Very small numbers of children are diagnosed every year with one of the rare childhood cancers. Because so few doctors see these diseases, diagnosis may be difficult and treatment may not be standardized. The uncommon cancers covered in this section are chronic myelocytic leukemia, histiocytosis, liver tumors, and soft tissue sarcomas. Although these diseases are discussed here briefly, the late effects that might develop after cure are discussed in greater depth in the chapters about organ systems.

If your disease is not covered in this chapter, go through the tables at the end of the chapter and the Children’s Oncology Group’s follow-up guidelines ( www.survivorshipguidelines.org ), find the treatments you received, and read about the tests you should get to monitor your health.

Chronic myelocytic leukemia

Chronic myelocytic leukemia (also called chronic myelogenous leukemia or CML) accounts for less than 5 percent of all childhood leukemias. In CML, large numbers of cancerous mature granulocytes (a type of white blood cell) appear.

The two major forms of chronic myelocytic leukemia are adult CML, which occurs primarily in adolescents and adults, and juvenile myelomonocytic leukemia (also called juvenile CML), which occurs mostly in infants.

Adult CML

Adult CML is characterized by a large spleen and high white blood cell count (usually more than 100,000). In more than 90 percent of teens with adult CML, analysis of cells in the bone marrow shows a genetic abnormality called the Philadelphia chromosome. This chromosome contains a translocation (where genetic material has traded places) involving chromosomes 9 and 22, abbreviated t(9;22).

Chemotherapy. The goal of treatment for adult CML is to lower the white blood cell count and to reduce the size of the liver and spleen. The current treatment is imatinib mesylate (Gleevec ^® ). Previously, hydroxyurea (Hydrea ^® ) or busulfan (Myleran ^® ) were used. In some cases, the biologic agent interferon alpha is given alone or in combination with hydroxyurea or cytarabine (ARA-C).

Radiation. Before chemotherapy was used to treat adult CML, radiation of the spleen was a common therapy. When clinical trials proved that it was inferior to chemotherapy in prolonging survival, it was used only to reduce the size of painful massive spleens in patients whose disease was resistant to chemotherapy.

Surgery. Removal of the spleen also was common practice in the past until clinical trials showed no improvement in prolonging the chronic phase or survival.

Stem cell transplantation. Although Gleevac ^® and interferon alpha slow the progress of adult CML, the best hope for cure is stem cell transplant. The highest cure rates occur when the patient is transplanted during the chronic phase with marrow or stem cells from an identical twin, HLA-matched family member, or HLA-matched non-family member. Descriptions of the types of stem cell transplants and their late effects are at the end of this chapter under “Stem cell transplantation.”

Juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (also called juvenile CML) usually strikes children younger than age 5. Unlike the adult form of CML, juvenile CML does not have a chronic phase, and the cells usually do not contain the Philadelphia chromosome. This disease progresses rapidly.

Stem cell transplantation. As with adult CML, chemotherapy generally is not a successful treatment for juvenile CML, and stem cell transplantation is the best hope for a cure. However, chemotherapy is sometimes used while preparing for transplant. Descriptions of the types of stem cell transplants and their late effects are at the end of this chapter under “Stem cell transplantation.”

Histiocytosis

Histiocytosis is a poorly understood and frequently misdiagnosed disease. Patients can have a wide array of symptoms ranging from skin conditions to bone lesions. Approximately 1,200 new cases are diagnosed in the United States each year, but the true incidence is unknown because so many different types of doctors treat various aspects of the disease. It is common for children with histiocytosis to be seen by dermatologists, endocrinologists, and orthopedists, as well as oncologists.

Histiocytosis is a disease in which histiocytes (a cell of bone marrow origin) multiply and accumulate in various organs or bones in the body. Symptoms mimic other childhood illnesses or conditions, so the only way to obtain a definitive diagnosis is the thorough examination of a sample of affected tissue under an electron microscope.

Organs commonly damaged by the multiplying histiocytes are skin, bone, ears, lymph nodes, glands, lung, eye, liver, spleen, and bone marrow. Less frequently involved body parts are kidneys, jaw, thymus, thyroid, and intestines. Many of the lesions spontaneously heal with time. Diabetes insipidus is also commonly found at diagnosis.

There are three types of histiocytosis:

• Langerhans’ cell histiocytosis.  The most common type of histiocytosis, in which Langerhans’ cells are found in lesions.

• Class II histiocytosis.  A very rare disorder in which Langerhans’ cells are not found in lesions. This is almost always a fatal disease, although stem transplantation is used experimentally to treat it.

• Class III malignant histiocytosis.  A very rare malignant disorder best identified by lymph node biopsy. The disorