are the site of 15% to 20% of vulvar carcinoma cases. The clitoris and Bartholin glands are less frequently involved.[1] Lesions are multifocal in about 5% of cases. More than 90% of invasive vulvar cancers are squamous cell carcinomas.[2]
Incidence and Mortality
Vulvar cancer accounts for about 6% of cancers of the female genital system in the United States.[3]
Estimated new cases and deaths from vulvar cancer in the United States in 2025:[3]
New cases: 7,480.
Deaths: 1,770.
Anatomy
The vulva is the area immediately external to the vagina, including the mons pubis, labia, clitoris, and Bartholin glands.
EnlargeAnatomy of the vulva. The vulva includes the mons pubis, clitoris, inner and outer lips of the vagina, and the openings of the urethra and vagina.
Risk Factors
Increasing age is the most important risk factor for most cancers. Other risk factors associated with vulvar cancer include:
Human papillomavirus (HPV) infection: In many cases, the development of vulvar cancer is preceded by condyloma or squamous dysplasia. The prevailing evidence favors HPV infection as a causative factor in many genital tract carcinomas.[4]
HPV-associated VIN, termed usual-type VIN when high grades 2 and 3, is most common in women younger than 50 years, whereas non–HPV-associated VIN, termed differentiated-type VIN when high grade 3, is most common in older women.[5,6]
The former lesion-type VIN grade 1 is no longer classified as a true VIN.[5,6] The HPV-related basaloid and warty types are associated with VIN. About 75% to 100% of basaloid and warty carcinomas harbor HPV infection. In addition to the much higher prevalence of HPV in these subtypes than in the keratinizing subtypes, the basaloid and warty subtypes also share many common risk factors with cervical cancers, including:
Prognosis depends on the pathological status of the inguinal lymph nodes and whether spread to adjacent structures has occurred.[8] In patients with operable disease without lymph node involvement, the overall survival (OS) rate is 90%. However, in patients with nodal involvement, the 5-year OS rate is approximately 50% to 60%.[9]
The size of the primary tumor is less important in defining prognosis.[8]
Follow-Up After Treatment
Invasive and preinvasive neoplasms of the vulva may be HPV-induced, and the carcinogenic effect may be widespread in the vulvar epithelium. As a result, patients are monitored regularly for signs or symptoms of recurrence.
References
Macnab JC, Walkinshaw SA, Cordiner JW, et al.: Human papillomavirus in clinically and histologically normal tissue of patients with genital cancer. N Engl J Med 315 (17): 1052-8, 1986. [PUBMED Abstract]
Eifel PJ, Klopp AH, Berek JS, et al.: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1171-1210.
American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
Hampl M, Sarajuuri H, Wentzensen N, et al.: Effect of human papillomavirus vaccines on vulvar, vaginal, and anal intraepithelial lesions and vulvar cancer. Obstet Gynecol 108 (6): 1361-8, 2006. [PUBMED Abstract]
Pepas L, Kaushik S, Bryant A, et al.: Medical interventions for high grade vulval intraepithelial neoplasia. Cochrane Database Syst Rev (4): CD007924, 2011. [PUBMED Abstract]
Sideri M, Jones RW, Wilkinson EJ, et al.: Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. J Reprod Med 50 (11): 807-10, 2005. [PUBMED Abstract]
Schiffman M, Kjaer SK: Chapter 2: Natural history of anogenital human papillomavirus infection and neoplasia. J Natl Cancer Inst Monogr (31): 14-9, 2003. [PUBMED Abstract]
Olawaiye AB, Hagemann I, Bhoshale P, et al.: Vulva. In: Goodman KA, Gollub M, Eng C, et al.: AJCC Cancer Staging System. Version 9. American Joint Committee on Cancer; American College of Surgeons, 2023.
Homesley HD, Bundy BN, Sedlis A, et al.: Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (a Gynecologic Oncology Group study). Am J Obstet Gynecol 164 (4): 997-1003; discussion 1003-4, 1991. [PUBMED Abstract]
Cellular Classification of Vulvar Cancer
The histological classification of vulvar disease and precursor lesions of cancer of the vulva was developed by the International Society for the Study of Vulvovaginal Disease (ISSVD).[1]
Nonneoplastic epithelial disorders of vulvar skin and mucosa
Lichen sclerosus (lichen sclerosus et atrophicus).
Low-grade squamous intraepithelial lesion (SIL) of the vulva (vulvar LSIL) encompasses flat condyloma or human papillomavirus effect.
High-grade SIL (vulvar HSIL) was termed VIN, usual type in the 2004 ISSVD terminology.
VIN, differentiated type.
Paget disease of the vulva
Characteristic large pale cells in the epithelium and skin adnexa.
Other histologies
Basal cell carcinoma.
Langerhans cell histiocytosis.
Malignant melanoma.
Sarcoma.
Verrucous carcinoma.
References
Bornstein J, Bogliatto F, Haefner HK, et al.: The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar Squamous Intraepithelial Lesions. J Low Genit Tract Dis 20 (1): 11-4, 2016. [PUBMED Abstract]
Stage Information for Vulvar Cancer
The staging evaluation for vulvar cancer may include the following procedures:
Cystoscopy.
Proctoscopy.
X-ray examination of the lungs.
Intravenous (IV) urography (also known as IV pyelography).
Suspected bladder or rectal involvement must be confirmed by biopsy.[1]
The Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) Staging
FIGO and the American Joint Committee on Cancer have designated staging to define vulvar cancer; the FIGO system is most commonly used.[1,2] Stage is based on pathological staging at the time of surgery or before any radiation or chemotherapy, if they are the initial treatment modalities.[3]
The staging system does not apply to malignant melanoma of the vulva, which is staged like melanoma of the skin.[1] For more information, see the Stage Information for Melanoma section in Melanoma Treatment.
Table 1. Definitions of FIGO Stage I, IA, and IBa
Stage
Definition
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[2]
bDepth of invasion is measured from the basement membrane of the deepest, adjacent, dysplastic, tumor-free rete ridge (or nearest dysplastic rete peg) to the deepest point of invasion.
I
Tumor confined to the vulva.
IA
Tumor size ≤2 cm and stromal invasion ≤1 mmb.
IB
Tumor size >2 cm or stromal invasion >1 mmb.
Table 2. Definition of FIGO Stage IIa
Stage
Definition
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[2]
II
Tumor of any size with extension to lower one-third of the urethra, lower one-third of the vagina, lower one-third of the anus with negative nodes.
Table 3. Definitions of FIGO Stage III, IIIA, IIIB, and IIICa
Stage
Definition
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[2]
bRegional refers to inguinal and femoral lymph nodes.
III
Tumor of any size with extension to upper part of adjacent perineal structures, or with any number of nonfixed, nonulcerated lymph nodes.
IIIA
Tumor of any size with disease extension to upper two-thirds of the urethra, upper two-thirds of the vagina, bladder mucosa, rectal mucosa, or regional lymph node metastases ≤5 mm.
IIIB
Regionalb lymph node metastases >5 mm.
IIIC
Regionalb lymph node metastases with extracapsular spread.
Table 4. Definitions of FIGO Stage IV, IVA, and IVBa
Stage
Definition
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[2]
bRegional refers to inguinal and femoral lymph nodes.
IV
Tumor of any size fixed to bone, or fixed, ulcerated lymph node metastases, or distant metastases.
IVA
Disease fixed to pelvic bone, or fixed or ulcerated regionalb lymph node metastases.
IVB
Distant metastases.
Grade is reported in registry systems and may differ between systems; a two-, three-, or four-grade system may be applied. If not specified, the following system is generally used:[1]
GX: Grade cannot be assessed.
G1: Well differentiated.
G2: Moderately differentiated.
G3: Poorly differentiated.
Overall, about 30% of patients with operable disease have lymph node spread. The pattern of spread is influenced by the histology. Risk factors for lymph node metastasis include:[4–8]
Clinical node status.
Age.
Degree of tumor differentiation.
Tumor stage.
Tumor thickness.
Depth of stromal invasion.
Presence of capillary-lymphatic space invasion.
Well-differentiated lesions tend to spread along the surface with minimal invasion, whereas anaplastic lesions are more likely to be deeply invasive. Spread beyond the vulva is either to adjacent organs such as the vagina, urethra, and anus, or via the lymphatics to the inguinal and femoral lymph nodes, followed by the deep pelvic nodes. Hematogenous spread appears to be uncommon.
References
Olawaiye AB, Hagemann I, Bhoshale P, et al.: Vulva. In: Goodman KA, Gollub M, Eng C, et al.: AJCC Cancer Staging System. Version 9. American Joint Committee on Cancer; American College of Surgeons, 2023.
Olawaiye AB, Cuello MA, Rogers LJ: Cancer of the vulva: 2021 update. Int J Gynaecol Obstet 155 (Suppl 1): 7-18, 2021. [PUBMED Abstract]
Hopkins MP, Reid GC, Johnston CM, et al.: A comparison of staging systems for squamous cell carcinoma of the vulva. Gynecol Oncol 47 (1): 34-7, 1992. [PUBMED Abstract]
Homesley HD, Bundy BN, Sedlis A, et al.: Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (a Gynecologic Oncology Group study). Am J Obstet Gynecol 164 (4): 997-1003; discussion 1003-4, 1991. [PUBMED Abstract]
Boyce J, Fruchter RG, Kasambilides E, et al.: Prognostic factors in carcinoma of the vulva. Gynecol Oncol 20 (3): 364-77, 1985. [PUBMED Abstract]
Sedlis A, Homesley H, Bundy BN, et al.: Positive groin lymph nodes in superficial squamous cell vulvar cancer. A Gynecologic Oncology Group Study. Am J Obstet Gynecol 156 (5): 1159-64, 1987. [PUBMED Abstract]
Binder SW, Huang I, Fu YS, et al.: Risk factors for the development of lymph node metastasis in vulvar squamous cell carcinoma. Gynecol Oncol 37 (1): 9-16, 1990. [PUBMED Abstract]
Homesley HD, Bundy BN, Sedlis A, et al.: Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group study) Gynecol Oncol 49 (3): 279-83, 1993. [PUBMED Abstract]
Treatment Option Overview for Vulvar Cancer
The primary treatment for vulvar cancer is surgery. Radiation therapy is also given to patients with stage III or IV disease.[1–3] Newer strategies have integrated surgery, radiation therapy, and chemotherapy and tailor the treatment to the extent of clinical and pathological disease. Patterns of practice in combining these treatments vary.[4]
Because there are few patients with advanced disease (stages III and IV), only limited data are available on treatment efficacy in this setting, and there is no standard chemotherapy regimen for these patients. Physicians may offer eligible patients with stage III or IV disease participation in clinical trials.
Information about ongoing clinical trials is available from the NCI website.
Wide local excision with or without radiation therapy
Radical vulvectomy and pelvic exenteration
Synchronous radiation therapy and cytotoxic chemotherapy with or without surgery
Surgery
Surgical resection
Since the 1980s, the trend of surgical resection in patients with vulvar cancer has been toward more limited surgery, often combined with radiation therapy to minimize morbidity.[5] In tumors clinically confined to the vulva or perineum, radical local excision with a margin of at least 1 cm has generally replaced radical vulvectomy; separate incision has replaced en bloc inguinal lymph node dissection; ipsilateral inguinal node dissection has replaced bilateral dissection for laterally localized tumors; and femoral lymph node dissection has been omitted in many cases.[2,5–7] However, the different surgical techniques have not been directly compared in randomized controlled trials. In addition, nonrandomized studies lack uniform staging definitions and clear descriptions of lymph node dissection or ancillary radiation.[8][Levels of evidence C2 and C3] The evidence base is, therefore, limited.
Sentinel lymph node dissection (SLND)
Another strategy to minimize the morbidity incurred by groin lymph node dissection in patients with early clinical-stage disease is SLND, reserving groin dissection for those with metastases to the sentinel node(s).
Evidence (SLND):
In a multicenter case series, 403 patients with primary vulvar squamous cell cancers smaller than 4 cm and clinically negative groin lymph nodes underwent 623 SLNDs (using radioactive tracer and blue dye for sentinel node identification).[9] All patients had radical resection of the primary tumor. Node metastases were identified in 26% of SLND procedures, and these patients went on to full inguinofemoral lymphadenectomy. The patients with negative sentinel nodes received no further therapy. After two local recurrences in 17 patients with multifocal primary tumors, the protocol was amended to allow only patients with unifocal tumors into the study.[9][Level of evidence C3]
Local morbidity was much lower in patients who underwent SLND than in patients with positive sentinel nodes who also underwent inguinofemoral lymphadenectomy (see Table 6).
Table 6. Comparisona of Local Morbidity in Patients Treated With SLND Versus SLND and Inguinofemoral Lymphadenectomy
Complications
Local Morbidity From SLND (%)
Local Morbidity From SLND and Inguinofemoral Lymphadenectomy (%)
SLND = Sentinel lymph node dissection.
aP < .0001 for all comparisons.
Wound breakdown
11.7
34
Cellulitis
4.5
21.3
Chronic lymphedema
1.9
25.2
The mean hospital stay was 8.4 days for patients who underwent SLND and 13.7 days for patients who underwent SLND and inguinofemoral lymphadenectomy (P < .0001).
The actuarial groin recurrence rate for all patients with negative SLND results at 2 years was 3% (95% confidence interval [CI], 1%–6%) and 2% (95% CI, 1%–5%) for those with unifocal primary tumors.
SLND may be useful when performed by a surgeon experienced in the procedure, and it may avoid the need for full groin lymph node dissection or radiation therapy in patients with clinically nonsuspicious lymph nodes.
Radiation Therapy
Radical radiation therapy can be used for patients unable to tolerate surgery or when surgery is not an option because of the site or extent of disease.[10–13]
Groin lymph node metastases are present in approximately 20% to 35% of patients with tumors clinically confined to the vulva and with clinically negative nodes.[9,14] Lymph node dissection is traditionally part of the primary surgical therapy in all but the smallest tumors. Some investigators recommend radiation therapy as a means to avoid the morbidity of lymph node dissection, but it is not clear whether radiation therapy can achieve the same local control rates or survival rates as lymph node dissection in early-stage disease.
Localized node-negative disease
A randomized trial to address the efficacy of radiation therapy in patients with clinically localized vulvar cancer has been reported.[14,15] In that study, women with disease clinically confined to the vulva, who did not have clinically suspicious groin lymph node metastases, underwent radical vulvectomy followed by either groin radiation (50 Gy at 2 Gy per fraction) or groin dissection (plus groin radiation if nodes were pathologically involved). Although the planned accrual was 300 patients, the study was stopped after 58 women were randomly assigned because of worse outcomes in the radiation therapy arm.
Five of 27 (18.5%) women in the radiation therapy arm and 0 of 25 women in the groin dissection arm had a groin recurrence, but this difference was not statistically significant (relative risk [RR], 10.21; 95% CI, 0.59–175.78).
There were ten deaths in the radiation therapy arm and three deaths in the groin dissection arm (RR, 4.31; 95% CI, 1.03–18.15).
Disease-specific mortality was not statistically significantly different between the two arms. However, there were eight vulvar cancer–related deaths in the radiation therapy arm versus two vulvar cancer–related deaths in the groin dissection arm (including one related to the groin dissection surgery) (RR, 3.70; 95% CI, 0.87–15.80).[14,15][Level of evidence A1]
There were fewer cases of lymphedema (none in the radiation therapy arm vs. seven in the groin dissection arm) and shorter hospital stays in the radiation therapy arm. The dose penetration of the radiation (3 cm for full dose) has been criticized as inadequate.[14]
In summary, the trial was stopped prematurely, and little can be said about the relative efficacy of the two treatment approaches.[14]
Pelvic node–positive disease
Pelvic radiation therapy has been compared with pelvic node resection in patients with documented groin node–positive disease.
Evidence (pelvic node resection vs. pelvic radiation therapy):
Patients with clinical stage I to stage IV primary squamous cell carcinoma of the vulva in whom groin node metastases were found at radical vulvectomy and bilateral groin lymph node dissection were randomly assigned (during the surgical procedure) to receive either ipsilateral pelvic node resection or pelvic radiation therapy (45 Gy–50 Gy at 1.8 Gy–2.0 Gy per fraction).[16] Because of a perceived emerging benefit of radiation therapy, the planned accrual of 152 patients was stopped after 114 patients were randomly assigned. However, the apparent benefit of radiation was subsequently attenuated with further follow-up.[16][Level of evidence A1]
After a median follow-up of 74 months, the 6-year overall survival (OS) rate was 51% in the pelvic radiation therapy arm versus 41% in the pelvic node resection arm (hazard ratio [HR], 0.61; 95% CI, 0.3–1.3; P = .18).
Vulvar cancer–specific mortality was statistically significantly lower in the pelvic radiation therapy arm (29% in the pelvic radiation therapy arm vs. 51% in the pelvic node resection arm) (HR, 0.49; 95% CI, 0.28–0.87; P = .015). However, there were 14 intercurrent deaths in the pelvic radiation therapy arm versus two deaths in the pelvic node resection arm.
Late chronic lymphedema was similar in both trial arms with 16% in the pelvic radiation therapy arm and 22% in the pelvic node resection arm.
Chemotherapy
There is no standard chemotherapy for vulvar cancer, and reports describing the use of this modality in the setting of metastatic or recurrent disease are anecdotal.[5]
Extrapolating from regimens used for anal or cervical squamous cell cancers, chemotherapy has been studied in combination with radiation in the neoadjuvant setting or as primary therapy in advanced disease. Chemotherapy regimens have included various combinations of fluorouracil (5-FU), cisplatin, mitomycin, or bleomycin.[5]
There is no clear evidence of improvement in survival or palliation. Given the advanced age and comorbidities of many patients with advanced or recurrent vulvar cancer, patient tolerance is a major consideration in the use of these agents.
Systemic treatment for inoperable patients
A systematic review of the use of neoadjuvant chemoradiation therapy in patients who were considered inoperable or who would have required extensive surgery, such as pelvic exenteration, colostomy, or urinary diversion, revealed no randomized trials.[17] Five nonrandomized studies that met the inclusion criteria of neoadjuvant chemoradiation therapy administered in this population with an intent to permit curative surgery were reviewed.[18–22] The five studies used four different chemoradiation therapy schedules and different radiation therapy dose-fractionation techniques. In the four studies using 5-FU with either cisplatin or mitomycin, the operability rate after chemoradiation therapy ranged from 63% to 92%.[18–21] In the one study using bleomycin, the operability rate was only 20%.[22]
In summary, there is evidence that neoadjuvant chemoradiation therapy with 5-FU plus either cisplatin or mitomycin may convert patients to a more operable status, but the evidence base is limited by study design. In addition to a paucity of randomized trials, interpretation of these studies is complicated by the lack of a standard definition of operability.[4][Level of evidence C3] Treatment-related toxicity is substantial.
Systemic treatment for operable patients
There is limited evidence about the use of neoadjuvant chemoradiation therapy in advanced operable vulvar cancer, and the available data do not suggest an advantage to this approach. A systematic review found only one randomized trial that addressed this issue, and it was published only in abstract form.[4,23] In that trial, 68 patients with advanced vulvar cancer (T2* >4 cm, T3*, any case with positive lymph nodes) were randomly assigned to either receive preoperative neoadjuvant radiation therapy (50 Gy) concomitantly with 5-FU and mitomycin or primary surgery. Neoadjuvant therapy–related serious toxicity was high (13 of 24 patients; 10 patients had wound diastasis). After a mean follow-up of 42 months, the 5-year OS rate was 30% in the neoadjuvant chemoradiation therapy arm and 49% in the primary surgery arm (RRdeath, 1.39; 95% CI, 0.94–2.06; P = .19).[4,23][Level of evidence A1] [Note: *T2 is defined as tumor confined to the vulva and/or perineum, more than 2 cm in greatest dimension, and T3 is defined as tumor that invades any of the following: the lower urethra, vagina, or anus.]
Fluorouracil dosing
The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[24,25] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[24–26] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[27–29] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[30] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[31]
References
Hacker NF, Van der Velden J: Conservative management of early vulvar cancer. Cancer 71 (4 Suppl): 1673-7, 1993. [PUBMED Abstract]
Thomas GM, Dembo AJ, Bryson SC, et al.: Changing concepts in the management of vulvar cancer. Gynecol Oncol 42 (1): 9-21, 1991. [PUBMED Abstract]
Homesley HD, Bundy BN, Sedlis A, et al.: Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 68 (6): 733-40, 1986. [PUBMED Abstract]
Eifel PJ, Klopp AH, Berek JS, et al.: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1171-1210.
Hoffman MS, Roberts WS, Lapolla JP, et al.: Recent modifications in the treatment of invasive squamous cell carcinoma of the vulva. Obstet Gynecol Surv 44 (4): 227-33, 1989. [PUBMED Abstract]
Heaps JM, Fu YS, Montz FJ, et al.: Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva. Gynecol Oncol 38 (3): 309-14, 1990. [PUBMED Abstract]
Ansink A, van der Velden J: Surgical interventions for early squamous cell carcinoma of the vulva. Cochrane Database Syst Rev (2): CD002036, 2000. [PUBMED Abstract]
Van der Zee AG, Oonk MH, De Hullu JA, et al.: Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol 26 (6): 884-9, 2008. [PUBMED Abstract]
Petereit DG, Mehta MP, Buchler DA, et al.: Inguinofemoral radiation of N0,N1 vulvar cancer may be equivalent to lymphadenectomy if proper radiation technique is used. Int J Radiat Oncol Biol Phys 27 (4): 963-7, 1993. [PUBMED Abstract]
Slevin NJ, Pointon RC: Radical radiotherapy for carcinoma of the vulva. Br J Radiol 62 (734): 145-7, 1989. [PUBMED Abstract]
Perez CA, Grigsby PW, Galakatos A, et al.: Radiation therapy in management of carcinoma of the vulva with emphasis on conservation therapy. Cancer 71 (11): 3707-16, 1993. [PUBMED Abstract]
Kumar PP, Good RR, Scott JC: Techniques for management of vulvar cancer by irradiation alone. Radiat Med 6 (4): 185-91, 1988 Jul-Aug. [PUBMED Abstract]
Stehman FB, Bundy BN, Thomas G, et al.: Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 24 (2): 389-96, 1992. [PUBMED Abstract]
van der Velden J, Fons G, Lawrie TA: Primary groin irradiation versus primary groin surgery for early vulvar cancer. Cochrane Database Syst Rev (5): CD002224, 2011. [PUBMED Abstract]
Kunos C, Simpkins F, Gibbons H, et al.: Radiation therapy compared with pelvic node resection for node-positive vulvar cancer: a randomized controlled trial. Obstet Gynecol 114 (3): 537-46, 2009. [PUBMED Abstract]
van Doorn HC, Ansink A, Verhaar-Langereis M, et al.: Neoadjuvant chemoradiation for advanced primary vulvar cancer. Cochrane Database Syst Rev 3: CD003752, 2006. [PUBMED Abstract]
Eifel PJ, Morris M, Burke TW, et al.: Prolonged continuous infusion cisplatin and 5-fluorouracil with radiation for locally advanced carcinoma of the vulva. Gynecol Oncol 59 (1): 51-6, 1995. [PUBMED Abstract]
Landoni F, Maneo A, Zanetta G, et al.: Concurrent preoperative chemotherapy with 5-fluorouracil and mitomycin C and radiotherapy (FUMIR) followed by limited surgery in locally advanced and recurrent vulvar carcinoma. Gynecol Oncol 61 (3): 321-7, 1996. [PUBMED Abstract]
Montana GS, Thomas GM, Moore DH, et al.: Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 48 (4): 1007-13, 2000. [PUBMED Abstract]
Moore DH, Thomas GM, Montana GS, et al.: Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 79-85, 1998. [PUBMED Abstract]
Scheiströen M, Tropé C: Combined bleomycin and irradiation in preoperative treatment of advanced squamous cell carcinoma of the vulva. Acta Oncol 32 (6): 657-61, 1993. [PUBMED Abstract]
Maneo A, Landoni F, Colombo A, et al.: Randomised study between neoadjuvant chemoradiotherapy and primary surgery for the treatment of advanced vulvar cancer. [Abstract] Int J Gynecol Cancer 13 (Suppl 1): A-PL19, 6, 2003.
Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]
Treatment of Vulvar Intraepithelial Neoplasia
Treatment Options for Vulvar Intraepithelial Neoplasia (VIN)
Carbon dioxide (CO2) laser surgery and vaporization.[2,3] A disadvantage of vaporization is that it does not provide tissue for histological examination to confirm complete removal of the lesion and the absence of invasive disease.
Traditionally, there were three grades of VIN, however, there is little evidence that all three grades are part of the same biological continuum or that grade 1 is even a cancer precursor. In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) changed its terminology, reserving the designation VIN for two categories of lesions based on morphological appearance.[9] In 2015, the ISSVD developed terminology for vulvar squamous intraepithelial lesions (SIL), which includes:[10]
Low-grade SIL of the vulva (vulvar LSIL) encompasses flat condyloma or human papillomavirus effect.
High-grade SIL (vulvar HSIL) was termed VIN, usual type in the 2004 ISSVD terminology.
VIN, differentiated type.
High-grade VIN is usually managed with active therapy because of a higher risk for progression to invasive disease.[2] Estimates of progression rates are imprecise. A systematic literature review that included 88 untreated patients with VIN 3 reported a 9% progression rate (8 of 88 patients) to invasive vulvar cancer during 12 to 96 months of observation. In the same review, the spontaneous regression rate was 1.2%, all of which occurred in women younger than 35 years.[1] However, in a single-center study, 10 of 63 (16%) untreated women with VIN 2 or VIN 3 progressed to invasive cancer after a mean of 3.9 years.[11]
VIN lesions may be multifocal or confluent and extensive. It is important to perform multiple biopsies in treatment planning to exclude occult invasive disease. VIN located in nonhairy areas can be considered an epithelial disease; however, VIN found in hairy sites usually involves the pilosebaceous apparatus and requires a greater depth of excision because it can track along hair roots.
Surgery
The principal treatment approach is surgery, but there is no consensus on the optimal surgical procedure. The goal is to remove or destroy the entire VIN lesion while preserving vulvar anatomy and function. Simple vulvectomy yields a 5-year survival rate of nearly 100% but is seldom indicated. Other more limited surgical procedures, including separate excision of multiple lesions, are less deforming.[12] The choice of treatment depends on the extent of the disease and the experience of the treating physician. There are no reliable data comparing the efficacy and safety of the various surgical approaches.
A systematic literature review identified only a single randomized trial comparing any of the surgical approaches.[2] In that trial, 30 women with high-grade VIN were randomly assigned to either receive CO2 laser ablation or ultrasound surgical aspiration.[3] There were no statistically significant differences in disease recurrence, painful dysuria or burning, adhesions, or eschar formation between the two treatments after 1 year of follow-up. Scarring was observed in 5 of 16 women treated with laser ablation and 0 of 14 women treated with ultrasound surgical aspiration (P < .01), but consequences of the scarring on sexual function or quality of life were not reported.[3][Level of evidence B1] The trial was too small to draw reliable conclusions about the relative efficacy of these surgical techniques. The remainder of the surgical literature is derived from case series and is prone to important study biases.[Level of evidence C2]
Whatever procedure is used, patients are at substantial risk of recurrence, particularly when the lesions are high grade or multifocal.[13] The most common sites of recurrence are the perianal skin, presacral area, and clitoral hood. About 4% of patients treated for VIN subsequently develop invasive cancer.[14,15]
Nonsurgical interventions
Topical imiquimod
Among women with high-grade VIN, substantial response rates and acceptable tolerability were reported for topical imiquimod 5%, an immune-response modifier with activity in human papillomavirus types 6- and 11-associated vulvar condylomata.
Evidence (imiquimod):
Three randomized placebo-controlled trials (including a total of 104 patients) with clinical response as the primary end points have been reported in either peer-reviewed-journals or in abstract format.[7];[4–6][Level of evidence B3] The results of these trials were summarized in a systematic review.[8]
At 5 to 6 months, the complete response rates in patients were 36 of 62 in the combined imiquimod arm versus 0 of 42 in the combined placebo arm, and the partial response rates were 18 of 62 in the combined imiquimod arm versus 1 of 42 in the combined placebo arm (relative risk, 11.95; 95% confidence interval, 3.21–44.51).
In the only trial reporting progression to cancer at 12 months, there was no difference in progression rate, but the trial was severely underpowered because only 3 of the total 52 women developed invasive disease by 12 months.[6]
The only trial reporting quality of life [6] showed no difference between imiquimod and placebo.
Local side effects of imiquimod included pain, edema, erythema, and a single case of erosion. However, no patients had to discontinue treatment as a result of toxicity.
Other nonsurgical interventions
Nonsurgical approaches have been studied because of the physical and psychosexual morbidity associated with many vulvar surgical procedures. Some of these approaches, including topical fluorouracil, recombinant interferon gamma, bleomycin, and trinitrochlorobenzene, have been largely abandoned because of high recurrence rates or intolerable local side effects, such as pain, irritation, and ulceration.[8,16]
Photodynamic therapy, using topically applied 5-aminolevulinic acid as the sensitizing agent for 635 nm laser light, has also been studied. However, data are limited to small case series with variable response rates.[17,18][Level of evidence C3]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
van Seters M, van Beurden M, de Craen AJ: Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol 97 (2): 645-51, 2005. [PUBMED Abstract]
Kaushik S, Pepas L, Nordin A, et al.: Surgical interventions for high grade vulval intraepithelial neoplasia. Cochrane Database Syst Rev (1): CD007928, 2011. [PUBMED Abstract]
von Gruenigen VE, Gibbons HE, Gibbins K, et al.: Surgical treatments for vulvar and vaginal dysplasia: a randomized controlled trial. Obstet Gynecol 109 (4): 942-7, 2007. [PUBMED Abstract]
Sterling JC, Smith NA, Loo WJ, et al.: Randomized, doubleblind, placebo-controlled trial for treatment of high grade vulval intraepithelial neoplasia with imiquimod. [Abstract] J Eur Acad Derm Venereol 19 (Suppl 2): A-FC06.1, 22, 2005.
Mathiesen O, Buus SK, Cramers M: Topical imiquimod can reverse vulvar intraepithelial neoplasia: a randomised, double-blinded study. Gynecol Oncol 107 (2): 219-22, 2007. [PUBMED Abstract]
van Seters M, van Beurden M, ten Kate FJ, et al.: Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med 358 (14): 1465-73, 2008. [PUBMED Abstract]
Terlou A, van Seters M, Ewing PC, et al.: Treatment of vulvar intraepithelial neoplasia with topical imiquimod: seven years median follow-up of a randomized clinical trial. Gynecol Oncol 121 (1): 157-62, 2011. [PUBMED Abstract]
Pepas L, Kaushik S, Bryant A, et al.: Medical interventions for high grade vulval intraepithelial neoplasia. Cochrane Database Syst Rev (4): CD007924, 2011. [PUBMED Abstract]
Sideri M, Jones RW, Wilkinson EJ, et al.: Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. J Reprod Med 50 (11): 807-10, 2005. [PUBMED Abstract]
Bornstein J, Bogliatto F, Haefner HK, et al.: The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar Squamous Intraepithelial Lesions. J Low Genit Tract Dis 20 (1): 11-4, 2016. [PUBMED Abstract]
Jones RW, Rowan DM, Stewart AW: Vulvar intraepithelial neoplasia: aspects of the natural history and outcome in 405 women. Obstet Gynecol 106 (6): 1319-26, 2005. [PUBMED Abstract]
Eifel PJ, Klopp AH, Berek JS, et al.: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1171-1210.
Küppers V, Stiller M, Somville T, et al.: Risk factors for recurrent VIN. Role of multifocality and grade of disease. J Reprod Med 42 (3): 140-4, 1997. [PUBMED Abstract]
Buscema J, Woodruff JD, Parmley TH, et al.: Carcinoma in situ of the vulva. Obstet Gynecol 55 (2): 225-30, 1980. [PUBMED Abstract]
Jones RW, Rowan DM: Vulvar intraepithelial neoplasia III: a clinical study of the outcome in 113 cases with relation to the later development of invasive vulvar carcinoma. Obstet Gynecol 84 (5): 741-5, 1994. [PUBMED Abstract]
Sillman FH, Sedlis A, Boyce JG: A review of lower genital intraepithelial neoplasia and the use of topical 5-fluorouracil. Obstet Gynecol Surv 40 (4): 190-220, 1985. [PUBMED Abstract]
Hillemanns P, Untch M, Dannecker C, et al.: Photodynamic therapy of vulvar intraepithelial neoplasia using 5-aminolevulinic acid. Int J Cancer 85 (5): 649-53, 2000. [PUBMED Abstract]
Fehr MK, Hornung R, Schwarz VA, et al.: Photodynamic therapy of vulvar intraepithelial neoplasia III using topically applied 5-aminolevulinic acid. Gynecol Oncol 80 (1): 62-6, 2001. [PUBMED Abstract]
Treatment of Stages I and II Vulvar Cancer
Treatment Options for Stages I and II Vulvar Cancer
Radical local excision with ipsilateral or bilateral inguinal and femoral lymph node dissection may be indicated. For stage I microinvasive lesions (<1 mm invasion) with no associated severe vulvar dystrophy, a wide (1 cm margin) excision (without lymph node dissection) may be done. For all other stage I lesions, if well lateralized, without diffuse severe dystrophy, and with clinically negative nodes, a radical local excision with complete unilateral lymphadenectomy may be done.[1] Candidates for this procedure should have lesions 2 cm or smaller in diameter with 5 mm or less invasion, no capillary-lymphatic space invasion, and clinically uninvolved nodes.[2,3]
For stage II disease, large T2* tumors may require modified radical vulvectomy or radical vulvectomy.[4] [Note: *T2 is defined as tumor confined to the vulva and/or perineum, more than 2 cm in greatest dimension.]
For both stage I and stage II disease, radical local excision and sentinel node dissection is indicated and groin dissection is reserved for those with metastasis to the sentinel node(s).[5]
Surgery and radiation therapy
Some investigators recommend radical excision and groin nodal radiation therapy as a means to avoid the morbidity of lymph node dissection. However, it is not clear whether radiation therapy can achieve the same local control rates or survival rates as lymph node dissection in early-stage disease. A randomized trial to address this issue in patients with clinically localized vulvar disease was stopped early as a result of early emergence of worse outcomes in the radiation therapy arm.[6,7] For stage II disease, adjuvant local radiation therapy may be indicated for surgical margins smaller than 8 mm, capillary-lymphatic space invasion, and thickness greater than 5 mm.[8,9]
Radiation therapy alone
For patients unable to tolerate radical surgery or deemed ineligible for surgery because of the site or extent of disease, radical radiation therapy may be associated with favorable survival.[10–13]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Malfetano JH, Piver MS, Tsukada Y, et al.: Univariate and multivariate analyses of 5-year survival, recurrence, and inguinal node metastases in stage I and II vulvar carcinoma. J Surg Oncol 30 (2): 124-31, 1985. [PUBMED Abstract]
Stehman FB, Bundy BN, Dvoretsky PM, et al.: Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group. Obstet Gynecol 79 (4): 490-7, 1992. [PUBMED Abstract]
Hacker NF, Van der Velden J: Conservative management of early vulvar cancer. Cancer 71 (4 Suppl): 1673-7, 1993. [PUBMED Abstract]
Eifel PJ, Klopp AH, Berek JS, et al.: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1171-1210.
Van der Zee AG, Oonk MH, De Hullu JA, et al.: Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol 26 (6): 884-9, 2008. [PUBMED Abstract]
Stehman FB, Bundy BN, Thomas G, et al.: Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 24 (2): 389-96, 1992. [PUBMED Abstract]
van der Velden J, Fons G, Lawrie TA: Primary groin irradiation versus primary groin surgery for early vulvar cancer. Cochrane Database Syst Rev (5): CD002224, 2011. [PUBMED Abstract]
Thomas GM, Dembo AJ, Bryson SC, et al.: Changing concepts in the management of vulvar cancer. Gynecol Oncol 42 (1): 9-21, 1991. [PUBMED Abstract]
Faul CM, Mirmow D, Huang Q, et al.: Adjuvant radiation for vulvar carcinoma: improved local control. Int J Radiat Oncol Biol Phys 38 (2): 381-9, 1997. [PUBMED Abstract]
Petereit DG, Mehta MP, Buchler DA, et al.: Inguinofemoral radiation of N0,N1 vulvar cancer may be equivalent to lymphadenectomy if proper radiation technique is used. Int J Radiat Oncol Biol Phys 27 (4): 963-7, 1993. [PUBMED Abstract]
Slevin NJ, Pointon RC: Radical radiotherapy for carcinoma of the vulva. Br J Radiol 62 (734): 145-7, 1989. [PUBMED Abstract]
Perez CA, Grigsby PW, Galakatos A, et al.: Radiation therapy in management of carcinoma of the vulva with emphasis on conservation therapy. Cancer 71 (11): 3707-16, 1993. [PUBMED Abstract]
Kumar PP, Good RR, Scott JC: Techniques for management of vulvar cancer by irradiation alone. Radiat Med 6 (4): 185-91, 1988 Jul-Aug. [PUBMED Abstract]
Modified radical or radical vulvectomy with inguinal and femoral lymphadenectomy is the standard therapy.[1] Nodal involvement is a key determinant of survival. Radiation therapy is given to patients with large primary lesions and narrow margins. Radiation therapy to the pelvis and groin is given if inguinal lymph nodes are positive.[2] Radiation therapy to the pelvis and groin is usually given if two or more groin nodes are involved.[2,3]
Localized adjuvant radiation therapy consisting of 45 Gy to 50 Gy may also be indicated when there is capillary-lymphatic space invasion and a thickness of greater than 5 mm, particularly if the nodes are involved.[1]
Radiation therapy or chemoradiation therapy followed by surgery
Preoperative neoadjuvant radiation therapy or chemoradiation therapy may be used to improve operability and even decrease the extent of surgery required.[4–10]
Radiation therapy with or without chemotherapy
For patients unable to tolerate radical surgery or deemed ineligible for surgery because of the site or extent of disease, radical radiation therapy may be associated with long-term survival.[11,12] Some physicians prefer to add concurrent fluorouracil (5-FU) or 5-FU and cisplatin.[1,13]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Thomas GM, Dembo AJ, Bryson SC, et al.: Changing concepts in the management of vulvar cancer. Gynecol Oncol 42 (1): 9-21, 1991. [PUBMED Abstract]
Kunos C, Simpkins F, Gibbons H, et al.: Radiation therapy compared with pelvic node resection for node-positive vulvar cancer: a randomized controlled trial. Obstet Gynecol 114 (3): 537-46, 2009. [PUBMED Abstract]
Homesley HD, Bundy BN, Sedlis A, et al.: Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group study) Gynecol Oncol 49 (3): 279-83, 1993. [PUBMED Abstract]
Boronow RC, Hickman BT, Reagan MT, et al.: Combined therapy as an alternative to exenteration for locally advanced vulvovaginal cancer. II. Results, complications, and dosimetric and surgical considerations. Am J Clin Oncol 10 (2): 171-81, 1987. [PUBMED Abstract]
Anderson JM, Cassady JR, Shimm DS, et al.: Vulvar carcinoma. Int J Radiat Oncol Biol Phys 32 (5): 1351-7, 1995. [PUBMED Abstract]
van Doorn HC, Ansink A, Verhaar-Langereis M, et al.: Neoadjuvant chemoradiation for advanced primary vulvar cancer. Cochrane Database Syst Rev 3: CD003752, 2006. [PUBMED Abstract]
Eifel PJ, Morris M, Burke TW, et al.: Prolonged continuous infusion cisplatin and 5-fluorouracil with radiation for locally advanced carcinoma of the vulva. Gynecol Oncol 59 (1): 51-6, 1995. [PUBMED Abstract]
Landoni F, Maneo A, Zanetta G, et al.: Concurrent preoperative chemotherapy with 5-fluorouracil and mitomycin C and radiotherapy (FUMIR) followed by limited surgery in locally advanced and recurrent vulvar carcinoma. Gynecol Oncol 61 (3): 321-7, 1996. [PUBMED Abstract]
Montana GS, Thomas GM, Moore DH, et al.: Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 48 (4): 1007-13, 2000. [PUBMED Abstract]
Moore DH, Thomas GM, Montana GS, et al.: Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 79-85, 1998. [PUBMED Abstract]
Perez CA, Grigsby PW, Galakatos A, et al.: Radiation therapy in management of carcinoma of the vulva with emphasis on conservation therapy. Cancer 71 (11): 3707-16, 1993. [PUBMED Abstract]
Slevin NJ, Pointon RC: Radical radiotherapy for carcinoma of the vulva. Br J Radiol 62 (734): 145-7, 1989. [PUBMED Abstract]
Eifel PJ, Klopp AH, Berek JS, et al.: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1171-1210.
Radical vulvectomy and pelvic exenteration may be indicated for patients with stage IVA vulvar cancer.
Surgery and radiation therapy
Surgery followed by radiation therapy may be done for large resected lesions with narrow margins. Localized adjuvant radiation therapy consisting of 45 Gy to 50 Gy may also be indicated when there is capillary-lymphatic space invasion and thickness greater than 5 mm.[1] Radiation therapy to the pelvis and groin is given if two or more groin lymph nodes are involved.[2,3]
Radiation therapy or chemoradiation therapy followed by surgery
Neoadjuvant radiation therapy or chemoradiation therapy of large primary lesions (to improve operability) may be done, followed by radical surgery.[4–10]
Radiation therapy with or without chemotherapy
For patients unable to tolerate radical vulvectomy or who are deemed ineligible for surgery because of the site or extent of disease, radical radiation therapy may be associated with long-term survival.[11,12] When radiation therapy is used for primary definitive treatment of vulvar cancer, some physicians prefer to add concurrent fluorouracil (5-FU) or 5-FU and cisplatin.[1,13–17]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Thomas GM, Dembo AJ, Bryson SC, et al.: Changing concepts in the management of vulvar cancer. Gynecol Oncol 42 (1): 9-21, 1991. [PUBMED Abstract]
Homesley HD, Bundy BN, Sedlis A, et al.: Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 68 (6): 733-40, 1986. [PUBMED Abstract]
Kunos C, Simpkins F, Gibbons H, et al.: Radiation therapy compared with pelvic node resection for node-positive vulvar cancer: a randomized controlled trial. Obstet Gynecol 114 (3): 537-46, 2009. [PUBMED Abstract]
Boronow RC, Hickman BT, Reagan MT, et al.: Combined therapy as an alternative to exenteration for locally advanced vulvovaginal cancer. II. Results, complications, and dosimetric and surgical considerations. Am J Clin Oncol 10 (2): 171-81, 1987. [PUBMED Abstract]
Anderson JM, Cassady JR, Shimm DS, et al.: Vulvar carcinoma. Int J Radiat Oncol Biol Phys 32 (5): 1351-7, 1995. [PUBMED Abstract]
van Doorn HC, Ansink A, Verhaar-Langereis M, et al.: Neoadjuvant chemoradiation for advanced primary vulvar cancer. Cochrane Database Syst Rev 3: CD003752, 2006. [PUBMED Abstract]
Eifel PJ, Morris M, Burke TW, et al.: Prolonged continuous infusion cisplatin and 5-fluorouracil with radiation for locally advanced carcinoma of the vulva. Gynecol Oncol 59 (1): 51-6, 1995. [PUBMED Abstract]
Landoni F, Maneo A, Zanetta G, et al.: Concurrent preoperative chemotherapy with 5-fluorouracil and mitomycin C and radiotherapy (FUMIR) followed by limited surgery in locally advanced and recurrent vulvar carcinoma. Gynecol Oncol 61 (3): 321-7, 1996. [PUBMED Abstract]
Montana GS, Thomas GM, Moore DH, et al.: Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 48 (4): 1007-13, 2000. [PUBMED Abstract]
Moore DH, Thomas GM, Montana GS, et al.: Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 79-85, 1998. [PUBMED Abstract]
Slevin NJ, Pointon RC: Radical radiotherapy for carcinoma of the vulva. Br J Radiol 62 (734): 145-7, 1989. [PUBMED Abstract]
Perez CA, Grigsby PW, Galakatos A, et al.: Radiation therapy in management of carcinoma of the vulva with emphasis on conservation therapy. Cancer 71 (11): 3707-16, 1993. [PUBMED Abstract]
Russell AH, Mesic JB, Scudder SA, et al.: Synchronous radiation and cytotoxic chemotherapy for locally advanced or recurrent squamous cancer of the vulva. Gynecol Oncol 47 (1): 14-20, 1992. [PUBMED Abstract]
Berek JS, Heaps JM, Fu YS, et al.: Concurrent cisplatin and 5-fluorouracil chemotherapy and radiation therapy for advanced-stage squamous carcinoma of the vulva. Gynecol Oncol 42 (3): 197-201, 1991. [PUBMED Abstract]
Koh WJ, Wallace HJ, Greer BE, et al.: Combined radiotherapy and chemotherapy in the management of local-regionally advanced vulvar cancer. Int J Radiat Oncol Biol Phys 26 (5): 809-16, 1993. [PUBMED Abstract]
Thomas G, Dembo A, DePetrillo A, et al.: Concurrent radiation and chemotherapy in vulvar carcinoma. Gynecol Oncol 34 (3): 263-7, 1989. [PUBMED Abstract]
Eifel PJ, Klopp AH, Berek JS, et al.: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1171-1210.
Local therapy must be individualized depending on the extent of local and metastatic disease.
There is no standard chemotherapy for metastatic disease, and reports describing the use of this modality are anecdotal.[1] However, by largely extrapolating from regimens used for anal or cervical cancer, chemotherapy has been studied. Regimens have included various combinations of fluorouracil, cisplatin, mitomycin, or bleomycin.[1–3] Given the advanced age and comorbidity of many patients with advanced or recurrent vulvar cancer, patient tolerance is a major consideration in the use of these agents.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Eifel PJ, Klopp AH, Berek JS, et al.: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1171-1210.
van Doorn HC, Ansink A, Verhaar-Langereis M, et al.: Neoadjuvant chemoradiation for advanced primary vulvar cancer. Cochrane Database Syst Rev 3: CD003752, 2006. [PUBMED Abstract]
Cormio G, Loizzi V, Gissi F, et al.: Cisplatin and vinorelbine chemotherapy in recurrent vulvar carcinoma. Oncology 77 (5): 281-4, 2009. [PUBMED Abstract]
Treatment of Recurrent Vulvar Cancer
Treatment Options for Recurrent Vulvar Cancer
Treatment options for recurrent vulvar cancer include:
Wide local excision with or without radiation therapy in patients with local recurrence.
Radical vulvectomy and pelvic exenteration in patients with local recurrence.
Synchronous radiation therapy and cytotoxic chemotherapy with or without surgery.[1]
Treatment and outcome depend on the site and extent of recurrence.[2] Radical excision of localized recurrence may be considered if technically feasible.[3] Palliative radiation therapy is used for some patients. Radiation therapy with or without chemotherapy may be associated with substantial disease-free periods in some patients with a small local recurrence.[1,4,5] When local recurrence occurs more than 2 years after primary treatment, a combination of radiation therapy and surgery may result in a 5-year survival rate of greater than 50%.[6,7]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Russell AH, Mesic JB, Scudder SA, et al.: Synchronous radiation and cytotoxic chemotherapy for locally advanced or recurrent squamous cancer of the vulva. Gynecol Oncol 47 (1): 14-20, 1992. [PUBMED Abstract]
Piura B, Masotina A, Murdoch J, et al.: Recurrent squamous cell carcinoma of the vulva: a study of 73 cases. Gynecol Oncol 48 (2): 189-95, 1993. [PUBMED Abstract]
Hopkins MP, Reid GC, Morley GW: The surgical management of recurrent squamous cell carcinoma of the vulva. Obstet Gynecol 75 (6): 1001-5, 1990. [PUBMED Abstract]
Miyazawa K, Nori D, Hilaris BS, et al.: Role of radiation therapy in the treatment of advanced vulvar carcinoma. J Reprod Med 28 (8): 539-41, 1983. [PUBMED Abstract]
Thomas G, Dembo A, DePetrillo A, et al.: Concurrent radiation and chemotherapy in vulvar carcinoma. Gynecol Oncol 34 (3): 263-7, 1989. [PUBMED Abstract]
Podratz KC, Symmonds RE, Taylor WF, et al.: Carcinoma of the vulva: analysis of treatment and survival. Obstet Gynecol 61 (1): 63-74, 1983. [PUBMED Abstract]
Shimm DS, Fuller AF, Orlow EL, et al.: Prognostic variables in the treatment of squamous cell carcinoma of the vulva. Gynecol Oncol 24 (3): 343-58, 1986. [PUBMED Abstract]
Latest Updates to This Summary (05/14/2025)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
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About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of vulvar cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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The lead reviewers for Vulvar Cancer Treatment are:
Olga T. Filippova, MD (Lenox Hill Hospital)
Marina Stasenko, MD (New York University Medical Center)
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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Vulvar Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/vulvar/hp/vulvar-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389203]
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Vulvar cancer usually forms slowly over years, most often on the vaginal lips or the sides of the vaginal opening. Infection with human papillomavirus (HPV) causes about half of all vulvar cancers. Explore the links on this page to learn more about vulvar cancer treatment, statistics, research, and clinical trials.
Results from a French clinical trial have identified what experts say should now be the recommended initial treatment of advanced leiomyosarcoma. In the trial, the combination of trabectedin (Yondelis) and doxorubicin improved survival by a median of 9 months.
Trial participants who stopped imatinib had a more rapid worsening of disease, a shorter time until resistance, and did not live as long as participants who continued the therapy uninterrupted.
Treatment with atezolizumab (Tecentriq) shrank tumors in about 40% of people with alveolar soft part sarcoma, including one complete response, new clinical trial findings show. Some people were later able to stop treatment without the cancer returning.
In a clinical trial, the drug nirogacestat shrank tumors in 40% of people with desmoid tumors. Treatment with nirogacestat also substantially improved progression-free survival, pain, and physical functioning, compared with patients treated with a placebo.
A clinical trial led by NCI has resulted in FDA approval of the immunotherapy drug atezolizumab (Tecentriq) to treat advanced alveolar soft part sarcoma.
An NCI study in mice has identified a drug combination that may help treat children with rhabdomyosarcoma. But one of the drugs, ganitumab, is no longer being made. Based on the study's promising results, the NCI researchers who led the study want to test the combination in humans.
The fusion protein that drives the growth and survival of some rhabdomyosarcoma tumors relies on the KDM4B enzyme, researchers have found. Treating mice with a KDM4B-blocking drug and chemotherapy nearly eliminated rhabdomyosarcoma tumors with the fusion protein.
For children and adults with advanced soft tissue sarcoma, adding pazopanib (Votrient) to chemotherapy and radiation before surgery may be a promising treatment option, early results from a clinical trial suggest.
For people with advanced AIDS-related Kaposi sarcoma in sub-Saharan Africa, results from a large clinical trial are expected to change treatment. In the trial, paclitaxel greatly improved outcomes compared with treatments typically used in the region.
Avapritinib (Ayvakit) has been approved for adults with gastrointestinal stromal tumors (GIST) whose tumors have an alteration in a portion of the PDGFRA gene called exon 18. The approval applies to those whose tumors cannot be removed with surgery or have spread.
Scientists may have pinpointed the cause of some gastrointestinal stromal tumors (GISTs), a rare cancer, according to a new NCI-funded study. However, the culprit isn’t a harmful genetic mutation, but another type of genetic change, what are called epigenetic alterations.
People with advanced alveolar soft part sarcoma (ASPS), a rare cancer, appear to benefit from a type of immunotherapy called an immune checkpoint inhibitor, according to results from a small clinical trial.
Interim results from a clinical trial for patients with desmoid tumors or aggressive fibromatosis (DT/DF) show that the drug sorafenib tosylate (Nexavar) extended progression-free survival compared with a placebo.
Two new targeted therapies have shown promise in patients with gastrointestinal stromal tumors (GIST) that have developed resistance to standard therapies.
The Food and Drug Administration (FDA) has granted accelerated approval to olaratumab (Lartruvo®) for the treatment of some patients with soft tissue sarcoma.
The FDA has approved eribulin mesylate for patients with liposarcoma whose cancers are advanced or cannot be removed by surgery and are no longer responding to anthracycline-based chemotherapy.
Childhood vascular tumors are abnormal growths of blood vessels or lymph vessels that can occur anywhere in the body. These tumors may be benign (which means they are not cancer) or cancer. There are many types of vascular tumors. The most common type is infantile hemangioma, which is a benign tumor that usually goes away on its own.
Tests to diagnose childhood vascular tumors
If your child has symptoms, such as discoloration on or under the skin, that suggest a vascular tumor, the doctor will need to find out if these are due to a vascular tumor or another problem. The doctor will ask when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family health history and do a physical exam. Depending on these results, they may recommend other tests. If your child is diagnosed with a vascular tumor, the results of these tests will help you and your child’s doctor plan treatment.
The tests used to diagnose a vascular tumor in children may include:
Ultrasound exam
An ultrasound uses high-energy sound waves (ultrasound) that bounce off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
EnlargeAbdominal ultrasound. An ultrasound transducer connected to a computer is pressed against the skin of the abdomen. The transducer bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).
CT scan (CAT scan)
A CT scan uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body. The pictures are taken from different angles and are used to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. Learn more about Computed Tomography (CT) Scans and Cancer.
EnlargeComputed tomography (CT) scan. The child lies on a table that slides through the CT scanner, which takes a series of detailed x-ray pictures of areas inside the body.
Magnetic resonance imaging (MRI)
MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
EnlargeMagnetic resonance imaging (MRI) scan. The child lies on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body. The positioning of the child on the table depends on the part of the body being imaged.
Chest x-ray
An x-ray is a type of radiation that can go through the body and make pictures. A chest x-ray makes pictures of the organs and bones inside the chest.
Biopsy
Biopsy is a procedure in which a sample of tissue is removed from the tumor so that a pathologist can view it under a microscope to check for cancer. While a biopsy is not always needed to diagnose a vascular tumor, it may help find gene mutations that will help with treatment planning.
Getting a second opinion
You may want to get a second opinion to confirm your child’s diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans. This doctor may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s tumor.
To learn more about choosing a doctor and getting a second opinion, visit Finding Health Care Services. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor or hospital that can provide a second opinion. For questions you might want to ask at your child’s appointments, visit Questions to Ask Your Doctor.
Types of childhood vascular tumors
Benign tumors
Benign vascular tumors are not cancer.
Infantile hemangioma
Infantile hemangioma (also called a strawberry mark) is the most common type of benign vascular tumor in children. It occurs when immature cells that are meant to form blood vessels form a tumor instead. It tends to appear between the ages of 3 to 6 weeks and is usually not seen at birth. The hemangioma often gets bigger for about 5 months and then stops growing. It slowly fades over the next several years, but a red mark or loose or wrinkled skin may remain. It is rare for an infantile hemangioma to come back after it has faded away.
Infantile hemangioma can develop anywhere on the body, including the skin, the tissue below the skin, or within an organ. It most commonly appears on the skin on the head and neck. Hemangioma may be a single lesion, one or more lesions spread over a larger area, or multiple lesions in different parts of the body. A hemangioma that covers a larger area, involves an organ, or has multiple lesions is more likely to cause problems.
Hemangioma in the airway usually occurs along with a large hemangioma on the face that looks like a beard. Airway hemangioma may cause the airway to narrow, leading to trouble breathing.
Periocular hemangioma involves the eye or tissues around the eye. It may cause vision problems or blindness and is sometimes linked with other eye problems.
Having more than five hemangiomas on the skin is a sign that there may be hemangiomas in an organ, such as the liver, heart, muscle, or thyroid gland. The liver is affected most often.
Some hemangiomas appear between the ages of 3 to 6 weeks but do not grow bigger. This type of hemangioma is called infantile hemangioma with minimal or arrested growth. The lesion appears as light and dark areas of redness on the skin of the lower body or the head and neck. Hemangiomas of this type go away over time without treatment.
Causes and risk factors for infantile hemangioma
Infantile hemangioma is caused by certain changes to how the vascular cells function, especially how they grow and divide into new cells. Often, the exact cause of these changes is unknown.
A risk factor is anything that increases the chance of getting a disease. Not every child with a risk factor will develop an infantile hemangioma. And it can develop in some children who don’t have a known risk factor.
Infantile hemangioma is more common in:
girls
White people
premature babies
twins, triplets, or other multiple births
babies conceived using in vitro fertilization
babies of mothers who are older at the time of the pregnancy, have pre-eclampsia (high blood pressure during pregnancy), or who have problems with the placenta during pregnancy
Other risk factors for infantile hemangioma include:
Having a family history of infantile hemangioma, usually in a mother, father, or sibling.
Having PHACE syndrome, a rare disorder marked by problems that affect the large blood vessels, heart, eyes, and/or brain. PHACE syndrome increases the risk of a hemangioma that spreads across a large area of the head or face and sometimes the neck, chest, or arm.
Having LUMBAR/PELVIS/SACRAL syndrome, a rare disorder marked by problems that affect the urinary system, genitals, rectum, anus, brain, spinal cord, and nerve functions. This syndrome increases the risk of a hemangioma that spreads across a large area of the lower back, arms, chest, or legs.
Talk with your child’s doctor if you think your child may be at risk.
Symptoms of infantile hemangioma
Infantile hemangioma may cause any of the following symptoms. It’s important to check with your child’s doctor if your child has a:
Lesion on the skin: An area of spidery veins or lightened or discolored skin may be the first sign of a hemangioma. This may develop into a firm, warm, bright red-to-crimson lesion on the skin that may look like a bruise. A lesion may also form an ulcer that is painful and can lead to bleeding, infection, and scarring. Later, as the hemangioma goes away, it becomes softer and begins fading in the center before flattening and losing color.
Lesion below the skin: A lesion that grows under the skin in the fat may appear blue or purple. If the lesion is deep enough under the skin surface, it may not be seen.
Lesion in an organ: There may be no symptoms if a hemangioma forms on an organ.
These symptoms may be caused by problems other than a hemangioma. The only way to know is for your child to see a doctor.
Diagnosis of infantile hemangioma
A physical exam and personal and family health history are usually all that are needed to diagnose infantile hemangioma. If the hemangioma looks unusual, a biopsy may be done. An ultrasound may be done if the hemangioma is deeper inside the body with no change to the skin or if the lesion covers a large area of the body. Infants with five or more hemangiomas on the skin should have an ultrasound of the liver to check for a liver hemangioma.
If the hemangioma is part of a syndrome, more tests, such as an echocardiogram, MRI, magnetic resonance angiogram, and eye exam, may be done.
Most hemangiomas fade and shrink without treatment. If a hemangioma is large, causing other health problems, or in an area where it could cause serious problems if it grows bigger, treatment may include:
topical beta-blocker therapy for a hemangioma that is in one area of the skin
steroid therapy, which may be used when beta-blocker therapy is being started or when beta-blockers cannot be used
laser surgery, including pulsed dye laser surgery, which may be used for a hemangioma that has an ulcer or has not completely gone away
surgery for a hemangioma that has an ulcer, causes vision problems, has not completely gone away, or is on the face and has not responded to other treatment
combined therapy, such as propranolol and steroid therapy or propranolol and topical beta-blocker therapy
Congenital hemangioma is a benign vascular tumor that begins forming before birth and is fully formed when the baby is born. It is usually on the skin but can be in another organ. A congenital hemangioma may occur as a rash of purple spots. The skin around the spot may be lighter.
There are three types of congenital hemangiomas. The differences between the three types relate to how they shrink (involute) over time:
Rapidly involuting congenital hemangioma (RICH) goes away on its own 12 to 15 months after birth. It can form an ulcer, bleed, and cause temporary heart and blood clotting problems. The skin may look a little different even after the hemangioma goes away.
Partial involuting congenital hemangioma (PICH) may shrink on its own but does not go away completely.
Non-involuting congenital hemangioma (NICH) stays the same size and never goes away on its own.
If your child has symptoms that suggest a congenital hemangioma, the doctor will ask about your child’s personal health history and do a physical exam and ultrasound exam to make the diagnosis.
The types of treatment your child may receive depend on whether the congenital hemangioma will shrink on its own.
Treatment of rapidly involuting congenital hemangioma and partial involuting congenital hemangioma may be observation.
Treatment of non-involuting congenital hemangioma may be surgery to remove the tumor, depending on where it is and whether it is causing symptoms.
a single lesion in one part of the liver (focal vascular lesion)
several lesions in one part of the liver (multiple liver lesions)
several lesions spread across different parts of the liver (diffuse liver lesions)
The liver has many functions, including filtering blood and making proteins that help with blood clotting. Sometimes, the tumor can block or slow the normal flow of blood through the liver. When this happens, blood is sent directly to the heart without going through the liver. This condition is known as a liver shunt. It can cause heart failure and problems with blood clotting.
If your child has symptoms that suggest a benign vascular tumor of the liver, the doctor will ask about your child’s personal health history and do a physical exam and ultrasound exam to make the diagnosis.
The treatment your child may receive depends on whether they have a focal vascular lesion, multiple liver lesions, or diffuse liver lesions.
A single lesion in one part of the liver (focal vascular lesion) is usually a rapidly involuting (shrinking) congenital hemangioma or a non-involuting congenital hemangioma. This lesion can be diagnosed before birth or shortly after the baby is born. Treatment of this type of lesion depends on whether symptoms occur and may include:
surgery, for lesions that do not respond to other treatments
Multiple and diffuse liver lesions are usually infantile hemangiomas. Diffuse liver lesions can cause serious effects, including problems with thyroid hormones and the heart. The liver can enlarge, press on other organs, and cause more symptoms.
Treatment of multiple liver lesions may include:
observation for lesions that do not cause symptoms
total hepatectomy and liver transplant, for lesions that do not respond to drug therapy or for diffuse liver lesions that are spreading and causing organ failure and there is no time to start treatment
Children with diffuse liver lesions may be diagnosed with hypothyroidism caused by the liver tumor using more of the thyroid hormone. These children may need thyroid hormone replacement therapy.
If a vascular liver lesion does not respond to treatment, a biopsy may be done to see if the tumor is cancer.
Spindle cell hemangioma
A spindle cell hemangioma contains cells called spindle cells. Under a microscope, spindle cells look long and slender. A spindle cell hemangioma is a painful red-brown or bluish lesion that usually appears on the arms or legs. It can begin as one lesion and develop into more lesions over the years. A spindle cell hemangioma can form in children and adults.
Some children may be at increased risk of developing a spindle cell hemangioma. A risk factor is anything that increases the chance of getting a disease. Not every child with a risk factor will develop a spindle cell hemangioma. And it can develop in some children who don’t have a known risk factor. Spindle cell hemangiomas are more likely to develop in children with the following syndromes:
Talk with your child’s doctor if you think your child may be at risk.
If your child has symptoms that suggest a spindle cell hemangioma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. If needed, tests may be done. Learn more about Tests to diagnose childhood vascular tumors.
Although there is no standard treatment for spindle cell hemangioma, surgery may be used to remove the tumor. Spindle cell hemangioma may come back after surgery.
Epithelioid hemangioma
An epithelioid hemangioma most often forms on or in the skin, especially the head, but can occur in other areas, such as bone. An epithelioid hemangioma is sometimes caused by injury. It occurs in children and adults.
On the skin, an epithelioid hemangioma may appear as firm pink-to-red bumps and may be itchy. Epithelioid hemangioma of the bone may cause swelling, pain, and weakened bone in the affected area or symptoms of nerve injury. These symptoms may be caused by problems other than an epithelioid hemangioma. The only way to know is for your child to see a doctor.
If your child has symptoms that suggest an epithelioid hemangioma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. An MRI, x-ray, or biopsy may also be done. Learn more about Tests to diagnose childhood vascular tumors.
There is no standard treatment for epithelioid hemangioma. Treatment may include:
Pyogenic granuloma is also called lobular capillary hemangioma. It is most common in older children and young adults but can occur at any age.
Pyogenic granuloma is sometimes caused by injury or from the use of certain medicines, including birth control pills and retinoids. It may also form for no known reason inside capillaries (the smallest blood vessels), arteries, veins, or other places on the body. Some lesions may be associated with capillary malformations.
Pyogenic granuloma is a raised, bright red lesion that may be small or large and smooth or bumpy. It grows quickly over weeks to months and may bleed a lot. The lesion is on the skin’s surface but may form in the tissues below the skin and look like other vascular lesions. Usually, there is only one lesion. Sometimes multiple lesions can occur in the same area or on different parts of the body. The only way to know if these symptoms are caused by a pyogenic granuloma is for your child to see a doctor.
If your child has symptoms that suggest a pyogenic granuloma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. If needed, tests may be ordered. Learn more about Tests to diagnose childhood vascular tumors.
Pyogenic granuloma can go away without treatment. Sometimes a pyogenic granuloma needs treatment that may include:
Angiofibroma is rare and appears as red bumps on the face. It is a benign skin lesion that usually occurs with tuberous sclerosis, an inherited disorder that causes skin lesions, seizures, and mental disabilities. Talk to your child’s doctor if you think your child may have an angiofibroma.
If your child has symptoms that suggest an angiofibroma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. If needed, tests may be ordered. Learn more about Tests to diagnose childhood vascular tumors.
Juvenile nasopharyngeal angiofibroma is a tumor that is not cancer but can grow into nearby tissues. It is most common in males and may form around the time of puberty. Juvenile nasopharyngeal angiofibroma begins in the nasalcavity and may spread to the nasopharynx, the paranasal sinuses, the bone around the eyes, and sometimes to the brain.
If your child has symptoms that suggest juvenile nasopharyngeal angiofibroma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. If needed, tests may be ordered. Learn more about Tests to diagnose childhood vascular tumors.
Treatment of juvenile nasopharyngeal angiofibroma may include:
Some intermediate tumors are likely to spread to the area around the tumor (locally), but not to other parts of the body.
Kaposiform hemangioendothelioma and tufted angioma
Kaposiform hemangioendothelioma and tufted angioma are blood vessel tumors that occur in infants or young children and affect males and females equally. These tumors can cause Kasabach-Merritt phenomenon, a condition in which the blood is not able to clot and serious bleeding may occur. This type of vascular tumor is not related to Kaposi sarcoma.
Symptoms of kaposiform hemangioendothelioma and tufted angioma
Kaposiform hemangioendothelioma and tufted angioma usually occur on the skin of the arms and legs, but may also form in deeper tissues, such as muscle or bone, or in the chest, abdomen, head, or neck.
Symptoms may include:
firm, warm, painful areas of skin that look bruised
People who have kaposiform hemangioendothelioma or tufted angioma may have anemia (weakness, feeling tired, or looking pale).
These symptoms may be caused by problems other than kaposiform hemangioendothelioma or tufted angioma. The only way to know is for your child to see a doctor.
Diagnosis of kaposiform hemangioendothelioma and tufted angioma
If a physical exam and MRI clearly show the tumor is a kaposiform hemangioendothelioma or a tufted angioma, a biopsy may not be needed. A biopsy is not always done because serious bleeding can occur. An ultrasound exam may also be used to diagnose a tufted angioma.
Treatment of kaposiform hemangioendothelioma and tufted angioma
Kaposiform hemangioendothelioma and tufted angioma are best treated by a vascular anomaly specialist. Treatment depends on the symptoms, size and location of the tumor, and the risk of bleeding. Infection, delay in treatment, and surgery can cause bleeding that is life-threatening.
Kaposiform hemangioendothelioma and tufted angioma may be called uncomplicated or complicated.
Uncomplicated tumors are in one area, smaller, cause few or no symptoms, and have a lower risk of bleeding. People with an uncomplicated tumor do not have Kasabach-Merritt phenomenon.
Treatment for uncomplicated kaposiform hemangioendothelioma and tufted angioma may include:
observation for tumors with a low risk of getting worse
Complicated tumors are larger, may cause symptoms, and affect how the body functions. People with a complicated tumor may have Kasabach-Merritt phenomenon, a serious condition that can be life-threatening and requires treatment.
Treatment for complicated kaposiform hemangioendothelioma and tufted angioma may include:
Even with treatment, these tumors do not fully go away and can come back. Pain and inflammation may get worse with age, often around puberty. Long-term effects include chronic pain, heart failure, bone problems, and lymphedema (the build up of lymph fluid in tissues).
Pseudomyogenic hemangioendothelioma can occur in children, but is most common in men aged 20 to 50 years. This tumor is rare, and usually occurs on or under the skin or in bone. Pseudomyogenic hemangioendothelioma may appear as a lump in soft tissue or may cause pain in the affected area. It may spread to nearby tissue but usually does not spread to other parts of the body. In most cases, there are multiple tumors. Talk to your child’s doctor if you think your child may have pseudomyogenic hemangioendothelioma.
If your child has symptoms that suggest pseudomyogenic hemangioendothelioma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. If needed, tests may be ordered. Learn about Tests to diagnose childhood vascular tumors.
Treatment of pseudomyogenic hemangioendothelioma may include:
surgery to remove the tumor when possible or amputation may be needed when there are multiple tumors in the bone
Retiform hemangioendothelioma is a slow-growing, flat tumor that occurs in young adults and sometimes children. This tumor usually occurs on or under the skin of the arms, legs, and trunk. It usually does not spread to other parts of the body. Talk to your child’s doctor if you think your child may have a retiform hemangioendothelioma.
If your child has symptoms that suggest retiform hemangioendothelioma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. If needed, tests may be ordered. Learn about Tests to diagnose childhood vascular tumors.
Treatment of retiform hemangioendothelioma may include:
Papillary intralymphatic angioendothelioma may appear as firm, raised, purplish bumps, which may be small or large. Papillary intralymphatic angioendothelioma forms in or under the skin anywhere on the body. Sometimes the lymph nodes are affected. Talk to your child’s doctor if you think your child may have papillary intralymphatic angioendothelioma.
If your child has symptoms that suggest papillary intralymphatic angioendothelioma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. If needed, tests may be ordered. Learn about Tests to diagnose childhood vascular tumors.
Treatment of papillary intralymphatic angioendothelioma is surgery.
Composite hemangioendothelioma has features of both benign and malignant vascular tumors. This tumor usually occurs on or under the skin of the arms or legs. It may also occur on the skin of the head, neck, or chest. Composite hemangioendothelioma is not likely to spread to nearby tissue or to other parts of the body, but it may come back in the same place. If the tumor spreads, it usually spreads to nearby lymph nodes. Composite hemangioendothelioma occurs in children and adults.
If your child has symptoms that suggest composite hemangioendothelioma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. If needed, tests may be ordered. Learn about Tests to diagnose childhood vascular tumors.
Treatment of composite hemangioendothelioma may include:
Kaposi sarcoma is a cancer that causes lesions to grow in the skin; the mucous membranes lining the mouth, nose, and throat; lymph nodes; or other organs. It is caused by human herpesvirus 8. This cancer rarely occurs in children. In the United States, Kaposi sarcoma occurs most often in children who have a weak immune system caused by rare immune system disorders, HIV infection, or drugs used in organ transplants. In sub-Saharan Africa, Kaposi sarcoma is endemic and often occurs in children and young adults.
Kaposi sarcoma are lesions that form in the skin, mouth, or throat. The lesions are red, purple, or brown and change from flat, to raised, to scaly areas called plaques, to nodules. Sometimes Kaposi sarcoma causes swollen lymph nodes. These symptoms may be caused by problems other than Kaposi sarcoma. The only way to know is to see your child’s doctor.
If your child has symptoms that suggest Kaposi sarcoma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. If needed, tests may be ordered. Learn about Tests to diagnose childhood vascular tumors.
Epithelioid hemangioendothelioma can occur in children, but is most common in adults aged 30 to 50 years. It may occur in the liver, lung, bone, skin, or soft tissue. Epithelioid hemangioendothelioma may be fast growing or slow growing. In about a third of patients with a tumor in the soft tissue, the tumor spreads to other parts of the body very quickly.
Symptoms of epithelioid hemangioendothelioma
The symptoms of epithelioid hemangioendothelioma depend on where the tumor is in the body. It’s important to check with your child’s doctor if your child has:
red-brown patches on the skin that are raised and rounded or flat and feel warm
early symptoms of lesions in the lung, which may not occur in all children with lung lesions:
These symptoms may be caused by problems other than an epithelioid hemangioendothelioma. The only way to know is for your child to see a doctor.
Diagnosis of epithelioid hemangioendothelioma
If your child has symptoms that suggest epithelioid hemangioendothelioma, the doctor will ask about your child’s personal health history and do a physical exam to make the diagnosis. The doctor may also order tests. Epithelioid hemangioendothelioma in the liver is found with an ultrasound exam, CT scan or MRI scan. X-rays of the chest or other areas of the body may also be done. Learn more about Tests to diagnose childhood vascular tumors.
Treatment of epithelioid hemangioendothelioma
Treatment of slow-growing epithelioid hemangioendothelioma may be observation. Surgery may be used when it is possible to remove the tumor.
Treatment of fast-growing epithelioid hemangioendothelioma may include:
Angiosarcoma is a fast-growing tumor that forms in blood vessels or lymph vessels in any part of the body, usually in the soft tissue. Most angiosarcoma is in the skin or in the soft tissue near the skin. Those in deeper soft tissue can form in the liver, spleen, and lung.
Angiosarcoma is very rare in children. Children sometimes have more than one tumor in the skin, liver, or both.
Causes and risk factors for angiosarcoma
A risk factor is anything that increases the chance of getting a disease. Not every child with a risk factor will develop angiosarcoma. And it can develop in some children who don’t have a known risk factor. Risk factors for angiosarcoma include:
Rarely, a benign vascular tumor, such as a hemangioma, may become an angiosarcoma.
Talk with your child’s doctor if you think your child may be at risk.
Symptoms of angiosarcoma
Symptoms of angiosarcoma depend on where the tumor is and may include:
red patches on the skin that bleed easily
purple tumors
These symptoms may be caused by problems other than an angiosarcoma. The only way to know is for your child to see a doctor.
Diagnosis of angiosarcoma
To make a diagnosis, the doctor will ask about your child’s personal health history and do a physical exam. If needed, tests may be ordered. Learn about Tests to diagnose childhood vascular tumors.
A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment for childhood vascular tumors. The pediatric oncologist works with other health care providers who are experts in treating children with cancer and also specialize in certain areas of medicine. Other specialists may include:
pediatric vascular anomaly specialist (expert in treating children with vascular tumors)
There are different types of treatment for children and adolescents with vascular tumors. You and your child’s care team will work together to decide treatment. Many factors will be considered, such as where the tumor is located, your child’s age and overall health, the type of vascular tumor, the risk of scarring, and the likelihood of completely treating the vascular tumor.
Your child’s treatment plan will include information about the tumor, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s care team before treatment begins about what to expect. For help every step of the way, see our booklet, Children with Cancer: A Guide for Parents.
Types of treatment your child might have include:
Beta-blocker therapy
Beta-blockers are drugs commonly used to lower blood pressure and heart rate, but they can also shrink certain types of vascular tumors, such as infantile hemangiomas. Beta-blocker therapy may be injected into a vein, taken by mouth, or placed on the skin (topical). How beta-blocker therapy is given depends on the type of vascular tumor being treated and where it first formed.
The beta-blocker propranolol is usually the first treatment for hemangiomas. Infants younger than 4 weeks, who have an underlying condition, or who are treated with IV propranolol may need to have their treatment started in a hospital. Infantile hemangioma may also be treated with propranolol and steroid therapy or propranolol and topical beta-blocker therapy. Propranolol is also used to treat benign vascular tumors of liver.
Other beta-blockers used to treat vascular tumors include atenolol, nadolol, and timolol.
Surgery
The following types of surgery may be used to remove many types of vascular tumors:
Excision is surgery to remove the entire tumor and some of the healthy tissue around it.
Laser surgery uses a laser beam (a narrow beam of intense light) as a knife to make bloodless cuts in tissue or remove a skin lesion such as a tumor. Surgery with a pulsed dye laser may be used for some hemangiomas. This type of laser uses a beam of light that targets blood vessels in the skin. The light is changed into heat and the blood vessels are destroyed without damaging nearby skin.
Curettage uses a small, spoon-shaped instrument with a sharp edge called a curette to remove abnormal tissue.
Total hepatectomy and liver transplant removes the entire liver followed by a transplant of a healthy liver from a donor.
Amputation removes an arm or leg when there are multiple tumors in the bone.
The type of surgery used depends on the type of vascular tumor and where it formed in the body.
After the doctor removes all the cancer that can be seen at the time of the surgery, some people may be given chemotherapy or radiation therapy to kill any cancer cells that are left. Treatment given after the surgery to lower the risk that the cancer will come back is called adjuvant therapy.
Photocoagulation
Photocoagulation is the use of an intense beam of light, such as a laser, to seal off blood vessels or destroy tissue. It is used to treat pyogenic granuloma.
Cryotherapy
Cryotherapy uses an instrument to freeze and destroy abnormal tissue, such as abnormal blood vessels in pyogenic granuloma. This type of treatment is also called cryosurgery.
Embolization uses particles, such as tiny gelatin sponges or beads, to block blood vessels in the liver. It may be used to block blood flow to some benign vascular tumors of the liver and kaposiform hemangioendothelioma.
Chemotherapy
Chemotherapy (also called chemo) uses drugs to stop the growth of tumor cells. Chemotherapy either kills the cancer cells or stops them from dividing. Chemotherapy may be given alone or with other types of treatment.
For some vascular tumors, chemotherapy is injected into a vein. When given this way, the drugs enter the bloodstream to reach tumor cells throughout the body.
Chemotherapy drugs that may be used alone or in combination to treat childhood vascular tumors include:
Other chemotherapy drugs not listed here may also be used.
Learn more about how chemotherapy works, how it is given, common side effects, and more at Chemotherapy to Treat Cancer.
Sclerotherapy
Sclerotherapy destroys the tumor and the blood vessels that lead to it. A liquid is injected into the blood vessels, causing them to scar and break down. Over time, the destroyed blood vessels are absorbed into normal tissue. The blood flows through nearby healthy veins instead. Sclerotherapy is used to treat epithelioid hemangioma.
Radiation therapy
Radiation therapy uses high-energy x-rays or other types of radiation to kill tumor cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with the tumor. It is used to treat some vascular tumors.
Targeted therapy uses drugs or other substances to block the action of specific enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Different types of targeted therapy are being used or studied to treat childhood vascular tumors:
Other drugs used to treat childhood vascular tumors or manage their effects include:
Steroid therapy: Steroids are hormones made naturally in the body. They can also be made in a laboratory and used as drugs. Steroid drugs help shrink some vascular tumors. Corticosteroids, such as prednisone and methylprednisolone, are used to treat infantile hemangioma.
Immunosuppressant therapy: These drugs decrease the body’s immune responses. Immunosuppressant therapy has been used to help shrink vascular tumors. Topical tacrolimus is used to treat kaposiform hemangioendotheliomas and tufted angiomas.
Thyroid hormone replacement therapy: These drugs replace hormones made by the thyroid and are used to treat a rare form of hypothyroidism caused by some vascular tumors, such as liver hemangiomas.
Observation
Observation is closely monitoring a person’s condition without giving any treatment until symptoms appear or change.
Clinical trials
For some children, joining a clinical trial may be an option. There are different types of clinical trials for childhood cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.
You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your child’s age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Treatments for vascular tumors can cause side effects. Which side effects your child might have depends on the type of treatment they receive, the dose, and how their body reacts. Talk with your child’s treatment team about which side effects to look for and ways to manage them.
Problems from cancer treatment that begin 6 months or later after treatment and continue for months or years are called late effects. Late effects of treatment may include:
physical problems
changes in mood, feelings, thinking, learning, or memory
second cancers (new types of cancer)
Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the possible late effects caused by some treatments. Learn more about Late Effects of Treatment for Childhood Cancer.
Follow-up care
As your child goes through treatment, they will have follow-up tests or check-ups. Some of the tests that were done to diagnose the vascular tumor may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your child’s condition has changed or if the tumor has come back.
When your child has a tumor, every member of the family needs support. Taking care of yourself during this difficult time is important. Reach out to your child’s treatment team and to people in your family and community for support. To learn more, visit Support for Families: Childhood Cancer and the booklet Children with Cancer: A Guide for Parents.
Related resources
For more childhood cancer information and other general cancer resources, visit:
Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.
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Purpose of This Summary
This PDQ cancer information summary has current information about the treatment of childhood vascular tumors. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
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Vascular anomalies are a spectrum of rare diseases classified as either vascular tumors or vascular malformations. Generally, vascular tumors are proliferative, while vascular malformations enlarge through expansion of a developmental anomaly without underlying proliferation.
Although these anomalies are not oncological, it is important for oncologists to understand the biology and clinical management of common vascular malformations. This is because many vascular malformations are caused by targetable somatic variants, which means that pediatric oncologists will be asked to help manage these lesions. While information about vascular malformations is covered at the beginning of this summary, the remainder of this summary focuses on tumors, not malformations.
Vascular Malformations
Vascular malformations are distinguished from vascular tumors by their low cell turnover and lack of invasiveness.[1] They tend to grow in proportion to the child and are generally stable in adulthood. Nonetheless, endothelial cells isolated from vascular malformations have been found in vitro to have some tumor-like behaviors, such as increased growth, migration, and resistance to apoptosis.[2]
In the International Society for the Study of Vascular Anomalies (ISSVA) classification, vascular malformations are subdivided according to vessel type.[3] Fast-flow lesions include arterial-venous fistulas and arterial-venous malformations. These complicated lesions can cause bleeding, ulceration, and organ dysfunction.
Slow-flow lesions include venous, lymphatic, capillary, or combined lesions. Complications from slow-flow lesions include pain, infection, bleeding, thrombosis, and organ dysfunction.
Regular monitoring and assessment of changes or development of symptoms is warranted in patients with vascular malformations. Treatment requires an interdisciplinary approach to care and includes observation, surgery, endovascular intervention, and medical management. Only a low level of evidence supports the choice of treatment between these options. Recurrence rates of these lesions are relatively high.[4]
Vascular malformations are most commonly caused by variants in the MAP2K/PIK3CA pathway. Most are activating somatic variants but, rarely, germline variants are identified. Approximately one-third to one-half of venous malformations result from somatic or, rarely, germline variants in the TEK (or TIE2) gene.[5] Another one-third of venous malformations, and nearly all lymphatic malformations, are caused by somatic variants in PIK3CA.[6] In most cases, PIK3CA variants are identical to canonical cancer variants. Lesions harboring PIK3CA variants are frequently associated with overgrowth of adjacent tissues, as seen in patients with Klippel-Trénaunay syndrome and CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevis, spinal/skeletal anomalies/scoliosis).[7]
Sirolimus was initially used to target the PI3K pathway in slow-flow malformations, leading to symptomatic improvement in many patients. It is unclear whether treatment reduces the size of lesions because there is usually considerable fluctuation in size, and treatment generally begins when lesions are enlarged. The use of sirolimus in venous and lymphatic malformations is supported by level C evidence (case series, other observational study designs, phase II studies).[8–10] Both lesions with PIK3CA and TEK variants appear to respond equally to treatment with sirolimus. Phase III clinical trials are underway in Europe (e.g., NCT02638389, NCT03987152, and NCT04980872). A 2018 study reported promising level C evidence for the use of the PI3K inhibitor BYL719 (alpelisib) to treat patients who have lesions with a PIK3CA variant.[11] From these studies, preliminary FDA approval has been obtained. For information about ongoing studies, see the Treatment Options Under Clinical Evaluation section.
There is some support for targeted therapy in fast-flow malformations and complicated lymphatic anomalies that are caused by somatic and germline variants in the MAPK pathway, including gain of function variants in MAP2K1, KRAS, NRAS, and BRAF.[12] Limited data suggest that MEK pathway inhibition may soon have a role in treating patients with these aggressive, highly symptomatic, and sometimes fatal lesions.[13–20] For information about ongoing studies, see the Treatment Options Under Clinical Evaluation section.
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
NCT04258046 (Trametinib in the Treatment of Complicated Extracranial Arterial Venous Malformation): This is a phase II study to assess the safety and efficacy of trametinib in the treatment of children and adults.
NCT05125471 (Cobimetinib in Extracranial Arteriovenous Malformations [COBI-AVM Study]): This is a phase II study to evaluate the safety and efficacy of cobimetinib in the treatment of children and adults.
NCT05948943 (Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Variant): This is a phase II/III study of adults and children (aged 6–17 years) that will determine the dose of alpelisib in stage 1, followed by confirmation of efficacy and safety in stage 2 of the study.
References
Mulliken JB, Glowacki J: Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 69 (3): 412-22, 1982. [PUBMED Abstract]
Lokmic Z, Mitchell GM, Koh Wee Chong N, et al.: Isolation of human lymphatic malformation endothelial cells, their in vitro characterization and in vivo survival in a mouse xenograft model. Angiogenesis 17 (1): 1-15, 2014. [PUBMED Abstract]
Wassef M, Blei F, Adams D, et al.: Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics 136 (1): e203-14, 2015. [PUBMED Abstract]
van der Vleuten CJ, Kater A, Wijnen MH, et al.: Effectiveness of sclerotherapy, surgery, and laser therapy in patients with venous malformations: a systematic review. Cardiovasc Intervent Radiol 37 (4): 977-89, 2014. [PUBMED Abstract]
Soblet J, Limaye N, Uebelhoer M, et al.: Variable Somatic TIE2 Mutations in Half of Sporadic Venous Malformations. Mol Syndromol 4 (4): 179-83, 2013. [PUBMED Abstract]
Luks VL, Kamitaki N, Vivero MP, et al.: Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr 166 (4): 1048-54.e1-5, 2015. [PUBMED Abstract]
Keppler-Noreuil KM, Rios JJ, Parker VE, et al.: PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A 167A (2): 287-95, 2015. [PUBMED Abstract]
Adams DM, Trenor CC, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [PUBMED Abstract]
Hammer J, Seront E, Duez S, et al.: Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study. Orphanet J Rare Dis 13 (1): 191, 2018. [PUBMED Abstract]
Maruani A, Tavernier E, Boccara O, et al.: Sirolimus (Rapamycin) for Slow-Flow Malformations in Children: The Observational-Phase Randomized Clinical PERFORMUS Trial. JAMA Dermatol 157 (11): 1289-1298, 2021. [PUBMED Abstract]
Venot Q, Blanc T, Rabia SH, et al.: Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 558 (7711): 540-546, 2018. [PUBMED Abstract]
Couto JA, Huang AY, Konczyk DJ, et al.: Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation. Am J Hum Genet 100 (3): 546-554, 2017. [PUBMED Abstract]
Dori Y, Smith C, Pinto E, et al.: Severe Lymphatic Disorder Resolved With MEK Inhibition in a Patient With Noonan Syndrome and SOS1 Mutation. Pediatrics 146 (6): , 2020. [PUBMED Abstract]
Nakano TA, Rankin AW, Annam A, et al.: Trametinib for Refractory Chylous Effusions and Systemic Complications in Children with Noonan Syndrome. J Pediatr 248: 81-88.e1, 2022. [PUBMED Abstract]
Homayun-Sepehr N, McCarter AL, Helaers R, et al.: KRAS-driven model of Gorham-Stout disease effectively treated with trametinib. JCI Insight 6 (15): , 2021. [PUBMED Abstract]
Foster JB, Li D, March ME, et al.: Kaposiform lymphangiomatosis effectively treated with MEK inhibition. EMBO Mol Med 12 (10): e12324, 2020. [PUBMED Abstract]
Chowers G, Abebe-Campino G, Golan H, et al.: Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition. Pediatr Res 94 (6): 1911-1915, 2023. [PUBMED Abstract]
Lekwuttikarn R, Lim YH, Admani S, et al.: Genotype-Guided Medical Treatment of an Arteriovenous Malformation in a Child. JAMA Dermatol 155 (2): 256-257, 2019. [PUBMED Abstract]
Nicholson CL, Flanagan S, Murati M, et al.: Successful management of an arteriovenous malformation with trametinib in a patient with capillary-malformation arteriovenous malformation syndrome and cardiac compromise. Pediatr Dermatol 39 (2): 316-319, 2022. [PUBMED Abstract]
Cooke DL, Frieden IJ, Shimano KA: Angiographic evidence of response to trametinib therapy for a spinal cord arteriovenous malformation. J Vasc Anom (Phila) 2 (3): e018, 2021. Available online. Last accessed July 6, 2023..
Childhood Vascular Tumors
Vascular tumors are proliferative tumors that can be benign or malignant. Growth and/or expansion of vascular tumors can cause clinical problems such as disfigurement, chronic pain, coagulopathies, organ dysfunction, and death.
The quality of evidence regarding childhood vascular tumors is limited by retrospective data collection, small sample size, cohort selection and participation bias, and heterogeneity of the disorders. Lack of consistent criteria and medical terminology has led to unreliable conclusions from the historical medical literature.[1–3]
In the past, limited treatment options were available, and efficacy was not validated in prospective clinical trials. Historically, therapies consisted of interventional and surgical procedures used to palliate symptoms. Limited medical therapies were available. Newer therapy options with propranolol and sirolimus are now available for the treatment of patients with complex vascular tumors. The first prospective clinical trial using propranolol for infantile hemangioma has been published, as well as the first prospective clinical trial that studied the effectiveness of sirolimus for complicated vascular anomalies, including vascular tumors.[4,5]
With a prevalence of 4% to 5%, infantile hemangiomas are the most common benign tumors of infancy. Other vascular tumors are rare. The classification of these tumors has been difficult, especially in the pediatric population, because of their rarity, unusual morphologic appearance, diverse clinical behavior, and the lack of independent stratification for pediatric tumors. In 2020, the World Health Organization (WHO) updated the classification of soft tissue vascular tumors.[6]
The International Society for the Study of Vascular Anomalies (ISSVA) classification of tumors is based on the WHO classification, but it uses more precise terminology and phenotypes. The General Assembly of the ISSVA adopted an updated classification system in 2014, with further additions in 2018 (ISSVA).[7,8] For more information, see Tables 1 and 2.
Table 1. 2020 World Health Organization Classification of Vascular Tumorsa
Category
Vascular Tumor Type
NOS = not otherwise specified.
aAdapted from the WHO Classification of Tumours Editorial Board.[6]
Liberale C, Rozell-Shannon L, Moneghini L, et al.: Stop Calling Me Cavernous Hemangioma! A Literature Review on Misdiagnosed Bony Vascular Anomalies. J Invest Surg 35 (1): 141-150, 2022. [PUBMED Abstract]
Boulogeorgou K, Avramidou E, Koletsa T: Identifying erroneously used terms for vascular anomalies: A review of the English literature. Hippokratia 26 (4): 126-130, 2022. [PUBMED Abstract]
Hassanein AH, Mulliken JB, Fishman SJ, et al.: Evaluation of terminology for vascular anomalies in current literature. Plast Reconstr Surg 127 (1): 347-351, 2011. [PUBMED Abstract]
Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al.: A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med 372 (8): 735-46, 2015. [PUBMED Abstract]
Adams DM, Trenor CC, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [PUBMED Abstract]
WHO Classification of Tumours Editorial Board: WHO Classification of Tumours. Volume 3: Soft Tissue and Bone Tumours. 5th ed., IARC Press, 2020.
International Society for the Study of Vascular Anomalies: ISSVA Classification of Vascular Anomalies. Milwaukee, Wi: International Society for the Study of Vascular Anomalies, 2018. Available online. Last accessed June 7, 2022.
Wassef M, Blei F, Adams D, et al.: Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics 136 (1): e203-14, 2015. [PUBMED Abstract]
Special Considerations for the Treatment of Children With Cancer
Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:
Primary care physicians.
Pediatric surgeons.
Transplant surgeons.
Pathologists.
Pediatric radiation oncologists.
Pediatric medical oncologists and hematologists.
Ophthalmologists.
Rehabilitation specialists.
Pediatric oncology nurses.
Social workers.
Child-life professionals.
Psychologists.
Nutritionists.
For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer.[3–5] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3,6,7] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.
References
Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 25, 2025.
Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
Childhood cancer. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. National Cancer Institute, 2013, Section 28. Also available online. Last accessed August 21, 2023.
Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. National Cancer Institute, 2013, Section 29. Also available online. Last accessed August 21, 2023.
National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 25, 2025.
Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.
Juvenile nasopharyngeal angiofibroma is not included in the World Health Organization (WHO) classification or the International Society for the Study of Vascular Anomalies (ISSVA) classification of vascular tumors. It is included here because growing evidence reveals vascular differentiation and proliferation in these tumors with response to vascular remodeling and antiproliferative agents.
Infantile Hemangioma
Incidence and epidemiology
Infantile hemangiomas (IH) are the most common benign vascular tumor of infancy, occurring in 4% to 5% of infants. The true incidence is unknown.[1] They are not usually present at birth and are diagnosed most commonly at age 3 to 6 weeks.[2–5] The lesion proliferates for an average of 5 months, stabilizes, and then involutes over several years.
Infantile hemangiomas are more common in females, non-Hispanic White patients, and premature infants. Multiple hemangiomas are more common in infants who are the product of multiple gestations or in vitro fertilization.[5–7] Infantile hemangiomas are associated with advanced maternal age, placenta previa, pre-eclampsia, and other placental anomalies.[5]
Clinical presentation
Most infantile hemangiomas are not present at birth, but precursor lesions such as telangiectasia or faint discoloration of the skin or hypopigmentation can often be seen. The lesion can be mistaken as a bruise from birth trauma or as a capillary malformation (port-wine stain) (see Figure 1).[8,9]
EnlargeFigure 1. The photos on the left depict the precursor lesion (faint color with halo). The photos on the right depict the hemangioma after proliferation (slightly raised with a brighter central color). Credit: Israel Fernandez-Pineda, M.D.
Infantile hemangiomas can be superficial in the dermis, deep in the subcutaneous tissue, combined, or in the viscera. Combined lesions are common and generally appear in the head and neck but can be anywhere on the body.
Infantile hemangiomas can be characterized as follows:
Local: Most lesions are localized and noted to be in a well-defined area without evidence of a geometric pattern.
Segmental: Most segmental hemangiomas occur in the head and neck region (PHACE syndrome) but can be seen in the genitourinary area, arm, chest, or legs (PELVIS/LUMBAR/SACRAL syndrome).
Diffuse hemangiomas of the face demonstrate defined cutaneous patterns. Several studies have evaluated the distributions of these hemangiomas and found the following four distinct patterns or segments:
Segment 1 involves the lateral forehead, anterior temporal scalp, and the lateral frontal scalp.
Segments 2 and 3 are located over the maxillary and mandibular area.
Segment 4 covers the medial frontal scalp, nose, and philtrum.
Two papers have noted this observation and suggest the involvement of neural crest derivatives in facial hemangioma development.[10,11] Segmental hemangiomas commonly occur in females and are more likely associated with complications and other syndromes.[12,13]
Multiple: More than one lesion but noted in the past as greater than five lesions, because of the increased risk of visceral involvement (mostly the liver).
The cutaneous appearance of infantile hemangiomas is usually red to crimson, firm, and warm in the proliferative phase. The lesion then lightens centrally and becomes less warm and softer; it then flattens and loses its color. The process of involution can take several years and once involution has occurred, regrowth is uncommon. In two patients treated with growth hormone, regrowth after involution was noted.[14] On further investigation, growth hormone receptors were found on the infantile hemangioma cells. Although preliminary, this may advance the research into the etiology of hemangioma growth.
Ulceration is the most common complication of infantile hemangiomas, occurring in 10% to 15% of patients. Ulceration typically occurs during the proliferative phase, and it can lead to bleeding and secondary infections.[15] Most other complications in the proliferative phase result from the impact of the mass on local structures (e.g., visual or auditory compromise, airway obstruction).[16]
Permanent sequelae, such as telangiectasia, anetodermal skin, redundant skin, and a persistent superficial component, can occur after hemangioma involution. Hemangiomas with a history of ulceration are more likely to cause scarring and potential local anatomical complications.[15] Rare instances of dysesthesias in sites of involuted infantile hemangiomas in the absence of ulceration have been described.[17][Level of evidence C1] In a retrospective cohort study of 184 hemangiomas, the overall incidence of significant sequelae was 54.9%. Sequelae were more common in combined hemangiomas, hemangiomas with a step or abrupt border, and cobblestone surface hemangiomas. Furthermore, this study revealed that the average age to hemangioma involution was 3.5 years.[18] Thus, prophylactic measures such as maintaining dermal integrity with moisturizing barrier agents are indicated for infantile hemangiomas and are important before and during the proliferative phase.[16] Once an ulceration has occurred, it is important to aggressively manage the ulceration to promote healing, prevent infection, and treat pain. In addition to pain control, management includes steroid ointments, antibiotic ointments or systemic antibiotics, laser therapy, or topical timolol.[16]
Biology and histopathology
Most infantile hemangiomas occur sporadically. However, they may rarely be caused by an abnormality of chromosome 5 and present in an autosomal dominant pattern.[19] In a study that evaluated inheritance patterns of infantile hemangiomas, 34% of patients had a family history of infantile hemangioma, most commonly in a first-degree relative.[19,20]
The exact mechanism that causes the initial proliferation of blood vessels followed by involution of the vascular component of hemangioma and replacement of fibrofatty tissue is unknown. Several cell types have been isolated from hemangiomas: progenitor/stem cells (HemSC), endothelial cells (HemEC), pericytes (HemPericytes), and mast cells.[21,22] These cells appear to play a role in the development of infantile hemangiomas.
HemSC represent a small percentage of proliferating hemangioma cells and have the ability for self renewal and multilineage differentiation. These cells differentiate into endothelial cells, adipocytes, and pericytes. When HemSC are implanted into immunodeficient mice, hemangioma-like lesions form and then spontaneously regress, similar to infantile hemangiomas.[23] This suggests that infantile hemangioma proliferation occurs during vasculogenesis (the formation of new blood vessels from angioblasts), as opposed to angiogenesis (the formation of new blood vessels from existing blood vessels).
HemEC are plump, metabolically active, and resemble fetal endothelial cells in the proliferative phase. Evaluation of infantile hemangioma endothelial cells suggest that they are clonal in nature.[23–25]
HemPericytes surround the vasculature and are abundant in the proliferative phase. These cells express markers of pericytes and smooth muscle cells, such as neural-glial antigen 2 (NG2), platelet-derived growth factor receptor beta (PDGFR-beta), calponin, alpha smooth muscle actin (SMA), and NOTCH3. HemPericytes are proangiogenic, as they express increased vascular endothelial growth factor A (VEGF-A), decreased angiopoietin-1 (ANGPT1), increased proliferation, increased vessel formation in vivo, and decreased ability to suppress proliferation.[26] One study reported that proliferating infantile hemangiomas contained higher levels of messenger RNA, proteins for NOTCH1, 3, and 4 receptors and their ligands, and the downstream coactivator MAML1 than did normal skin, involuting infantile hemangiomas, and propranolol-treated infantile hemangiomas.[27]
Mast cells are found largely in the early involuting phase, but they are also found in small numbers in the proliferative phase and at the end of involution. Their function in infantile hemangiomas is unknown but they have been shown to play a role in other skin tumors such as basal cell carcinoma, squamous cell carcinoma, and melanoma.[22]
Provasculogenic factors are expressed during proliferation; these factors include VEGF, fibroblast growth factor (FGF), CD34, CD31, CD133, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), and insulin-like growth factor 2 (IGF-2).[28–31] During involution, infantile hemangiomas show increased apoptosis.[31] During this phase, there are also increased mast cells and levels of metalloproteinase, as well as upregulation of interferon and decreased basic FGF (bFGF).[31–33] Throughout proliferation and involution, endothelial cells in infantile hemangioma express a particular phenotype showing positive staining for GLUT1 and placenta-associated antigens (Fc-gamma receptor II, merosin, and Lewis Y antigen). These markers are absent in normal capillaries and in other vascular tumors such as congenital hemangioma and vascular malformations. Placental chorionic villi share these same markers. However, no relationship between hemangiomas and placental chorionic villi has been found.[28]
Hypoxia appears to have a critical role in the pathogenesis of hemangiomas. There is an association between hemangiomas and placental hypoxia, which is increased in prematurity, multiple pregnancies, and placental anomalies.[2,5] Multiple targets of hypoxia [34,35] are demonstrated in proliferating hemangiomas, including VEGF-A, GLUT1, and IGF-2.[28,30,36] The hypothesis suggests that a proliferating hemangioma is an attempt to normalize hypoxic tissue that occurred in utero.
Diagnostic evaluation
Infantile hemangiomas are usually diagnosed by the history and clinical appearance. Biopsy is rarely needed and performed only if there is an atypical appearance and/or atypical history and presentation. Imaging is not usually necessary, but diagnostic ultrasonography is beneficial if there is a deeper lesion without a cutaneous component and reveals a well-circumscribed, hypoechoic, high-flow lesion with a typical Doppler wave characteristic.[37] Additionally, infants with five or more cutaneous hemangiomas should undergo ultrasonography of the liver to screen for hepatic hemangioma.[38]
Infantile hemangioma with minimal or arrested growth
Infantile hemangioma with minimal or arrested growth (IH-MAG) is a variant of hemangioma that can be confused with capillary malformation because of their unusual characteristics. These hemangiomas are mostly fully formed at birth and are characterized by telangiectasia and venules with light and dark areas of skin coloration (see Figure 2). They resolve spontaneously and are pathologically GLUT1 positive.[39] They are mainly located on the lower body but can be present in the head and neck area. If they are segmental, they can be associated with PHACE syndrome.[40] Associated soft tissue hypertrophy may persist through childhood.[41]
EnlargeFigure 2. Patient 4 at (A) presentation and (B) resolution. Patient 5 at (C) presentation and (D) resolution. Ma, E. H., Robertson, S. J., Chow, C. W., and Bekhor, P. S. (2017), Infantile Hemangioma with Minimal or Arrested Growth: Further Observations on Clinical and Histopathologic Findings of this Unique but Underrecognized Entity. Pediatr Dermatol, 34: 64–71. doi:10.1111/pde.13022. Used with permission.
Airway infantile hemangioma
Airway infantile hemangiomas are usually associated with segmental hemangiomas in a bearded distribution, which may include all or some of the following—the preauricular skin, mandible, lower lip, chin, or anterior neck. It is important for an otolaryngologist to proactively assess lesions in this distribution before signs of stridor occur. Airway infantile hemangioma incidence increases with a larger area of bearded involvement.[42]
Airway infantile hemangiomas can occur without skin lesions. A retrospective study of the Vascular Anomaly Database at the Children’s Hospital of Pittsburgh analyzed 761 cases of infantile hemangioma. Thirteen patients (1.7%) had subglottic hemangiomas. Of those 13 patients, 4 (30%) had bearded distributions, 2 (15%) had cutaneous hemangiomas, and 7 (55%) had no cutaneous lesions.[43] For information about the treatment of airway infantile hemangiomas, see the Propranolol therapy section.
Ophthalmologic involvement of hemangiomas
Periorbital hemangiomas can cause visual compromise.[44] This usually occurs with hemangiomas of the upper medial eyelid but any hemangioma around the eye that is large enough can distort the cornea or obstruct the visual axis. Subcutaneous periocular hemangiomas can extend into the orbit, causing exophthalmos or globe displacement with only limited cutaneous manifestations. Issues with these lesions include astigmatism from direct pressure of the growing hemangioma, ptosis, proptosis, and strabismus. One of the leading causes of preventable blindness in children is stimulus-deprivation amblyopia caused by hemangioma obstruction. All periorbital hemangiomas or those with any possibility of potential visual impairment should have an ophthalmologic evaluation.
Two institutions in France and Canada performed a retrospective analysis of patients in a vascular anomalies practice. The investigators reviewed the records of all patients with a diagnosis of segmental facial or periorbital focal infantile hemangioma who had clinical photographs and brain magnetic resonance imaging (MRI) available.[45][Level of evidence C1] The study included 122 children (90 girls, 32 boys; mean age, 16.6 months). Forty-five children (36.9%) had a facial infantile hemangioma larger than 5 cm. Twenty-two patients (18.0%) had PHACES or possible PHACES syndrome. Cerebrovascular structural anomalies were seen in 14 of 22 patients with PHACES syndrome and no patients without PHACES syndrome. Brain anomalies were seen in 6 of 22 patients with PHACES syndrome and 1 patient without PHACES syndrome (P < .001). Cardiovascular anomalies were seen in six patients, and ocular anomalies were seen in eight patients. Of these 14 patients, 13 had PHACES syndrome. The authors concluded that clinical concern about associated extracutaneous anomalies is warranted for all children with facial segmental or periorbital focal infantile hemangiomas, including those with small hemangiomas.
Infantile hemangiomas can occur in the conjunctiva (see Figure 3). These hemangiomas can be associated with other ophthalmologic abnormalities and are treated with oral or topical beta-blockers.[46]
Posterior fossa–brain malformations; Hemangiomas; Arterial, Cardiac, and Eye abnormalities (PHACE) syndrome:PHACE syndrome represents a spectrum of diseases and is defined by the presence of large segmental infantile hemangiomas, usually on the face or head, but can include the neck, chest, or arm, in association with one or more congenital malformations (see Figure 4).[47] PHACE syndrome is more common in girls and in full-term, normal birth weight and singleton infants.[13,48–52] The syndrome is not rare among patients with infantile hemangiomas. A prospective study of 108 infants with large facial hemangiomas observed that 31% of patients had PHACE syndrome.[53] Rare cases of PHACE syndrome have been reported in infants with hemangiomas smaller than 5 cm.[45][Level of evidence C1]
EnlargeFigure 4. A large segmental infantile hemangioma (plaque-like) in a bearded distribution. This patient has an increased risk of PHACE syndrome, airway infantile hemangioma, and ulceration. A tracheostomy was placed secondary to a very diffuse airway hemangioma. Credit: Denise Adams, M.D. Garzon MC, Epstein LG, Heyer GL, et al.: PHACE Syndrome: Consensus-Derived Diagnosis and Care Recommendations. J Pediatr 178: 24-33.e2, 2016. PMID: 27659028
Consensus criteria for definite and possible PHACE syndrome were updated at an expert panel meeting, as follows:[47]
PHACE
Posterior fossa abnormalities. Posterior fossa malformations include Dandy-Walker complex, cerebellar hypoplasia, atrophy, and dysgenesis/agenesis of the vermis. Effects of these anomalies include developmental delays and pituitary dysfunction.[54]
A large segmental hemangioma over the face and/or scalp with a surface area of 22 cm2 or greater (5 cm × 4.5 cm).
A large segmental hemangioma of the neck, trunk, or proximal upper extremity.
Infants with two major criteria of PHACE (e.g., supraumbilical raphe and coarctation of the aorta) but lacking cutaneous infantile hemangiomas should undergo complete evaluation for PHACE.
Arterial abnormalities. Cerebrovascular anomalies can include carotid artery abnormalities (including tortuosity) and absence, dilation/aneurysm, or narrowing of cerebral vessels. These anomalies, especially related to the carotid arteries, can lead to progressive arterial occlusion and even stroke. The risk categories are as follows:[51,52,59–61]
Low risk: This category includes patients with arterial anomalies frequently seen in a general screening population. It also includes findings that have either no or very minimal clinical impact on patient outcome, even if rarely seen in the general population. Examples are persistent embryonic arteries, anomalous arterial origin or course, and circle of Willis variants.
Intermediate risk: Includes patients with nonstenotic dysgenesis, including those with ectatic or segmentally enlarged arteries. It also includes patients with a narrowing or occlusion of arteries proximal to the circle of Willis, with no perceived hemodynamic risk. An evaluation of the patency of the circle of Willis is essential.
High risk: This category includes patients with one or more of the following:
Significant narrowing (>25%) or occlusion of principal cerebral vessels within or above the circle of Willis that results in an isolated circulation.
Tandem or multiple arterial stenoses associated with complex blood flow that may potentially result in diminished cerebral perfusion. Patients with cerebrovascular stenosis in the setting of coarctation of the aorta are likely at higher risk of transient and permanent neurological ischemic events.
Imaging findings in the brain parenchyma suggestive of chronic or silent ischemia, or progressive steno-occlusive disease. These parenchymal brain MRI findings include existing infarction, chronic or border zone ischemic changes, and presence of lenticulostriate collateral dilation or pial collaterals.
Cardiac abnormalities. Aortic arch anomalies observed in PHACE syndrome are unusually complex, with involvement of the transverse and descending aorta arch. The arch obstruction is most often long-segment. The obstruction is frequently characterized by areas of arch narrowing with adjacent segments of marked aneurysmal dilatation.
Eye abnormalities. Ophthalmologic anomalies can include microphthalmos, retinal vascular abnormalities, persistent fetal retinal vessels, exophthalmos, coloboma, and optic nerve atrophy. These abnormalities are rare and occur in 7% to 10% of patients.[62]
A retrospective review identified midline rhabdomyomatous mesenchymal hamartomas and chin hamartomas in a small number of children with PHACE or LUMBAR syndrome.[63] These are not currently included as minor criteria.
Diagnosis of PHACE syndrome requires clinical examination, cardiac evaluation with echocardiogram, ophthalmologic evaluation, and MRI/magnetic resonance angiogram (MRA) of the head and neck. All patients with intermediate-risk and high-risk central nervous system (CNS) findings should be monitored by a neurologist and/or neurosurgeon. Coarctation of the aorta requires immediate cardiology consultation, and a cardiac MRI/MRA may be warranted. A report of two patients with retro-orbital infantile hemangiomas and arteriopathy suggested a possible new presentation of PHACE syndrome.[58] For patients with proptosis, globe deviation, and strabismus, an MRI/MRA is recommended. Further workup for PHACE syndrome may be needed based on CNS findings.
Short- and long-term issues related to PHACE syndrome include the following:[64–66]; [67][Level of evidence C1]
Headache.
May present at an early age.
Can be severe.
New-onset headaches should be evaluated for vasculopathy and/or cerebral ischemia.
Neurology referral is recommended.
Vasoconstrictive medications are contraindicated.
Hearing loss and speech-language delays.
Speech-language delays may be a consequence of hearing deficits, prolonged hospitalizations, or may occur because of other neurodevelopmental anomalies.
Sensorineural hearing loss is the most common type, and it is usually ipsilateral to the infantile hemangioma, which may involve the ipsilateral cranial nerve VIII.
Early detection is crucial.
All patients with PHACE syndrome should undergo hearing screening as a newborn and at least one follow-up if initial screening is normal.
Dysphagia, feeding disorders, speech disorders, and/or language delay.
Increased in patients with posterior fossa malformations, lip/oropharynx or airway hemangiomas, hearing loss, and those with a history of cardiac surgery.
Patients should undergo an initial speech language evaluation before age 24 months.
Patients with feeding difficulties should be referred for evaluation by a pediatric speech-language pathologist at any age.
Dysphagia may be secondary to the disease location (lip, oral cavity, and pharynx) or oral motor coordination.
Endocrine abnormalities.
Thyroid dysfunction and hypopituitarism resulting in growth hormone deficiency are the most frequently reported abnormalities.
Other manifestations of hypopituitarism, including hypogonadotropic hypogonadism and adrenal insufficiency, have been described.
Patients should undergo neonatal screening and repeat studies if symptomatic.
Growth hormone deficiency: Most reported cases are associated with hypopituitarism with empty or partially empty sella turcica noted on MRI, but it may also occur without evidence of central nervous system malformations.
Neonatal hypoglycemia can be a sign of hypopituitarism and should prompt additional endocrinologic evaluation.
Other consequences of pituitary dysfunction include hypogonadotropic hypogonadism, manifesting with delayed pubertal onset and late-onset adrenal insufficiency. These findings emphasize the importance of focused assessment of height, weight, and developmental milestones in the care of children with PHACE.
Dental abnormalities (enamel hypoplasia).
A study of 18 children with PHACE or possible PHACE syndrome revealed that 28% of patients had enamel hypoplasia. All of the affected children had intraoral hemangiomas. Five of 11 (45%) patients with intraoral hemangiomas had enamel defects. Children with enamel hypoplasia are at increased risk of developing caries.
Patients should be examined for the presence of intraoral hemangiomas. If they are present, patients should be referred to a pediatric dentist by age 1 year for early screening and management.
Long-term outcomes and quality of life.
An international group of experts published a report of a multicenter study that used cross-sectional interviews and chart review to examine long-term outcomes and quality of life for patients older than 10 years with PHACE syndrome.[68] Individuals were defined as having definite PHACE by previously reported guidelines.[47] This was the largest cohort of adolescents and adults with PHACE. Of 153 individuals who were contacted, 104 participated in the study (68%). The median age was 14 years (range, 10–77 years). This study found that PHACE syndrome was associated with long-term, mild-to-severe morbidities, including infantile hemangioma residua (94.1%), headaches/migraines (72.1%), learning differences (45.1%), and progressive arteriopathy (29.4%). Additional findings from the study are reported in Table 3.
Most patients with hemangioma residua were satisfied or very satisfied with their appearance (89.5%). Those with surgery and/or ulceration were less likely to report a minimal impact on self-confidence. Of the 68 patients with arteriopathy and available follow-up imaging, 6 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite this finding, the proportion of patients with ischemic stroke was low (2 of 104; 1.9%). Patient-Reported Outcomes Measurement Information System (PROMIS) global health scores were lower than population norms by at least 1 standard deviation. Given the overall prevalence of PHACE, it was not possible to obtain the proper power to accurately assess all outcomes. The authors of the study concluded that primary and specialty follow-up care is important for patients with PHACE into adulthood. Further study is needed to identify precise guidelines for long-term follow-up.[68]
Table 3. Additional Findings Identified Among the PHACE Syndrome Cohorta
Symptom
Prevalence
Symptom
Prevalence
ADHD = attention-deficit/hyperactivity syndrome; IH = infantile hemangioma.
aAdapted from: Mitchell Braun, Ilona J. Frieden, Dawn H. Siegel, Elizabeth George, Christopher P. Hess, Christine K. Fox, Sarah L. Chamlin, Beth A. Drolet, Denise Metry, Elena Pope, Julie Powell, Kristen Holland, Caden Ulschmid, Marilyn G. Liang, Kelly K. Barry, Tina Ho, Chantal Cotter, Eulalia Baselga, David Bosquez, Surabhi Neerendranath Jain, Jordan K. Bui, Irene Lara-Corrales, Tracy Funk, Alison Small, Wenelia Baghoomian, Albert C. Yan, James R. Treat, Griffin Stockton Hogrogian, Charles Huang, Anita Haggstrom, Mary List, Catherine C. McCuaig, Victoria Barrio, Anthony J. Mancini, Leslie P. Lawley, Kerrie Grunnet-Satcher, Kimberly A. Horii, Brandon Newell, Amy Nopper, Maria C. Garzon, Margaret E. Scollan, Erin F. Mathes, Multicenter Study of Long-Term Outcomes and Quality of Life in PHACE Syndrome after Age 10, The Journal of Pediatrics, Volume 267, 2024, 113907, ISSN 0022-3476, https://doi.org/10.1016/j.jpeds.2024.113907. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Infantile hemangiomas located over the lumbar or sacral spine may be associated with genitourinary, anorectal anomalies, or neurological issues such as tethered cord.[69–72] The following criteria have been used to describe segmental infantile hemangioma syndrome in the lumbar, pelvic, and sacral areas. This syndrome has been described in the literature using several acronyms.
LUMBAR
Lower-body hemangiomas and other cutaneous defects.
Urogenital anomalies or ulceration.
Myelopathy.
Bony deformities.
Anorectal malformations or arterial anomalies.
Renal anomalies.
PELVIS
Perineal hemangiomas.
External genital malformations.
Lipomyelomeningocele.
Vesicorenal abnormalities.
Imperforate anus.
Skin tag.
SACRAL
Spinal dysraphism.
Anogenital.
Cutaneous.
Renal and urologic anomalies Associated with an angioma of Lumbosacral localization.
Segmental lesions over the gluteal cleft and lumbar spine need to be evaluated with either ultrasonography or MRI, depending on the age of the patient. In several studies, ultrasonography evaluations have failed to identify some spinal abnormalities that were later found on MRI evaluation.[73,74]
Multiple hemangiomas
Infants with more than five hemangiomas need to be evaluated for visceral hemangiomas. The most common site of involvement is the liver, in which multiple or diffuse lesions can be noted.[75–77] Often these lesions are asymptomatic, but in a minority of cases, symptoms such as heart failure secondary to large vessel shunts, compartment syndrome, or profound hypothyroidism can occur because of the expression of iodothyronine deiodinase by the hemangioma cells.[78] Multiple or diffuse liver hemangiomas can occur in the absence of skin lesions. Other rare potential complications of visceral hemangiomas depend on specific organ involvement and are caused by mass effects. These complications include gastrointestinal hemorrhage, obstructive jaundice, and CNS sequelae. For more information, see the Hepatic Vascular Tumors (HVT) section.
Treatment of infantile hemangioma
The decision to treat patients with hemangiomas is based on several factors, including the following:[79]
Size of the lesions.
Type of hemangioma.
Location of hemangioma.
Presence or risk of complications, including ulceration, possibility of scarring or disfigurement, the age of the patient, and the stage of growth of the hemangioma.
This decision is individualized among patients, and it is important to carefully consider the risks and benefits of treatment.
The American Academy of Pediatrics has published clinical practice guidelines on this topic. An early therapeutic intervention was noted to be critical for complex infantile hemangiomas to prevent medical complications and permanent disfigurement. The timing of interventions was noted to be best in the first 1 to 3 months of age. Photos were used to triage low-risk versus high-risk infantile hemangiomas,[80] and a scoring system was used for primary care physicians to encourage early referral to hemangioma specialists.[81] The guidelines indicated that hemangioma specialists are practitioners with expertise in the management and care of hemangiomas who have knowledge of risk stratification and treatment options. These providers consisted of experts in the fields of dermatology, hematology/oncology, pediatrics, plastic surgery, general surgery, otolaryngology, and ophthalmology.[82]
Treatment options for infantile hemangioma include the following:
Usually reserved for ulcerated infantile hemangiomas and residual lesions, such as telangiectasias after the proliferative period.[83] Pulsed dye laser therapy helps with pain from ulcerative infantile hemangiomas. The use of pulsed dye laser therapy as an up-front treatment for infantile hemangiomas is controversial.
A Russian pilot study employed multiline laser equipment using the Nd:YAP Q-Sw/KTP emitters combined with two wavelengths of 1079/540 nm to treat patients with infantile hemangiomas.[84] Laser treatment was performed on 109 patients with 119 hemangiomas. Evaluation of posttreatment samples revealed restoration of normal color, skin relief, and the absence of scars.
A retrospective study in China included 180 patients with superficial hemangiomas who were treated with a 595-nm pulsed dye laser. The study reported that younger children (aged <2 months) received fewer treatments, had shorter courses of disease, and experienced better effects with fewer adverse events when compared with older children.[85]
Excisional surgery. With the advent of new medical treatments, the use of surgery is reserved for ulcerated lesions, residual lesions, large periocular lesions that interfere with vision, and facial lesions with aesthetic impact that do not respond to medical therapy.[86]
Propranolol, a nonselective beta-blocker, is first-line therapy for infantile hemangiomas. Early studies suggested that propranolol might act through inducing vasoconstriction and/or by decreasing expression of VEGF and bFGF, leading to apoptosis.[87,88] Subsequent studies indicate that the activity of propranolol for infantile hemangiomas is not secondary to beta blockade resulting from action of the S(-) enantiomer of propranolol but rather resulting from the ability of the R(+) enantiomer of propranolol to inhibit SOX18, a transcription factor that acts as a master regulator of vasculogenesis.[89–91] The R(+) enantiomer interferes with transcriptional activation by SOX18, disrupts SOX18-chromatin binding dynamics, and inhibits SOX18 dimer formation. These biochemical effects result in inhibition of hemangioma stem cell differentiation into endothelial cells and in inhibition of vasculogenesis.[91]
The use of propranolol was first noted in two infants treated for cardiac issues in Europe. A change in color, softening, and decrease in hemangioma size was noted. Since that time, the results of a randomized controlled trial have been reported.[92] In 2014, the U.S. Food and Drug Administration (FDA) approved Hemangeol, the pediatric formulation of propranolol hydrochloride, for the treatment of proliferating infantile hemangiomas. Generic propranolol remains in common use.
There are many other published reports about the efficacy and safety of propranolol.[93–97] Lack of response to treatment is rare. Propranolol therapy is usually used during the proliferative phase but has been effective in patients older than 12 months with infantile hemangiomas.[98]; [99][Level of evidence C3]
Evidence (propranolol therapy):
In a large industry-sponsored randomized trial, 456 infants aged 5 weeks to 5 months with proliferating infantile hemangiomas of at least 1.5 cm received either a placebo or propranolol (1 mg/kg per day or 3 mg/kg per day) for 3 or 6 months. After interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg/kg per day for 6 months was selected for the final efficacy analysis.[92][Level of evidence B3]
Of patients who received the selected regimen, 88% showed improvement by week 5, compared with 5% of patients who received the placebo.
Adverse events occurred infrequently.
A retrospective study of 635 infants with infantile hemangiomas who were treated with propranolol (2 mg/kg per day) had the following results:[97][Level of evidence C3]
The overall response rate was 91%, with most patients demonstrating regression.
Two percent of patients had side effects, none of which were severe.
A meta-analysis that evaluated 5,130 patients from 61 studies concluded that propranolol was more effective and safer than were other treatments for infantile hemangioma.[100]
Airway infantile hemangioma lesions are rare. A meta-analysis of 61 patients reported the following results:[101]
There was a trend in decreased treatment failure with increased dosing strategies, which is consistent with the use of higher doses of propranolol in these patients (3 mg/kg per day).
The analysis also suggested that the concurrent use of steroids and propranolol may have reduced efficacy in patients with segmental airway hemangiomas, but prior treatment with steroids had no deleterious effect.
Additional prospective studies are needed to validate these findings.
Diffuse (segmental) hemangiomas of the airway are very rare, and their clinical behavior is different from that of isolated airway lesions.
Intralesional administration of propranolol has been used for periorbital lesions in a limited capacity and showed no advantages over oral administration.[102][Level of evidence B3]
Several expert consensus panel recommendations have been reported, including recommendations from the FDA and the European Medicines Agency after a randomized controlled trial of oral propranolol in infantile hemangioma patients led to FDA approval.[103–105]
Considerations for the use of propranolol include the following:[103,105,106]
Initiation of treatment: Guidance from consensus panels suggested that treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. They suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[103]
Infant aged 4 weeks or younger (corrected for gestational age).
Infant of any age with inadequate social support.
Infant of any age with comorbid conditions affecting the cardiovascular or respiratory system, including symptomatic airway infantile hemangiomas.
Infant of any age with conditions affecting blood glucose maintenance.
The pretreatment evaluation (inpatient or outpatient) includes the following:
History, with focus on cardiovascular and respiratory abnormalities (e.g., poor feeding, dyspnea, tachypnea, diaphoresis, wheezing, heart murmur) and family history of heart block or arrhythmia.
Physical examination, including cardiac and pulmonary assessment and measurement of heart rate.
No need for echocardiogram or electrocardiogram for standard-risk patients. Two studies found no contraindication to beta-blocker therapy in 6.5% to 25% of patients who had electrocardiogram abnormalities.[106,107] Electrocardiogram should be considered in children with heart rate lower than normal for age and history of arrhythmia or arrhythmia detected during examination.
Family history of congenital heart disease or maternal history of connective tissue disease.
Dosing: According to the consensus panels, the dosing used is generally 1 mg/kg per day to 3 mg/kg per day divided into two or three doses. The starting dose varies depending on risk factors and location of initiation. Outpatients and inpatients are initially started at a dose of 0.5 mg/kg per day to 1 mg/kg per day and increased over time.[104–106] A retrospective review of initial dosing indicates a starting dose of 2 mg/kg may also be well tolerated. This initial dosing could decrease the need for up-titration and more frequent clinic visits, although prospective studies are needed.[108] Initially, dosing of three times per day is recommended for infants younger than 5 weeks and for patients with PHACE syndrome.[47,103]
Monitoring: Monitoring varies depending on the institution. However, oral propranolol peaks at 1 to 3 hours after administration and most centers measure heart rate and blood pressure 1 and 2 hours after each dose with initiation and then when the dose is increased by at least 0.5 mg/kg per day. Parent and patient education includes when to withhold the medication, signs of hypoglycemia, feeding necessity through the night, and when to call the physician with issues, such as illness, that may interfere with oral intake or lead to dehydration or respiratory problems.
A large retrospective multicenter study assessed the safety of outpatient administration of propranolol and evaluated the need for monitoring. In this study, 783 patients with 1,148 office visits were evaluated. No symptomatic bradycardia or hypotension was noted. Blood pressure evaluation was unreliable. The results suggested that outpatient evaluation may not be necessary for standard-risk patients with infantile hemangiomas.[109]
Contraindications: Propranolol treatment is contraindicated in infants and children with the following:[103–105]
Sinus bradycardia.
Hypotension.
Heart block greater than first degree.
Heart failure.
Asthma.
Hypersensitivity.
PHACE syndrome. PHACE syndrome with CNS arterial disease and/or coarctation of the aorta may be a relative contraindication. A retrospective multi-institutional study that investigated the safety of propranolol therapy for patients with PHACE syndrome identified 76 infants, including 12 patients who were at high risk of having a stroke.[110] The incidence of adverse events in these patients was similar to the incidence in 726 infants who received oral propranolol therapy for hemangioma but did not meet the criteria for PHACE syndrome. A decision to treat should be made in consultation with neurology/neurosurgery and cardiology.
Adverse effects of propranolol include the following:[111]
Hypoglycemia.
One study in Japan monitored hypoglycemia in infants with infantile hemangiomas who started treatment with propranolol.[112] After treatment with propranolol, the incidences of severe hypoglycemia and hypoglycemic convulsions were approximately 0.54% and 0.35%, respectively. The incidence of hypoglycemic convulsions appeared to be higher in Japan than in Western countries. Severe hypoglycemia was common in infants younger than 1 year when propranolol was used for 6 months or longer. Severe hypoglycemia often developed from 5:00 AM to 9:00 AM, and it was frequently associated with prolonged periods of fasting, poor feeding, or poor physical conditions.
Hypotension.
Bradycardia.
Sleep disturbance.
Diarrhea/constipation.
Cold extremities.
These complications have been reported in several studies, and severe complications have been rare.[111,113] The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.
A retrospective review of 1,260 children with infantile hemangiomas who were treated with propranolol identified 26 patients (2.1%) with side effects that required discontinuation of propranolol.[114] Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 patients received atenolol and 3 patients received prednisolone as second-line therapy. In the multivariate analysis, only younger age (95% confidence interval [CI], 1.201–2.793; P = .009) and lower body weight (95% CI, 1.036–1.972; P = .014) were associated with intolerable side effects.
Duration of treatment: There are no consensus guidelines for the treatment duration of propranolol. In a prospective, multi-institutional study that assessed efficacy and safety of propranolol in high-risk patients, the administration of propranolol for a minimum of 6 months, up to a maximum of age 12 months, increased treatment success; dosing of propranolol was 3 mg/kg per day. Treatment results were sustained for up to 3 months after discontinuation of therapy. Efficacy and safety of propranolol in this study were similar to those reported in other studies.[115]
Rebound growth after propranolol therapy: Rebound refers to the growth of infantile hemangiomas after propranolol cessation. A multi-institutional, retrospective review of 997 patients with infantile hemangiomas found a rebound rate of 25.3% in 912 patients with adequate data. On univariate analysis, the factors associated with rebound included discontinuation of treatment before age 9 months, female sex, location on the head or neck, segmental pattern, and deep or mixed skin involvement. On multivariate analysis, only deep infantile hemangiomas and female sex were significantly related.[116] A single-center retrospective review examined 198 patients with infantile hemangioma who underwent oral propranolol therapy. The study reported 35 patients (18%) with rebound growth 1 to 3 months after discontinuation of propranolol treatment. Of the 35 patients, 23 were re-treated with propranolol for up to 3 months. All patients had good responses.[117][Level of evidence C3]
Late growth of infantile hemangiomas: Hemangioma growth can occur in patients older than 3 years, and growth as late as age 8.5 years has been reported. Associated risk factors include segmental morphology, large hemangiomas, PHACE syndrome, and deep cutaneous and subcutaneous lesions in the head and neck.[118,119]
Selective and other beta-blocker therapy
Because of the nonselective and lipophilic nature of propranolol and its ability to cross the blood-brain barrier, other beta-blockers are being used for the treatment of infantile hemangiomas.
Evidence (beta-blocker therapy):
In two small comparison studies, there was no difference in efficacy between propranolol and atenolol.[120,121]
In support of a previous retrospective study, a prospective double-blind study compared nadolol with propranolol in 71 infants (aged 1–6 months).[122][Level of evidence A3]
The study demonstrated noninferiority with respect to efficacy and treatment.
A prospective study of 76 infants treated with atenolol noted efficacy and safety similar to propranolol.[123][Level of evidence C3]
In one published report, nadolol was associated with the death of an infant (aged 17 weeks) after 10 days of no stool output.[124] There is limited information about the pharmacokinetics and safety of nadolol in infants. The drug has a narrow therapeutic index, and it is excreted and remains unchanged in the feces. If an infant is given nadolol, it is critical to monitor for regular stool output.
Additional studies are needed to assess differences between the toxicities of these agents and the toxicities of propranolol.
There is some suggestion that the more selective beta-blockers have fewer side effects.[125] A study has suggested that the R(+) enantiomer of propranolol, carried over in drug synthesis rather than the anti–beta-adrenergic L(-) enantiomer (commercially available drug is a racemic mixture), may carry the therapeutic anti-infantile hemangioma effect.[89,90]
Corticosteroid therapy
Before propranolol, corticosteroids were the first line of treatment for infantile hemangiomas. They were first used in the late 1950s but were never approved by the U.S. FDA for this indication. Corticosteroid therapy has become less popular because of the acute and long-term side effects of steroids (gastrointestinal irritability, immunosuppression, adrenocortical suppression, cushingoid features, and growth failure).
Corticosteroids (prednisone or methylprednisolone) are used at times when there is a contraindication to beta-blocker therapy or as initial treatment while a patient is started on beta-blocker therapy.[126]
Topical beta-blocker therapy
Topical beta-blockers are used mainly for the treatment of small, localized, superficial hemangiomas as an alternative to observation. They have also been used in combination with systemic therapy in complicated hemangiomas or to prevent rebound in hemangiomas being tapered off of systemic treatment.[127–129] The same precautions (assessment of comorbidities and family history), as noted previously for propranolol, should be followed for topical beta-blockers. Systemic absorption (plasma and urine) of timolol is variable and prescreening for normal cardiac, pulmonary, and endocrine issues are essential. Recent medical histories and physical examinations are also important. Cautious administration is necessary for ulcerated and deep hemangiomas because higher plasma concentrations of timolol can be seen.[130,131]
The topical timolol that is used is the ophthalmic gel-forming solution 0.5%. One drop is applied to the hemangioma two times per day until stable response is achieved.
This treatment has limited side effects, but infants with a postmenstrual age of younger than 44 weeks and weight at treatment initiation of less than 2,500 grams may be at risk of adverse events, including bradycardia, hypotension, apnea, and hypothermia.[131,132] Close monitoring of temperature, blood pressure, and heart rate in premature and low birth weight infants with infantile hemangiomas at initiation of and during therapy with topical timolol is necessary.
Evidence (topical timolol therapy):
A retrospective cohort study included 666 patients with infantile hemangioma who were treated with topical timolol for 12 months.[133]
Of these patients, 583 (87.5%) had visible reductions in the size of their lesions.
A total of 188 children (28.2%) had excellent responses (no remaining visible abnormality), 127 of whom had complete responses earlier than 12 months.
Of the remaining patients, 292 (43.8%) had good outcomes (i.e., the hemangioma was less than half its original size), while 103 (15.5%) had fair outcomes (i.e., a visibly smaller hemangioma but not less than half its original size), and 83 (12.5%) had poor outcomes (i.e., there was no change in hemangioma size or it was larger).
Patients aged 3 months and younger were more likely to have better outcomes than those older than 3 months (P < .001).
Patients with small infantile hemangiomas (maximum diameter, 1.5–≤5 cm) also had better outcomes than those with large infantile hemangiomas (5–≤10 cm) (P = .046).
In a multicenter, retrospective, cohort study, 731 children with predominantly superficial hemangiomas were treated with topical timolol 0.5% twice daily.[129]
Ninety-two percent of patients showed significant improvement in hemangioma color.
Seventy-seven percent of patients showed improvement in hemangioma size, extent, and volume.
Topical timolol is generally well tolerated; however, data on its safety are limited.
A Spanish consortium performed a prospective randomized trial to evaluate the efficacy and safety of topical timolol for the treatment of infantile hemangioma in the early proliferative stage.[134] This multicenter, randomized, double-blind, placebo-controlled, phase IIa pilot clinical trial included patients aged 10 to 60 days with focal or segmental hemangiomas (superficial, deep, mixed, or minimal/arrested growth). Patients were randomly assigned to treatment with either topical timolol maleate solution, 0.5%, or placebo, twice daily for 24 weeks.
At 24 weeks, there were no significant differences between the timolol treatment and the placebo for complete or nearly complete infantile hemangioma resolution (42% for timolol [n = 11] vs. 36% for placebo [n = 11]; P = .37).
Combined therapy for complicated hemangiomas
Combined therapy is considered either at initiation of treatment in complicated lesions in which there is functional impairment or organ compromise or used at the end of systemic therapy to prevent hemangioma rebound. Further investigation of efficacy and safety is needed for these regimens.
Evidence (combined therapy for complicated hemangiomas):
A prospective randomized study that compared propranolol and 2 weeks of steroid therapy with propranolol alone revealed the following:[135]
Decreased sizes of hemangiomas at 2, 4, and 8 weeks in the combined-therapy group but no statistical difference in the sizes at 6 months.
A prospective randomized study that compared timolol and propranolol with propranolol alone reported the following:[136]
Decreased color of the infantile hemangiomas in the timolol group but no difference in overall sizes of the infantile hemangiomas between the two treatment groups.
Treatment options under clinical evaluation for infantile hemangiomas
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
In response to the COVID-19 pandemic, the Hemangioma Investigator Group is studying the administration of propranolol for low-risk and standard-risk patients through virtual visits.[139]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Congenital Hemangiomas
Clinical features and diagnostic evaluation
Congenital hemangiomas can be difficult to diagnose, especially for clinicians who are unfamiliar with these lesions. Diagnostic criteria include a purpuric lesion fully formed at birth, frequently with a halo around the lesion, with high flow noted on ultrasound imaging. Essential to the diagnosis is serial observation for decrease or, at least stability, in size over time. These lesions do not enlarge unless there is hemorrhage into the tumor.
Congenital hemangiomas are divided into the following three forms:
Rapidly involuting congenital hemangiomas (RICH). These lesions are large high-flow lesions that are completely formed at birth but rapidly involute by age 12 to 15 months. They can ulcerate and bleed and can cause transient heart failure and mild coagulopathy. After involution, usually some residual changes in the skin are present (see Figure 5).[140–143]
In a retrospective case series of congenital hemangiomas, several high-risk ultrasound findings were noted for RICH. Venous lakes were associated with cardiac failure, and an increased risk of bleeding was noted with venous lakes and venous ectasia. Infants with RICH should be evaluated with ultrasonography and monitored closely if these high-risk features are noted.[144]
EnlargeFigure 5. Typical appearance of a cutaneous congenital hemangioma at birth. Note the pedunculated mass. This RICH lesion involuted over time but some residual skin changes remained. Credit: Denise Adams, M.D.
Partial involuting congenital hemangiomas (PICH). These lesions are completely formed at birth and involute only partially.[145]
Non-involuting congenital hemangiomas (NICH). These lesions are formed at birth and never involute. Depending on the location of the lesions and whether they cause functional impairment, the lesions may need to be removed surgically.[146,147]
Histopathology and molecular features
Congenital hemangiomas are benign vascular tumors that proliferate in utero. Development of these lesions is complete at birth. Histologically, these lesions are GLUT1 negative, unlike infantile hemangiomas. They are usually cutaneous, but can be found in the viscera. Complications include hemorrhage, transient heart failure, and transient coagulopathy.[148]
Somatic activating variants of GNAQ and GNA11 have been found to be associated with congenital hemangiomas.[149] Additional research is necessary to assess the significance of these findings, as this may aid in diagnosis and pathophysiology.
Hepatic Vascular Tumors
With the development of the new WHO and ISSVA classifications, the terminology of pediatric hepatic vascular tumors (HVT) has changed.[150–152] The historical Dehner classification of types 1, 2, and 3 liver hemangioendothelioma is no longer favored by pathologists.[153] The term hemangioendothelioma is not considered an isolated entity.
On MRI, vascular tumors of the liver are hyperintense on T2 imaging and hypointense on T1 imaging, with postcontrast imaging demonstrating early peripheral enhancement with eventual diffuse enhancement.[76] In practice, these tumors have been classified according to their clinical characteristics and radiological assessment.[76,154] In general, hepatic vascular tumors can be benign or malignant.
The differential diagnosis of vascular liver lesions always includes malignant liver tumors. Thus, alpha-fetoprotein (AFP) measurements should be included in the initial lab work. AFP is very high in all newborns but will rapidly fall to normal levels in several months. AFP levels should rapidly diminish, but failure to do so or a rising trend of AFP should elicit concern for a hepatoblastoma. There are no prospective studies investigating AFP elevation in patients with hemangiomas.[155,156] Some hypervascular hepatoblastomas in neonates with congestive heart failure have been mistaken for infantile hemangiomas. Other tumors in the differential diagnosis include angiosarcomas, metastatic neuroblastomas, and mesenchymal hamartomas. If there is any question about the diagnosis, a biopsy is recommended, although bleeding is a risk of the procedure.[157]
Benign hepatic vascular tumors
These lesions are usually divided into the following three categories:[76,154]
A more appropriate classification uses an interdisciplinary evaluation, including pathological classification with genomic assessment, radiological imaging evaluation, and clinical history and examination. This is based on the ISSVA and WHO classifications. A study analyzed clinicopathologic characteristics in 33 cases of pediatric hepatic vascular tumors diagnosed between 1970 and 2021.[158] Thirteen cases were identified as hepatic congenital hemangiomas. All were single lesions, and most of these were RICH. Ten patients had hepatic infantile hemangiomas. Three patients had hepatic angiosarcoma, and one patient had hepatic epithelioid hemangioendothelioma. Six patients were excluded from the study, five with vascular malformations and one with vascular dominant mesenchymal hamartoma. The study revealed the importance of an interdisciplinary team approach in the assessment of these tumors.
Congenital hemangiomas
Focal lesions of the liver are usually congenital hemangiomas (RICH or NICH, rarely PICH) (see Figure 6). RICH can present with symptoms of heart failure and mild to moderate coagulopathy but are typically detected by antenatal ultrasonography or as an asymptomatic mass in the newborn period.
Treatment options for focal vascular lesions of the liver include the following:
Supportive management. Most lesions are asymptomatic and can be monitored through involution using ultrasonography.
Embolization. This procedure is considered for severe symptomatic shunting that is unresponsive to treatment for congestive heart failure. These procedures need to be performed by interventional radiologists with expertise in vascular anomalies.[159]
Surgery. Patients with massive focal symptomatic hepatic congenital hemangioma unresponsive to supportive management or radiological intervention may be candidates for surgical resection. This is a rare circumstance and needs to be evaluated by an interdisciplinary vascular anomaly team. Indication for surgical removal includes rupture, bleeding, and nonresolving coagulopathy. Two patients were reported to require surgical resection after the development of clinically significant ascites as their RICH involuted.[160,161]
No medication has proven to be an effective treatment for these lesions, and infants need to be supported during the initial period until involution begins.[76,154] These lesions may be diagnosed prenatally. In rare situations, maternal treatment with medications such as steroids appeared to be effective but, more likely, natural involution may have been responsible.[162]
EnlargeFigure 6. Single liver lesion (intrahepatic congenital hemangioma). MRI image of a congenital hemangioma. Note the central enhancement, which is typical for an intrahepatic congenital hemangioma. Credit: Denise Adams, M.D.
Infantile hemangiomas
Multifocal hepatic lesions are infantile hemangiomas. Multifocal lesions may not need to be treated if the patient is asymptomatic. These lesions typically follow the same proliferative and involution course as cutaneous hemangiomas.[76,154] These lesions are monitored closely and if there is growth, propranolol therapy should be considered. If propranolol is needed, doses of up to 2 mg/kg per day are effective.
Diffuse hepatic infantile hemangiomas
Diffuse liver lesions are very serious (see Figure 7). Complications include hypothyroidism caused by the expression of iodothyronine deiodinase, high-output or congestive heart failure, and abdominal compartment syndrome.[75,76,163,164]
EnlargeFigure 7. Diffuse liver lesions with classical imaging on CT. Note the peripheral enhancement in early contrast phase. Credit: Denise Adams, M.D.
Treatment options for diffuse liver lesions may include the following:
Propranolol: Beta-blockers are the most common treatment for diffuse and some multifocal infantile hemangiomas of the liver. Treatment doses of 2 to 3 mg/kg per day are indicated.[92]
Thyroid hormone replacement: Thyroid hormone replacement therapy must be aggressive if hypothyroidism is diagnosed. Treatment with higher doses of hormones may be needed because the deficiency is caused by the aggressive consumption of the hormone by the tumor.[78]
Chemotherapy: Steroids, cyclophosphamide, and vincristine have been used to treat diffuse liver infantile hemangioma.[76,165,166]
Liver transplant: If a patient does not respond to medical management, a transplant may be indicated.[167] Transplant is considered only for patients with severe diffuse lesions who have multisystem organ failure and there is insufficient time for effective pharmacologic therapy.
Malignant hepatic vascular tumors
There have been isolated reports of malignancy in patients with diffuse hepatic infantile hemangiomas.[168,169] It is not clear that all cases were caused by the transformation of a benign lesion to a malignant phenotype. However, if the lesion does not respond to standard therapy, biopsy should be considered. Further evaluation and consensus is needed to assess whether these patients need to be monitored over a longer period of time with liver ultrasonography. For more information, see the Angiosarcoma section.
Hepatic angiosarcoma
Hepatic angiosarcoma (HA) in children is extremely rare, and there are approximately 80 cases reported in the medical literature. There is a female predilection, and the median age at diagnosis is 40 months. Hepatic angiosarcomas present rapidly and are diagnosed by histopathology (see Table 4). These malignant tumors are treated with chemotherapy, embolization, antiangiogenic agents, and liver transplant (for those without metastases). Patients have a poor prognosis.[170] For more information, see the Angiosarcoma section.
Hepatic epithelioid hemangioendothelioma
Hepatic epithelioid hemangioendothelioma is a very rare tumor in the liver, especially in children. There is also a female predilection, and it occurs most frequently in young adults. This tumor may often involve extrahepatic disease, reportedly in over one-third of patients. It presents similarly to other hepatic tumors, with hepatomegaly and abdominal pain. However, hepatic epithelioid hemangioendothelioma behaves more moderately than hepatic angiosarcoma, and patients with hepatic epithelioid hemangioendothelioma have better outcomes.
Imaging is very helpful in diagnosing hepatic epithelioid hemangioendothelioma. In addition to a hypoechoic lesion on ultrasonography, ultrasonography with contrast or MRI with contrast show a typical target sign, due to concentric filling of the tumor. This is thought to be due to concentric areas of necrosis and alternating areas of dense, active tumor cells. In addition, hepatic epithelioid hemangioendothelioma is known for avid glucose uptake. The use of fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET), with computed tomography (CT) or MRI (PET-CT/PET-MRI), is helpful in confirming the diagnosis and determining organ involvement since these tumors often have extrahepatic disease. This imaging modality is also helpful in monitoring patients for disease recurrence after intervention. Ultimately, histopathological diagnosis is the preferred method, and these tumors exhibit both epithelioid and histiocytic/dendritic cells and a characteristic immunohistochemistry pattern in tumor samples (see Table 4).[171]
Treatment of hepatic epithelioid hemangioendothelioma is primarily surgical resection, either hepatectomy or liver transplant. Interventional procedures can also be used. Studies are evaluating whether incorporating chemotherapy into the treatment plan improves outcomes.[171]
Table 4. Distinguishing Features of Pediatric Hepatic Vascular Tumorsa
Clinical presentation, molecular features, and histopathology
Spindle cell hemangiomas, initially called spindle cell hemangioendotheliomas, often occur as superficial (skin and subcutis), painful lesions involving distal extremities in children and adults.[172,173] The tumors appear as red-brown or bluish lesions that can begin as a single nodule and develop into multifocal painful lesions over years. The hemangiomas are well circumscribed, occasionally contain phleboliths, and consist of cavernous blood spaces alternating with areas of nodular spindle cell proliferation. A significant percentage of spindle cell hemangiomas are completely intravascular. The vein containing the tumor is abnormal, as are blood vessels apart from the tumor mass.[174,175]
Spindle cell hemangiomas can be seen in patients with Maffucci syndrome (cutaneous spindle cell hemangiomas occurring with cartilaginous tumors, enchondromas) and Klippel-Trénaunay syndrome (capillary/lymphatic/venous malformations), generalized lymphatic anomalies, lymphedema, and organized thrombus.[174,175] In Maffucci syndrome, spindle cell hemangiomas are associated with IDH1 or IDH2 variants.[176]
Treatment of spindle cell hemangioma
There is no standard treatment for spindle cell hemangioma because it has not been studied in clinical trials. Surgical removal is usually curative, although there is a risk of recurrence.[174,175]
Epithelioid Hemangioma
Clinical presentation and histopathology
Epithelioid hemangiomas (EH) are benign lesions that usually occur in the skin and subcutis but can occur in other areas such as the bone, with focal and multifocal lesions.[174,177] Epithelioid hemangiomas may be a reactive process, as they can be associated with local trauma and can develop in pregnancy. Patients usually present with local swelling and pain at the involved site. In the bone, they present as well-defined lytic lesions that involve the metaphysis and diaphysis of long bones.[174,178] They can have a mixed lytic and sclerotic pattern of bone destruction.
On pathological evaluation, epithelioid hemangiomas have small caliber capillaries with eosinophilic, vacuolated cytoplasm and large oval, grooved, and lobulated nuclei. The endothelial cells are plump and are mature, well-formed vessels surrounded by multiple epithelioid endothelial cells within abundant cytoplasm. They lack cellular atypia and mitotic activity.[174,177–179]
In a study of 58 cases of epithelioid hemangiomas, 29% were found to have FOS gene rearrangements. FOS gene rearrangements were noted more often in cellular epithelioid hemangiomas and intraosseous lesions compared with lesions in the skin, soft tissue, and head and neck. This genetic abnormality can be helpful in distinguishing epithelioid hemangiomas from other malignant epithelioid vascular tumors.[179]
A single-institution report reviewed 11 patients with epithelioid hemangiomas (median age, 14.4 years) who were diagnosed between 1999 and 2017. Lesions occurred in the lower extremities (five patients), skull (three patients), pelvis (two patients), and spine (one patient). Five patients had multifocal disease. Patients presented with localized pain and neurological symptoms, including cranial nerve injury. No significant cytological atypia was noted, and the endothelial cells were positive for CD31 and ERG, and negative for cytokeratin and CAMPTA1. Median follow-up was 1.5 years. Various modalities of treatments were used, including surgery, endovascular embolization, cryoablation, and medical management. One patient received sirolimus, and another patient received interferon; the lesions of both patients shrank within the first year of follow-up. The youngest patient, aged 2.5 years, had multifocal skull lesions that partially regressed 1 year later without treatment.[180]
Treatment of epithelioid hemangioma
There is no standard treatment for epithelioid hemangioma because it has not been studied in clinical trials. Treatment usually consists of curettage, sclerotherapy, or resection. In rare cases, radiation therapy may be used.[174,178]
Pyogenic Granuloma (Lobular Capillary Hemangioma)
Clinical presentation, histopathology, and molecular features
Pyogenic granulomas (PG), known as lobular capillary hemangiomas, are benign reactive lesions. Pyogenic granulomas can present at any age—including at birth (congenitally), during the neonatal period, during infancy, or during pregnancy—although they are most common in older children and young adults. These lesions can arise spontaneously, in sites of trauma, or within capillary and arteriovenous malformations. Pyogenic granulomas have also been associated with medications including oral contraceptives and retinoids.
Pyogenic granulomas occur as solitary growths, but multiple (grouped) or rarely disseminated lesions have been described.[181] These lesions appear as small or large, smooth or lobulated vascular nodules that can grow rapidly, sometimes over weeks to months and have a tendency to bleed profusely. These lesions are usually cutaneous, but deep-seated/subcutaneous pyogenic granulomas have been reported and mimic other vascular lesions.[182] Histologically, these lesions are composed of capillaries and venules with plump endothelial cells separated into lobules by fibromyxoid stroma. Some untreated lesions eventually atrophy, become fibromatous, and slowly regress. A retrospective review of a series of eight children with disseminated congenital or neonatal pyogenic granulomas reported the occurrence of hemorrhagic central nervous system lesions in seven patients, five of whom developed neurological sequelae. Four of the eight patients had transient coagulopathy.[183][Level of evidence C2]
The pathogenesis of pyogenic granulomas associated with capillary malformations and those that are sporadic are unknown. A study investigated ten patients with pyogenic granulomas arising from a capillary malformation and found eight with BRAF c.1799T>A variants, one with an NRAS c.182A>G variant, and one with a GNAQ c.548G>A variant. This GNAQ variant was also found in the underlying capillary malformation. In 25 patients with pyogenic granulomas and no capillary malformation, 3 patients had BRAF c.1799T>A variants and 1 patient had a KRAS c.37G>C variant. These genetic findings will help with future treatment modalities for this benign vascular tumor.[184]
Treatment of pyogenic granuloma
Full-thickness excision is the treatment with the lowest recurrence rate (around 3%),[185] but curettage, laser photocoagulation, or cryotherapy can also be used.[186] Topical timolol and propranolol have also been used.
Evidence (topical beta-blockers):
In a single-arm series of patients with acquired ocular pyogenic granulomas, a small number of pediatric patients were treated for 21 days to 6 weeks with twice-daily topical timolol, 0.5%.[187,188][Level of evidence C3]
Complete or near-complete responses without subsequent recurrence or progression were noted in 75% to 100% of the patients (all ages).
A study of 22 patients with cutaneous pyogenic granulomas who were treated with topical 1% propranolol ointment with occlusion had the following results:[189]
Fifty-nine percent of patients achieved complete responses (mean, 66 days), 18% of patients had stable disease, and 22% of patients did not respond to the treatment.
In this study, only skin toxicity was assessed.
The authors did not comment on the penetrance of the propranolol formulation or include a safety evaluation of the side effects such as hypoglycemia and the effects on heart rate or blood pressure.
Angiofibroma
Clinical presentation
Angiofibromas are rare, benign neoplasms in the pediatric population. Typically, they are cutaneous lesions associated with tuberous sclerosis, appearing as red papules on the face.
Treatment of angiofibroma
Excision of the tumor, laser treatments, and topical treatments, such as sirolimus, have been used.[190–192]
Evidence (topical sirolimus):
A prospective, randomized, placebo-controlled trial of nine cancer centers that included 62 patients who received sirolimus gel demonstrated the following results:[193]
Sixty percent of patients who received sirolimus showed significant improvement in the size and color of the lesion, which was assessed at week 12.
In another prospective, multicenter, randomized, double-blind, vehicle-controlled study that included six monthly clinic visits, 179 patients with tuberous sclerosis complex–related facial angiofibromas were treated with topical rapamycin (sirolimus) 0.3 g per 30 g (1%).[194]
According to the Angiofibroma Grading Scale, patients who were treated with topical rapamycin showed a statistically and clinically significant improvement in facial angiofibromas.
Juvenile Nasopharyngeal Angiofibroma
Clinical presentation and histopathology
Juvenile nasopharyngeal angiofibromas (JNA) account for 0.5% of all head and neck tumors.[195] They typically occur in peri-pubertal males. While juvenile nasopharyngeal angiofibromas have not classically been included among vascular tumors, histologically, these tumors appear to be vascular tumors, with cells expressing vascular endothelial marker CD31, VEGFA, and VEGFR1.
Despite their benign-appearing histology, juvenile nasopharyngeal angiofibromas can be locally destructive, spreading from the nasal cavity to the nasopharynx, paranasal sinuses, and orbit skull base, with intracranial extension. Some publications have suggested a hormonal influence on juvenile nasopharyngeal angiofibromas, with emphasis on the molecular mechanisms involved.[196,197] Nineteen patients with clinico-radiologically diagnosed primary juvenile nasopharyngeal angiofibromas underwent gallium Ga 68-[DOTA, 1-Nal3]-octreotide (68Ga-DOTANOC) PET-CT scans.[198] The rationale for using this scan was the high expression of somatostatin receptors (SSTRs) in these tumors. DOTANOC expression was noted in all 19 cases of primary juvenile nasopharyngeal tumors (100%). The mean DOTANOC maximum standardized uptake value ratio of tumor and background was 6.9 (±1.4) (range, 3.8–9.5). Intracranial extension in 13 of 19 patients was prominently visualized because of the absence of DOTANOC uptake in the brain. The authors suggested that these findings open possibilities for physiological diagnostic imaging, with a promise of greater specificity and sensitivity. This scan may be applicable in ambivalent diagnostic situations, such as the detection of recurrence.
Treatment of juvenile nasopharyngeal angiofibroma
Surgical excision is the treatment of choice, but this can be challenging because of the extent of the lesion. A single-institution retrospective review of juvenile nasopharyngeal angiofibromas identified 37 patients with lateral extension.[199] Anterior lateral extension to the pterygopalatine fossa occurred in 36 patients (97%) and further to the infratemporal fossa in 20 patients (54%). In 16 patients (43%), posterior lateral spread was observed (posterior to the pterygoid process and/or between its plates). The recurrence rate was 29.7% (11 of 37 patients). The recurrence rate in patients with anterior and/or posterior lateral extension was significantly higher than in patients with anterior lateral extension only.
Juvenile nasopharyngeal angiofibromas have also been treated with radiation therapy, chemotherapy, alpha-interferon therapy, and sirolimus.[200–204]
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Wasserman JD, Mahant S, Carcao M, et al.: Vincristine for successful treatment of steroid-dependent infantile hemangiomas. Pediatrics 135 (6): e1501-5, 2015. [PUBMED Abstract]
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Sundar Alagusundaramoorthy S, Vilchez V, Zanni A, et al.: Role of transplantation in the treatment of benign solid tumors of the liver: a review of the United Network of Organ Sharing data set. JAMA Surg 150 (4): 337-42, 2015. [PUBMED Abstract]
Jeng MR, Fuh B, Blatt J, et al.: Malignant transformation of infantile hemangioma to angiosarcoma: response to chemotherapy with bevacizumab. Pediatr Blood Cancer 61 (11): 2115-7, 2014. [PUBMED Abstract]
Rutten C, Ackermann O, Lambert V, et al.: Pediatric hepatic hemangiomas: spectrum and prognostic significance of initial ultrasound findings. Pediatr Radiol 53 (12): 2446-2457, 2023. [PUBMED Abstract]
Kou K, Chen YG, Zhou JP, et al.: Hepatic epithelioid hemangioendothelioma: Update on diagnosis and therapy. World J Clin Cases 8 (18): 3978-3987, 2020. [PUBMED Abstract]
Perkins P, Weiss SW: Spindle cell hemangioendothelioma. An analysis of 78 cases with reassessment of its pathogenesis and biologic behavior. Am J Surg Pathol 20 (10): 1196-204, 1996. [PUBMED Abstract]
Fletcher CD, Beham A, Schmid C: Spindle cell haemangioendothelioma: a clinicopathological and immunohistochemical study indicative of a non-neoplastic lesion. Histopathology 18 (4): 291-301, 1991. [PUBMED Abstract]
Enjolras O, Mulliken JB, Kozakewich HPW: Vascular tumors and tumor-like lesions. In: Mulliken JB, Burrows PE, Fishman SJ, eds.: Mulliken & Young’s Vascular Anomalies: Hemangiomas and Malformations. 2nd ed. Oxford University Press, 2013, pp 259-324.
Hoeger PH, Colmenero I: Vascular tumours in infants. Part I: benign vascular tumours other than infantile haemangioma. Br J Dermatol 171 (3): 466-73, 2014. [PUBMED Abstract]
Pansuriya TC, van Eijk R, d’Adamo P, et al.: Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 43 (12): 1256-61, 2011. [PUBMED Abstract]
Guo R, Gavino AC: Angiolymphoid hyperplasia with eosinophilia. Arch Pathol Lab Med 139 (5): 683-6, 2015. [PUBMED Abstract]
O’Connell JX, Nielsen GP, Rosenberg AE: Epithelioid vascular tumors of bone: a review and proposal of a classification scheme. Adv Anat Pathol 8 (2): 74-82, 2001. [PUBMED Abstract]
Huang SC, Zhang L, Sung YS, et al.: Frequent FOS Gene Rearrangements in Epithelioid Hemangioma: A Molecular Study of 58 Cases With Morphologic Reappraisal. Am J Surg Pathol 39 (10): 1313-21, 2015. [PUBMED Abstract]
Liu KX, Duggan EM, Al-Ibraheemi A, et al.: Characterization of long-term outcomes for pediatric patients with epithelioid hemangioma. Pediatr Blood Cancer 66 (1): e27451, 2019. [PUBMED Abstract]
Putra J, Rymeski B, Merrow AC, et al.: Four cases of pediatric deep-seated/subcutaneous pyogenic granuloma: Review of literature and differential diagnosis. J Cutan Pathol 44 (6): 516-522, 2017. [PUBMED Abstract]
Alomari MH, Kozakewich HPW, Kerr CL, et al.: Congenital Disseminated Pyogenic Granuloma: Characterization of an Aggressive Multisystemic Disorder. J Pediatr 226: 157-166, 2020. [PUBMED Abstract]
Groesser L, Peterhof E, Evert M, et al.: BRAF and RAS Mutations in Sporadic and Secondary Pyogenic Granuloma. J Invest Dermatol 136 (2): 481-6, 2016. [PUBMED Abstract]
Lee J, Sinno H, Tahiri Y, et al.: Treatment options for cutaneous pyogenic granulomas: a review. J Plast Reconstr Aesthet Surg 64 (9): 1216-20, 2011. [PUBMED Abstract]
Patrizi A, Gurioli C, Dika E: Pyogenic granulomas in childhood: New treatment modalities. Dermatol Ther 28 (5): 332, 2015 Sep-Oct. [PUBMED Abstract]
Oke I, Alkharashi M, Petersen RA, et al.: Treatment of Ocular Pyogenic Granuloma With Topical Timolol. JAMA Ophthalmol 135 (4): 383-385, 2017. [PUBMED Abstract]
Jaiswal H, Patidar N, Shah C, et al.: Topical timolol 0.5% as the primary treatment of ophthalmic pyogenic granuloma: A prospective, single-arm study. Indian J Ophthalmol 69 (5): 1155-1160, 2021. [PUBMED Abstract]
Neri I, Baraldi C, Balestri R, et al.: Topical 1% propranolol ointment with occlusion in treatment of pyogenic granulomas: An open-label study in 22 children. Pediatr Dermatol 35 (1): 117-120, 2018. [PUBMED Abstract]
Haemel AK, O’Brian AL, Teng JM: Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol 146 (7): 715-8, 2010. [PUBMED Abstract]
Pignatti M, Spaggiari A, Sala P, et al.: Laser treatment of angiofibromas in tuberous sclerosis. Minerva Pediatr 66 (6): 585-6, 2014. [PUBMED Abstract]
Lee YI, Lee JH, Kim DY, et al.: Comparative Effects of Topical 0.2% Sirolimus for Angiofibromas in Adults and Pediatric Patients with Tuberous Sclerosis Complex. Dermatology 234 (1-2): 13-22, 2018. [PUBMED Abstract]
Wataya-Kaneda M, Ohno Y, Fujita Y, et al.: Sirolimus Gel Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex: A Randomized Clinical Trial. JAMA Dermatol 154 (7): 781-788, 2018. [PUBMED Abstract]
Koenig MK, Bell CS, Hebert AA, et al.: Efficacy and Safety of Topical Rapamycin in Patients With Facial Angiofibromas Secondary to Tuberous Sclerosis Complex: The TREATMENT Randomized Clinical Trial. JAMA Dermatol 154 (7): 773-780, 2018. [PUBMED Abstract]
Coutinho-Camillo CM, Brentani MM, Nagai MA: Genetic alterations in juvenile nasopharyngeal angiofibromas. Head Neck 30 (3): 390-400, 2008. [PUBMED Abstract]
Liu Z, Wang J, Wang H, et al.: Hormonal receptors and vascular endothelial growth factor in juvenile nasopharyngeal angiofibroma: immunohistochemical and tissue microarray analysis. Acta Otolaryngol 135 (1): 51-7, 2015. [PUBMED Abstract]
Sakthivel P, Kumar R, Arunraj ST, et al.: 68 Ga DOTANOC PET/CT Scan in Primary Juvenile Nasopharyngeal Angiofibroma – A Pilot Study. Laryngoscope 131 (7): 1509-1515, 2021. [PUBMED Abstract]
Szymańska A, Szymański M, Czekajska-Chehab E, et al.: Two types of lateral extension in juvenile nasopharyngeal angiofibroma: diagnostic and therapeutic management. Eur Arch Otorhinolaryngol 272 (1): 159-66, 2015. [PUBMED Abstract]
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Intermediate Tumors (Locally Aggressive)
Kaposiform Hemangioendothelioma and Tufted Angioma
Kaposiform hemangioendothelioma (KHE) and tufted angioma are rare vascular tumors that typically occur during infancy or early childhood but have been reported in adults. Both tumors are thought to be a spectrum of the same disease, because both can be locally aggressive and cause Kasabach-Merritt phenomenon, a serious life-threatening coagulopathy characterized by profound thrombocytopenia and hypofibrinogenemia. They are discussed here as a single entity, kaposiform hemangioendothelioma.
Incidence
The exact incidence of kaposiform hemangioendothelioma is unknown but is estimated to be 0.07 cases per 100,000 children per year.[1–3] This lesion affects both sexes equally, with most developing in the neonatal period, one-half presenting at birth, and others presenting during childhood or adulthood.[4]
Clinical presentation
Kaposiform hemangioendothelioma most frequently involves the extremities and less frequently involves the trunk and head and neck area.[3] Most lesions involve the skin (see Figure 8). Deeper lesions (retroperitoneum, thoracic cavity, and muscle) can appear as a bluish-purpuric hue on the skin, whereas superficial lesions can be firm, purpuric or ecchymotic, and painful. Primary bone lesions may cause pain or other nonspecific findings, even without an obvious mass on physical examination.[5][Level of evidence C2] Lesions are usually unifocal and growth is expansive and contiguous. Local lymph nodes may be involved, but there are no reports of distant metastasis. Rare multifocal presentations have been reported, mostly in the bone.[1–3]
EnlargeFigure 8. Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon. The lesion is indurated, firm, and warm with petechiae and purpura. Credit: Denise Adams, M.D.
Fifty to seventy percent of patients with kaposiform hemangioendothelioma develop Kasabach-Merritt phenomenon (KMP), which is a life-threatening complication. The risk of developing Kasabach-Merritt phenomenon is highest in patients with congenital lesions, lesions larger than 6 to 8 cm, deeper lesions, and when kaposiform hemangioendothelioma arises in the retroperitoneum or mediastinum.[3,6,7] This condition is characterized by profound thrombocytopenia (range, 3,000/µL–60,000/µL) and hypofibrinogenemia (<1 g/L). D-dimer and fibrin degradation products are elevated. Severe anemia can occur secondary to tumor sequestration. Severe hemorrhage is rare; however, trauma (biopsy, surgical procedure), ulceration, infection, or delay in initiating treatment may induce progression to disseminated intravascular coagulation, serious bleeding, and even death. Aggressive replacement of blood products, especially platelets, can increase the size of the lesion, causing significant pain and should only be considered with active bleeding and under the direction of a vascular anomalies specialist.[3] The mortality rate is unclear but it has been reported to be as high as 30%.[3,6]
Histopathology
Kaposiform hemangioendothelioma is characterized by sheets of spindle cells with an infiltrative pattern in the dermis, subcutaneous fat, and muscle. There are often areas of fibrosis, with dilated thin-walled vessels infiltrated around the areas of spindle cells. Mixed within these areas are nests of rounded epithelioid cells of vascular origin and aggregates of capillaries with round or irregularly shaped lumens containing platelet-rich fibrin thrombi. There are usually abnormal lymphatic spaces, either within or at the periphery of the lesion. The rate of mitosis is usually low but can be variable. Tufted angioma is characterized by multiple, discrete lobules of tightly packed capillaries (tufts) scattered in the dermis and sometimes in the subcutis, a so-called cannonball pattern.[8] Mitoses are rare.
The pathogenesis is poorly understood. There is some evidence that kaposiform hemangioendothelioma may be derived from lymphatic endothelium, as the spindle cell expresses the vascular markers CD31 and CD34, the vascular endothelial growth factor receptor-3 (VEGFR-3) (a receptor required for lymphangiogenesis), and the lymphatic markers D2-40 and PROX1.[8–10] There is no evidence of association with human herpesvirus 8 infection as is present in Kaposi sarcoma.[10]
Genomic data are limited. There have been reports of a small number of patients with GNA14 variants but not in all cases.[11,12]
High serum levels of angiopoietin-2 (Ang-2) have been found in high-risk patients with kaposiform hemangioendothelioma and kaposiform lymphangiomatosis. The Ang-2 levels have also been noted to decrease in response to therapy with sirolimus, which raises the possibility of an effect on the endothelial cells of the kaposiform hemangioendothelioma tumor.[13] Ang-2 is produced and stored in the endothelial cells and acts as a TEK tyrosine kinase antagonist. Ang-2 can promote neovascularization in conjunction with VEGF, and in humans, Ang-2 is greatly increased in vascular remodeling that occurs with sepsis, inflammation, and lymphangiogenesis.[14] These levels have been used for the diagnosis of vascular tumors and assessment of response to therapy.
Diagnostic evaluation
The diagnosis is based on the combination of clinical, histological, and imaging features. Laboratory evaluation is essential for the diagnosis of Kasabach-Merritt phenomenon. Whenever possible, histological confirmation should be obtained, because prolonged therapy is often needed. However, if clinical and imaging findings are highly suggestive of the diagnosis, deferring biopsy may be an option, but this decision should be reached via an interdisciplinary discussion and approach.
Magnetic resonance imaging (MRI) is the preferred imaging modality, especially for kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon and large lesions. T1-weighted sequences typically show a poorly circumscribed soft tissue mass with soft tissue and dermal thickening and diffuse enhancement with gadolinium. T2-weighted sequences show a diffuse increased signal, with stranding in the subcutaneous fat. Gradient sequences show mildly dilated vessels in and around the soft-tissue mass.[3]
For small and superficial lesions, ultrasonography can be useful for diagnosis and can distinguish tufted angioma from kaposiform hemangioendothelioma. Tufted angiomas are more superficial, with well-defined borders and are hyperechoic. Kaposiform hemangioendothelioma has a more infiltrative pattern, with ill-defined borders and mixed echogenicity. Kaposiform hemangioendotheliomas also have an increased vascular density than do tufted angiomas.[15]
Treatment of kaposiform hemangioendothelioma and tufted angioma
Treatment of uncomplicated kaposiform hemangioendothelioma and tufted angioma
There is no evidence-based standard of care for kaposiform hemangioendotheliomas and tufted angiomas. Treatment varies according to size, location, presence of symptoms, and severity of coagulopathy.
Treatment options for uncomplicated kaposiform hemangioendotheliomas and tufted angiomas include the following:
Observation.
Surgical excision.
Pulse-dye laser.
Topical agents.
Propranolol.
Sirolimus with or without steroid therapy.
Observation is an option for patients with low-risk tumors (i.e., no Kasabach-Merritt phenomenon, small tumor size, asymptomatic). Spontaneous regression and/or stability has been noted.[16]
Kaposiform hemangioendotheliomas and tufted angiomas that are uncomplicated and localized can be treated with surgical excision, pulse-dye laser, or topical agents (steroids, sirolimus, or tacrolimus).[16–18]
Propranolol therapy has been reported as a treatment option for patients with kaposiform hemangioendotheliomas based on positive results of propranolol use for other more benign vascular tumors. Results have been mixed, with a report of improved effectiveness using higher doses of propranolol.[19,20] Preliminary results indicate that propranolol should be reserved for patients with kaposiform hemangioendotheliomas without Kasabach-Merritt phenomenon and with smaller, less complicated lesions.
Treatment of complicated kaposiform hemangioendothelioma and tufted angioma
Patients who have Kasabach-Merritt phenomenon and/or functional compromise and are symptomatic need aggressive therapy. An American and Canadian multidisciplinary expert panel published guidelines for the management of complicated kaposiform hemangioendotheliomas.[21] A number of treatment therapies have been reported but none have been uniformly effective.[22,23]
Treatment options for complicated kaposiform hemangioendotheliomas and Kasabach-Merritt phenomenon include the following:
The most common treatment option for complicated kaposiform hemangioendotheliomas with or without Kasabach-Merritt phenomenon has traditionally been steroid therapy with or without vincristine or other agents.[21–26] However, many institutions are now using the mTOR inhibitor sirolimus, with or without steroid therapy, as primary treatment for high-risk patients.[27–31] Steroid therapy has not been effective as a single agent for complicated kaposiform hemangioendotheliomas, even at high doses. Patients treated with steroid therapy have a response rate of 10% to 20% and a significant number of side effects.[21]
Vincristine was shown to have a hematologic response and reduction in tumor volume in patients with high-risk kaposiform hemangioendotheliomas.[22] Furthermore, in a retrospective review of 37 children with kaposiform hemangioendotheliomas whose lesions did not respond to steroids, 26 of the lesions achieved complete remission, with platelet counts reaching normal levels within 7.6 (± 5.2) weeks after vincristine treatment.[24][Level of evidence C3] Vincristine monotherapy in other studies has not been shown to be effective.[27,31] Successful management of patients with kaposiform hemangioendotheliomas who were treated with vincristine and ticlopidine has also been reported.[32]
In 2013, consensus guidelines for the management of complicated kaposiform hemangioendotheliomas proposed the use of vincristine with or without steroids as first-line therapy. This recommendation was based on available evidence.[21]
Sirolimus with or without steroid therapy
Secondary to promising case reports, case series, and a prospective clinical trial, sirolimus may be considered an alternative first-line therapy for patients with kaposiform hemangioendotheliomas.[28,29,33] There are limited studies investigating the effect of sirolimus on kaposiform hemangioendotheliomas/tufted angiomas without Kasabach-Merritt phenomenon.
Evidence (sirolimus therapy):
In a prospective study that assessed the efficacy and safety of sirolimus for the treatment of complicated vascular anomalies, 13 patients with kaposiform hemangioendotheliomas were treated with sirolimus.[31]
In patients with kaposiform hemangioendotheliomas and Kasabach-Merritt phenomenon, ten of ten patients had partial responses, with normalization of their platelet count and fibrinogen at the end of 6 and 12 courses.
Of the three patients with kaposiform hemangioendotheliomas without Kasabach-Merritt phenomenon, two patients experienced partial responses by the end of course 12, and the third patient with multifocal bony disease had disease progression.
Side effects were minimal in this group of young patients, and no patient with a kaposiform hemangioendothelioma required a dose adjustment or was removed from the study because of toxicity of sirolimus.
A retrospective study of sirolimus therapy in patients who had nearly all received previous other treatments reported a complete response rate of 73%. All patients assessed as having Kasabach-Merritt phenomenon had recovery of platelet counts between 1 day and 3 weeks (mean, 1.3 weeks).[34]
One death occurred in this study from a respiratory infection in a child with a pleural effusion and multifocal disease involving the thoracic cavity. Biopsy was not routinely used in this study to confirm diagnosis, raising the possibility that this child had an unrecognized complex lymphatic anomaly.
A multicenter, retrospective cohort study analyzed 52 Chinese patients with progressive kaposiform hemangioendotheliomas. Thirty-seven patients (71%) had Kasabach-Merritt phenomenon. Those without Kasabach-Merritt phenomenon received sirolimus alone, and 21 of the patients with Kasabach-Merritt phenomenon received a combination of sirolimus and prednisone.[30]
Overall, 96% of patients at 6 months and 98% of patients at 12 months demonstrated improvement in notable symptoms and/or had improved complications.
A single case report of a child with a kaposiform hemangioendothelioma who developed recurrence of pain and fibrosis years after initial therapy and was treated with sirolimus for 26 months observed the following:[33]
The patient’s contracture and range of motion improved, the lesion shrank, and the child was well 2 years later.
A prospective randomized study of patients with kaposiform hemangioendothelioma associated with Kasabach-Merritt syndrome compared sirolimus monotherapy with sirolimus in combination with prednisolone. The primary outcome was defined as achievement of a durable platelet response (platelet count >100 × 109/L) at week 4.[35][Level of evidence A3]
At week 4, a durable platelet response was achieved in 35 of 37 patients who received sirolimus and prednisolone, compared with 24 of 36 patients who received sirolimus monotherapy (difference, 27.9%; 95% CI, 10.0%–44.7%).
Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in measures of durable platelet responses at all points during the initial 3-week treatment period. The durable platelet responses included median platelet counts during weeks 1 to 4, an increased number of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at 12 months.
The frequencies of total and serious adverse events were similar in both groups.
Patients who received combination therapy had lower total disease sequelae and fewer blood transfusions.
Most high-risk patients (kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon) are treated with sirolimus to achieve serum blood levels of 8 to 15 ng/mL.[30,31,36,37]
Supportive care and close monitoring of infants on sirolimus
A case report described two children with kaposiform hemangioendotheliomas and Kasabach-Merritt syndrome who died of pulmonary infections after treatment with sirolimus.[38] Another child who received sirolimus and prednisolone developed Pneumocystis jirovecii pneumonia.[39] P. jirovecii pneumonia prophylaxis and close monitoring of patients on sirolimus (especially infants) is encouraged.
Surgical excision
Surgical excision may be possible for lesions that did not respond to medical management or are life threatening. Embolization may be performed in conjunction with surgery or medical therapy; usually, it is a temporizing measure.[40]
Long-term outcomes
Even with therapy, these lesions do not fully regress and can recur. Worsened symptomatology (pain, inflammation) can occur with age, especially around the time of puberty.[41]
Long-term effects include chronic pain, lymphedema, heart failure, and orthopedic issues.[40,41] These lesions prove to be a difficult dilemma for the practitioner because they have a varied clinical spectrum and response to therapy.
Treatment options under clinical evaluation for kaposiform hemangioendothelioma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
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Fernandez-Pineda I, Lopez-Gutierrez JC, Ramirez G, et al.: Vincristine-ticlopidine-aspirin: an effective therapy in children with Kasabach-Merritt phenomenon associated with vascular tumors. Pediatr Hematol Oncol 27 (8): 641-5, 2010. [PUBMED Abstract]
Fernandez-Pineda I, Lopez-Gutierrez JC, Chocarro G, et al.: Long-term outcome of vincristine-aspirin-ticlopidine (VAT) therapy for vascular tumors associated with Kasabach-Merritt phenomenon. Pediatr Blood Cancer 60 (9): 1478-81, 2013. [PUBMED Abstract]
Kai L, Wang Z, Yao W, et al.: Sirolimus, a promising treatment for refractory Kaposiform hemangioendothelioma. J Cancer Res Clin Oncol 140 (3): 471-6, 2014. [PUBMED Abstract]
Hammill AM, Wentzel M, Gupta A, et al.: Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 57 (6): 1018-24, 2011. [PUBMED Abstract]
Blatt J, Stavas J, Moats-Staats B, et al.: Treatment of childhood kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer 55 (7): 1396-8, 2010. [PUBMED Abstract]
Ji Y, Chen S, Xiang B, et al.: Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study. Int J Cancer 141 (4): 848-855, 2017. [PUBMED Abstract]
Adams DM, Trenor CC, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [PUBMED Abstract]
López V, Martí N, Pereda C, et al.: Successful management of Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon using vincristine and ticlopidine. Pediatr Dermatol 26 (3): 365-6, 2009 May-Jun. [PUBMED Abstract]
Oza VS, Mamlouk MD, Hess CP, et al.: Role of Sirolimus in Advanced Kaposiform Hemangioendothelioma. Pediatr Dermatol 33 (2): e88-92, 2016 Mar-Apr. [PUBMED Abstract]
Wang Z, Yao W, Sun H, et al.: Sirolimus therapy for kaposiform hemangioendothelioma with long-term follow-up. J Dermatol 46 (11): 956-961, 2019. [PUBMED Abstract]
Ji Y, Chen S, Zhou J, et al.: Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial. Blood 139 (11): 1619-1630, 2022. [PUBMED Abstract]
Zhang G, Chen H, Gao Y, et al.: Sirolimus for treatment of Kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon: a retrospective cohort study. Br J Dermatol 178 (5): 1213-1214, 2018. [PUBMED Abstract]
Mariani LG, Schmitt IR, Garcia CD, et al.: Low dose sirolimus treatment for refractory tufted angioma and congenital kaposiform hemangioendothelioma, both with Kasabach-Merritt phenomenon. Pediatr Blood Cancer 66 (8): e27810, 2019. [PUBMED Abstract]
Ying H, Qiao C, Yang X, et al.: A Case Report of 2 Sirolimus-Related Deaths Among Infants With Kaposiform Hemangioendotheliomas. Pediatrics 141 (Suppl 5): S425-S429, 2018. [PUBMED Abstract]
Russell TB, Rinker EK, Dillingham CS, et al.: Pneumocystis Jirovecii Pneumonia During Sirolimus Therapy for Kaposiform Hemangioendothelioma. Pediatrics 141 (Suppl 5): S421-S424, 2018. [PUBMED Abstract]
Ji Y, Chen S, Yang K, et al.: Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet J Rare Dis 15 (1): 39, 2020. [PUBMED Abstract]
Schaefer BA, Wang D, Merrow AC, et al.: Long-term outcome for kaposiform hemangioendothelioma: A report of two cases. Pediatr Blood Cancer 64 (2): 284-286, 2017. [PUBMED Abstract]
Intermediate Tumors (Rarely Metastasizing)
Intermediate vascular tumors (rarely metastasizing) include the following:
Pseudomyogenic hemangioendotheliomas usually present in young men aged 20 to 50 years.[1,2] Multifocal disease occurs in 70% of patients and sites of involvement include the dermis, subcutis, and bones. Patients usually present with pain or a soft tissue mass.[1,3]
Histopathology and molecular features
Pseudomyogenic hemangioendotheliomas are rare, newly designated, distinct vascular tumors. They are characterized as intermediate-grade tumors with moderately aggressive local spread and rare distant metastatic disease. The etiology for this tumor is unclear, although a balanced translocation t(7;19) resulting in the SERPINE1::FOSB fusion gene has been reported.[4]
Pseudomyogenic hemangioendotheliomas are characterized by loose fascicles of plump spindle and epithelioid cells with abundant eosinophils, cytoplasm, and coexpression of keratins and endothelial markers.[1,2,5]
Treatment of pseudomyogenic hemangioendothelioma
Most patients with pseudomyogenic hemangioendotheliomas are treated with surgery, including amputation for multifocal bony disease.[1] In reported cases, chemotherapy has produced responses.[6,7] Recently, the mammalian target of rapamycin (mTOR) inhibitors have been considered as treatment options.[7,8] An additional case report noted efficacy of sirolimus with the addition of zoledronic acid in a patient with multifocal bony disease.[9] Tyrosine kinase inhibitors (pazopanib and telatinib) have also been used to successfully treat pseudomyogenic hemangioendothelioma.[10,11]
Retiform Hemangioendothelioma
Clinical presentation
Retiform hemangioendotheliomas are slow growing, exophytic, flat tumors found in young adults and occasionally children.[12] They are usually located in the limbs and trunk. Local recurrences are common, but distinct metastases are extremely rare.[13]
Histopathology
Histologically, retiform hemangioendotheliomas are located in the dermis and subcutaneous tissue. Vessels exhibit a pattern resembling the rete testis and are lined by protruding endothelial cells. They do not express lymphatic markers but stain positive for endothelial markers.[13]
Treatment of retiform hemangioendothelioma
Treatment for patients with retiform hemangioendotheliomas includes surgical excision with adequate tumor margins and monitoring for local recurrence. There are case reports describing the use of radiation therapy and chemotherapy for inoperable and recurrent tumors.[14–17]
Papillary Intralymphatic Angioendothelioma
Clinical presentation
Papillary intralymphatic angioendotheliomas, also known as Dabska tumors, can occur in the adult and pediatric population.[18] The lesions occur in the dermis and subcutis on all body parts and there have been some reports of lymph node involvement. They can be large or small raised purplish firm nodules.
Histopathology
Pathologically, papillary intralymphatic angioendothelioma lesions reveal intravascular growth of well-differentiated endothelial cells in a columnar configuration. They have thickened hyaline walls with hobnailed endothelium. Vascular endothelial growth factor receptor type 3, a marker for lymphatic endothelium, is positive in most cases. There is minimal cytological atypia.[19] Some lesions are associated with vascular malformations.
Treatment of papillary intralymphatic angioendothelioma
Surgical excision is the treatment of choice for patients with papillary intralymphatic angioendotheliomas.[20]
Composite Hemangioendothelioma
Clinical presentation
Composite hemangioendotheliomas usually occur in the dermis and subcutis of the distal extremities but has been found in other areas such as the head, neck, and mediastinum.[21] They have been reported in all age groups.[21]
Composite hemangioendotheliomas recur locally and rarely metastasize.[21,22] Regional lymph nodes are the most likely site of metastasis and require imaging evaluation for surveillance.[21]
Histopathology
Composite hemangioendotheliomas are very rare vascular tumors classified as intermediate because of the combined benign and malignant vascular components. Usually, combined epithelioid and retiform variants are noted but some tumors have three components (epithelioid, retiform, and spindle cell).[21] Angiosarcoma foci have been noted. Pathology reveals positivity for CD31, factor VIII, and vimentin.[21,22] Rarely, D-240 is positive with a Ki-67 index of approximately 20%.[21]
Treatment of composite hemangioendothelioma
Surgical removal is the treatment of choice for patients with composite hemangioendotheliomas, although radiation therapy and chemotherapy have been used for metastatic disease.[23,24]
Kaposi Sarcoma
Clinical presentation
Kaposi sarcoma (KS) is a rare malignant vascular tumor associated with a viral etiology (human herpesvirus 8).[25] The skin lesions were first described in 1872 by Moritz Kaposi. The incidence has increased worldwide because of the HIV-AIDS epidemic. It is an extremely rare diagnosis in children. Epidemic and iatrogenic forms of Kaposi sarcoma in children result from profound acquired T-cell deficiency that is caused by HIV infections, rare immune disorders, or solid organ transplants.
A retrospective study has investigated the presentation of Kaposi sarcoma in children in endemic areas of Africa. Children usually present with cutaneous lesions, lymphadenopathy, and intrathoracic and oral lesions. Cutaneous lesions initially appear as red, purple, or brown macules, later developing into plaques and then nodules.[26–28]
Treatment of Kaposi sarcoma
Children with Kaposi sarcoma have responded to treatment with chemotherapy regimens, including bleomycin, vincristine, and taxanes, although there are no prospective clinical trials. Because Kaposi sarcoma is rare in the pediatric population, there are few evidence-based studies.
Evidence (chemotherapy):
Fifty-six Malawian children aged 3 to 12 years with Kaposi sarcoma were treated with six courses of vincristine, bleomycin, and oral etoposide. This was a high-risk population because 48 of the patients (86%) were HIV positive, 36 of whom (77%) were on antiretroviral therapy (ART).[29][Level of evidence C1]
Eighteen patients (32%) had a complete remission.
At 12 months, the overall survival (OS) rate was 71%, and the event-free survival rate was 50%.
Quality of life improved in 45 patients (80%).
In one retrospective series, 207 children and adolescents with endemic or HIV-related Kaposi sarcoma were treated with unspecified protocols and ART between 2006 and 2015. The study reported a 7-year OS rate of 37% (76 patients). Of these patients, 62% had complete responses, and 8% had stable partial responses. Four of the patients with complete responses had been treated with ART without chemotherapy.[30][Level of evidence C1]
Even in adults, the evidence and quality of studies are poor, and it is difficult to recommend particular treatment regimens. Other treatment options have been based on adult studies (refer directly below).
In a systematic review of treatment for classic Kaposi sarcoma, 26 articles published from 1980 to 2010 were reviewed. Articles describing populations at high risk secondary to previous transplant and endemic and epidemic Kaposi sarcoma were excluded.[31] All articles had a minimum of five patients per intervention. A greater than 50% decrease in the size of the lesions or lymphedema was considered a response. The quality of the articles was considered poor, primarily because of lack of uniform staging criteria and variable means of assessing response. The following response rates for systemic treatments were noted:
Pegylated doxorubicin: 71% to 100%.
Vinca alkaloids: 58% to 90%.
Etoposide: 74% to 76%.
Taxanes: 93% to 100%.
Gemcitabine: 100%.
Vinblastine and bleomycin: 97%.
Interferon alfa-2: 71% to 100%.
For local therapies, the following response rates were reported:
Amary MF, O’Donnell P, Berisha F, et al.: Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma: characterization of five cases. Skeletal Radiol 42 (7): 947-57, 2013. [PUBMED Abstract]
Walther C, Tayebwa J, Lilljebjörn H, et al.: A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma. J Pathol 232 (5): 534-40, 2014. [PUBMED Abstract]
Mirra JM, Kessler S, Bhuta S, et al.: The fibroma-like variant of epithelioid sarcoma. A fibrohistiocytic/myoid cell lesion often confused with benign and malignant spindle cell tumors. Cancer 69 (6): 1382-95, 1992. [PUBMED Abstract]
Pranteda G, Magri F, Muscianese M, et al.: The management of pseudomyogenic hemangioendothelioma of the foot: A case report and review of the literature. Dermatol Ther 31 (6): e12725, 2018. [PUBMED Abstract]
Joseph J, Wang WL, Patnana M, et al.: Cytotoxic and targeted therapy for treatment of pseudomyogenic hemangioendothelioma. Clin Sarcoma Res 5: 22, 2015. [PUBMED Abstract]
Ozeki M, Nozawa A, Kanda K, et al.: Everolimus for Treatment of Pseudomyogenic Hemangioendothelioma. J Pediatr Hematol Oncol 39 (6): e328-e331, 2017. [PUBMED Abstract]
Danforth OM, Tamulonis K, Vavra K, et al.: Effective Use of Sirolimus and Zoledronic Acid for Multiosteotic Pseudomyogenic Hemangioendothelioma of the Bone in a Child: Case Report and Review of Literature. J Pediatr Hematol Oncol 41 (5): 382-387, 2019. [PUBMED Abstract]
Alhanash A, Aseafan M, Atallah J: Pazopanib as Treatment Option for Pseudomyogenic Hemangioendothelioma: A Case Report. Cureus 14 (5): e25250, 2022. [PUBMED Abstract]
van IJzendoorn DGP, Sleijfer S, Gelderblom H, et al.: Telatinib Is an Effective Targeted Therapy for Pseudomyogenic Hemangioendothelioma. Clin Cancer Res 24 (11): 2678-2687, 2018. [PUBMED Abstract]
El Darouti M, Marzouk SA, Sobhi RM, et al.: Retiform hemangioendothelioma. Int J Dermatol 39 (5): 365-8, 2000. [PUBMED Abstract]
Colmenero I, Hoeger PH: Vascular tumours in infants. Part II: vascular tumours of intermediate malignancy [corrected] and malignant tumours. Br J Dermatol 171 (3): 474-84, 2014. [PUBMED Abstract]
Keiler SA, Honda K, Bordeaux JS: Retiform hemangioendothelioma treated with Mohs micrographic surgery. J Am Acad Dermatol 65 (1): 233-5, 2011. [PUBMED Abstract]
Hirsh AZ, Yan W, Wei L, et al.: Unresectable retiform hemangioendothelioma treated with external beam radiation therapy and chemotherapy: a case report and review of the literature. Sarcoma 2010: , 2010. [PUBMED Abstract]
Enjolras O, Mulliken JB, Kozakewich HPW: Vascular tumors and tumor-like lesions. In: Mulliken JB, Burrows PE, Fishman SJ, eds.: Mulliken & Young’s Vascular Anomalies: Hemangiomas and Malformations. 2nd ed. Oxford University Press, 2013, pp 259-324.
Tamhankar AS, Vaidya A, Pai P: Retiform hemangioendothelioma over forehead: A rare tumor treated with chemoradiation and a review of literature. J Cancer Res Ther 11 (3): 657, 2015 Jul-Sep. [PUBMED Abstract]
Dabska M: Malignant endovascular papillary angioendothelioma of the skin in childhood. Clinicopathologic study of 6 cases. Cancer 24 (3): 503-10, 1969. [PUBMED Abstract]
Fanburr-Smith JC: Papillary intralymphatic angioendothelioma. In: Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. IARC Press, 2013, pp 148.
Neves RI, Stevenson J, Hancey MJ, et al.: Endovascular papillary angioendothelioma (Dabska tumor): underrecognized malignant tumor in childhood. J Pediatr Surg 46 (1): e25-8, 2011. [PUBMED Abstract]
Shang Leen SL, Fisher C, Thway K: Composite hemangioendothelioma: clinical and histologic features of an enigmatic entity. Adv Anat Pathol 22 (4): 254-9, 2015. [PUBMED Abstract]
Mahmoudizad R, Samrao A, Bentow JJ, et al.: Composite hemangioendothelioma: An unusual presentation of a rare vascular tumor. Am J Clin Pathol 141 (5): 732-6, 2014. [PUBMED Abstract]
Tateishi J, Saeki H, Ito K, et al.: Cutaneous composite hemangioendothelioma on the nose treated with electron beam. Int J Dermatol 52 (12): 1618-9, 2013. [PUBMED Abstract]
Soldado F, Fontecha CG, Haddad S, et al.: Composite vascularized fibular epiphyseo-osteo-periosteal transfer for hip reconstruction after proximal femoral tumoral resection in a 4-year-old child. Microsurgery 32 (6): 489-92, 2012. [PUBMED Abstract]
Jackson CC, Dickson MA, Sadjadi M, et al.: Kaposi Sarcoma of Childhood: Inborn or Acquired Immunodeficiency to Oncogenic HHV-8. Pediatr Blood Cancer 63 (3): 392-7, 2016. [PUBMED Abstract]
Dow DE, Cunningham CK, Buchanan AM: A Review of Human Herpesvirus 8, the Kaposi’s Sarcoma-Associated Herpesvirus, in the Pediatric Population. J Pediatric Infect Dis Soc 3 (1): 66-76, 2014. [PUBMED Abstract]
El-Mallawany NK, Kamiyango W, Slone JS, et al.: Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study. PLoS One 11 (4): e0153335, 2016. [PUBMED Abstract]
Rees CA, Keating EM, Lukolyo H, et al.: Mapping the Epidemiology of Kaposi Sarcoma and Non-Hodgkin Lymphoma Among Children in Sub-Saharan Africa: A Review. Pediatr Blood Cancer 63 (8): 1325-31, 2016. [PUBMED Abstract]
Macken M, Dale H, Moyo D, et al.: Triple therapy of vincristine, bleomycin and etoposide for children with Kaposi sarcoma: Results of a study in Malawian children. Pediatr Blood Cancer 65 (2): , 2018. [PUBMED Abstract]
Silverstein A, Kamiyango W, Villiera J, et al.: Long-term outcomes for children and adolescents with Kaposi sarcoma. HIV Med 23 (2): 197-203, 2022. [PUBMED Abstract]
Régnier-Rosencher E, Guillot B, Dupin N: Treatments for classic Kaposi sarcoma: a systematic review of the literature. J Am Acad Dermatol 68 (2): 313-31, 2013. [PUBMED Abstract]
Tsao MN, Sinclair E, Assaad D, et al.: Radiation therapy for the treatment of skin Kaposi sarcoma. Ann Palliat Med 5 (4): 298-302, 2016. [PUBMED Abstract]
Singh NB, Lakier RH, Donde B: Hypofractionated radiation therapy in the treatment of epidemic Kaposi sarcoma–a prospective randomized trial. Radiother Oncol 88 (2): 211-6, 2008. [PUBMED Abstract]
Lebbe C, Garbe C, Stratigos AJ, et al.: Diagnosis and treatment of Kaposi’s sarcoma: European consensus-based interdisciplinary guideline (EDF/EADO/EORTC). Eur J Cancer 114: 117-127, 2019. [PUBMED Abstract]
Epithelioid hemangioendothelioma was first described in soft tissue by Weiss and Enzinger in 1982. These tumors can occur in younger patients, but the peak incidence is in the fourth and fifth decades of life. The number of pediatric patients reported in the literature is limited.
Epithelioid hemangioendotheliomas can have an indolent or very aggressive course, with an overall survival rate of 73% at 5 years. There are case reports of patients with untreated multiple lesions who have a very benign course. However, other patients have a very aggressive course. Some pathologists have tried to stratify patients to evaluate risks and adjust treatment, but more research is needed.[1–7]
A multi-institutional case series reported on 24 patients aged 2 to 26 years with epithelioid hemangioendotheliomas.[8][Level of evidence C2] Most patients presented with multiorgan disease. Progression was seen in 63% of patients, with a mean time to progression of 18.4 months (range, 0–72 months).
The presence of effusions, tumor size larger than 3 cm, and a high mitotic index (>3 mitoses/50 high-power fields) have been associated with unfavorable outcomes.[3]
Clinical presentation and diagnostic evaluation
Common sites of involvement are liver alone (21%), liver plus lung (18%), lung alone (12%), and bone alone (14%).[3,9,10] Clinical presentation depends on the site of involvement, as follows:
Liver: Hepatic nodules have central vascularity on ultrasound, contrast-enhancing lesions by computed tomography, and low T1 signal and moderate T2 signal on magnetic resonance imaging. These may be incidental findings in asymptomatic patients, but most patients commonly present with signs or symptoms of cholestasis, including pruritus, jaundice, or scleral icterus.
Lung: Pulmonary epithelioid hemangioendothelioma may be an asymptomatic finding on chest x-ray or be associated with pleuritic pain, hemoptysis, anemia, and fibrosis.
Bone: Bone metastasis may be associated with pathological fracture. On x-rays, they are well-defined osteolytic lesions and can be multiple or solitary.
Soft tissue: Thirty percent of soft tissue cases are associated with metastases. When present, metastatic disease can be very aggressive and have a limited response to chemotherapy.
Skin: Cutaneous lesions can be raised and nodular or can be warm, red-brown plaques.
Genomic alterations and histopathological features
WWTR1::CAMTA1 gene fusions have been found in most patients. Less commonly, YAP1::TFE3 gene fusions have been reported.[1] These gene fusions are not directly targetable with current medications. Monoclonality has been described in multiple liver lesions, suggesting a metastatic process.
Histologically, these lesions are characterized as epithelioid lesions arranged in nests, strands, and trabecular patterns, with infrequent vascular spaces. Features that may be associated with aggressive clinical behavior include cellular atypia, one or more mitoses per 10 high-power fields, an increased proportion of spindled cells, focal necrosis, and metaplastic bone formation.[3]
Treatment of epithelioid hemangioendothelioma
Treatment options for epithelioid hemangioendothelioma include the following:
Observation.
Surgery.
Immunotherapy.
Targeted therapy.
Chemotherapy.
Radiation therapy.
For indolent cases, observation is warranted. Surgery is performed when resection is possible. Liver transplant has been used with aggressive liver lesions, both with and without metastases.[3,11–13]
For more aggressive cases, several different drugs have been used, including interferon, thalidomide, sorafenib, pazopanib, and sirolimus.[11,14,15] The most aggressive cases are treated with angiosarcoma-type chemotherapy.
A multi-institutional case series reported on 24 patients aged 2 to 26 years with epithelioid hemangioendothelioma.[8][Level of evidence C2]
Three patients who were treated with sirolimus had stable disease or partial responses for more than 2.5 years.
A report from 2020 that investigated sirolimus treatment in children aimed to add to the previous experience of sirolimus in adults. A retrospective review identified six pediatric patients with disseminated epithelioid hemangioendothelioma who were treated with sirolimus.[16]
Four of the six patients demonstrated partial responses or disease stabilization.
A report from the European paediatric Soft Tissue Sarcoma Study Group analyzed ten patients with localized disease and one patient with metastatic disease from two studies.[17] The median age was 14.3 years (range, 9.0–18.8 years). Local therapy was initial primary surgery in seven patients, and five patients received systemic therapy. No patients received radiation therapy.
After a median follow-up of 50 months (range, 6–176 months), nine patients remained alive and off therapy and two patients died.
The 5-year progression-free survival rate was 77.1% (95% confidence interval [CI], 34.5%–93.9%).
The 5-year overall survival rate was 74.1% (95% CI, 28.1%–93.0%).
Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.
Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Treatment options under clinical evaluation for epithelioid hemangioendothelioma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Angiosarcoma
Incidence and clinical presentation
Angiosarcomas are rare (accounting for 2% of sarcomas), aggressive, vascular tumors that can arise in any part of the body but is more common in soft tissues. Angiosarcoma has an estimated incidence of 2 cases per 1 million people. In the United States, it affects approximately 600 people annually, who are typically aged 60 to 70 years.[18]
Angiosarcomas are extremely rare in children. It is unclear if the pathophysiology of angiosarcomas in children differs from that of angiosarcomas in adults. Cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are GLUT1 positive.[19–22] Most angiosarcomas involve the skin and superficial soft tissue, although the liver, spleen, and lung can be affected; bone is rarely affected.
Nomenclature of these liver lesions has been difficult and confusing with use of outdated terminology proposed in 1971 (e.g., type I hemangioendothelioma: infantile hemangioma; type II hemangioendothelioma: low-grade angiosarcoma; type III hemangioendothelioma: high-grade angiosarcoma).[20] A report of eight cases of liver angiosarcomas in children highlighted the misuse of the term hemangioendothelioma and the importance of early diagnosis and treatment of these tumors.[23]
Risk factors
Established risk factors include the following:[24]
Vinyl chloride exposure.
Radiation exposure.
Chronic lymphedema from any cause, including Stewart-Treves syndrome.
Genomic alterations and histopathological features
Angiosarcomas are largely aneuploid tumors. The rare cases of angiosarcoma that arise from benign lesions such as hemangiomas have a distinct pathway that needs to be investigated. MYC amplification is seen in radiation-induced angiosarcoma. KDR variants and FLT4 amplifications have been seen with a frequency of less than 50%.[24]
Histopathological diagnosis can be very difficult because there can be areas of varied atypia. A common feature of angiosarcoma is an irregular network of channels in a dissective pattern along dermal collagen bundles. There is varied cellular shape, size, mitosis, endothelial multilayering, and papillary formation. Epithelioid cells can also be present. Necrosis and hemorrhage are common. Tumors stain for factor VIII, CD31, and CD34. Some liver lesions can mimic infantile hemangiomas and have focal GLUT1 positivity.[20]
Treatment of angiosarcoma
Treatment options for angiosarcoma include the following:
Localized disease can be cured by aggressive surgery. Complete surgical excision appears to be crucial for the long-term survival of patients with angiosarcomas and lymphangiosarcomas, despite evidence of tumor shrinkage in some patients who were treated with local or systemic therapy.[21,25–27] Data on liver transplant for localized angiosarcomas are limited.[28][Level of evidence C1]
Evidence (surgery):
A review of 222 patients (median age, 62 years; range, 15–90 years) reported the following:[27]
An overall disease-specific survival (DSS) rate of 38% at 5 years.
The 5-year DSS rate was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis.
One case report suggested that liver transplant may contribute to prolonged disease-free survival.[29][Level of evidence C2]
Radiation therapy
Localized disease, especially cutaneous angiosarcomas, can be treated with radiation therapy or combined chemotherapy (e.g., paclitaxel) and radiation therapy.[30] Most of these reported cases are in adults.[31] When radiation is used, the doses are high (50–70 Gy), the cutaneous volumes are extensive because of the infiltrating nature of the disease, and regional (draining) nodes are often included, even if clinically negative.[32,33] Because of these factors, radiation therapy is rarely used to treat children.
Surgery, chemotherapy, and radiation therapy
Multimodal treatment with surgery, systemic chemotherapy, and radiation therapy is used for metastatic disease, although it is rarely curative.[33,34] Disease control is the objective in patients with metastatic angiosarcomas. Published progression-free survival is between 3 months and 7 months,[35] and the median overall survival (OS) is 14 to 18 months.[36] In both adults and children, the 5-year OS rates are between 20% and 35%.[21,22,37]
One child who was diagnosed with angiosarcoma secondary to malignant transformation from infantile hemangioma responded to treatment with bevacizumab (a monoclonal antibody against vascular endothelial growth factor) combined with systemic chemotherapy.[19,34]
Biologic agents that inhibit angiogenesis have shown activity in adults with angiosarcomas.[20,37]
There is one case report of a pediatric patient with metastatic cardiac angiosarcoma who was successfully treated with conventional chemotherapy, radiation, surgery, and targeted therapies, including pazopanib.[38]
Palliative care
Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Treatment options under clinical evaluation for angiosarcoma
Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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Raheja A, Suri A, Singh S, et al.: Multimodality management of a giant skull base hemangioendothelioma of the sphenopetroclival region. J Clin Neurosci 22 (9): 1495-8, 2015. [PUBMED Abstract]
Ahmad N, Adams DM, Wang J, et al.: Hepatic epithelioid hemangioendothelioma in a patient with hemochromatosis. J Natl Compr Canc Netw 12 (9): 1203-7, 2014. [PUBMED Abstract]
Otte JB, Zimmerman A: The role of liver transplantation for pediatric epithelioid hemangioendothelioma. Pediatr Transplant 14 (3): 295-7, 2010. [PUBMED Abstract]
Stacchiotti S, Provenzano S, Dagrada G, et al.: Sirolimus in Advanced Epithelioid Hemangioendothelioma: A Retrospective Case-Series Analysis from the Italian Rare Cancer Network Database. Ann Surg Oncol 23 (9): 2735-44, 2016. [PUBMED Abstract]
Semenisty V, Naroditsky I, Keidar Z, et al.: Pazopanib for metastatic pulmonary epithelioid hemangioendothelioma-a suitable treatment option: case report and review of anti-angiogenic treatment options. BMC Cancer 15: 402, 2015. [PUBMED Abstract]
Engel ER, Cournoyer E, Adams DM, et al.: A Retrospective Review of the Use of Sirolimus for Pediatric Patients With Epithelioid Hemangioendothelioma. J Pediatr Hematol Oncol 42 (8): e826-e829, 2020. [PUBMED Abstract]
Orbach D, Van Noesel MM, Brennan B, et al.: Epithelioid hemangioendothelioma in children: The European Pediatric Soft Tissue Sarcoma Study Group experience. Pediatr Blood Cancer 69 (10): e29882, 2022. [PUBMED Abstract]
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Jeng MR, Fuh B, Blatt J, et al.: Malignant transformation of infantile hemangioma to angiosarcoma: response to chemotherapy with bevacizumab. Pediatr Blood Cancer 61 (11): 2115-7, 2014. [PUBMED Abstract]
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Grassia KL, Peterman CM, Iacobas I, et al.: Clinical case series of pediatric hepatic angiosarcoma. Pediatr Blood Cancer 64 (11): , 2017. [PUBMED Abstract]
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Latest Updates to This Summary (04/17/2025)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added text to state that lack of consistent criteria and medical terminology has led to unreliable conclusions from the historical medical literature (cited Liberale et al., Boulogeorgou et al., and Hassanein et al. as references 1, 2, and 3, respectively).
Added text to state that prophylactic measures such as maintaining dermal integrity with moisturizing barrier agents are indicated for infantile hemangiomas and are important before and during the proliferative phase. Once an ulceration has occurred, it is important to aggressively manage the ulceration to promote healing, prevent infection, and treat pain. In addition to pain control, management includes steroid ointments, antibiotic ointments or systemic antibiotics, laser therapy, or topical timolol.
Added text to state that a retrospective review of initial propranolol dosing indicates a starting dose of 2 mg/kg may also be well tolerated. This initial dosing could decrease the need for up-titration and more frequent clinic visits, although prospective studies are needed (cited Huang et al. as reference 108).
Added text about the results of a retrospective cohort study that included 666 patients with infantile hemangioma who were treated with topical timolol for 12 months (cited Xia et al. as reference 133).
Added text to state that in general, hepatic vascular tumors can be benign or malignant.
Revised text to state that the risk of developing Kasabach-Merritt phenomenon is highest in patients with congenital lesions, lesions larger than 6 to 8 cm, deeper lesions, and when kaposiform hemangioendothelioma arises in the retroperitoneum or mediastinum (cited Chen et al. as reference 7).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood vascular tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Vascular Tumors Treatment are:
Denise Adams, MD (Children’s Hospital Boston)
Sally J. Cohen-Cutler, MD, MS (Children’s Hospital of Philadelphia)
Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
Holcombe Edwin Grier, MD
Michael Jeng, MD (Stanford Medicine Children’s Health)
Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta – Egleston Campus)
Malcolm A. Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Vascular Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/soft-tissue-sarcoma/hp/child-vascular-tumors-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26844334]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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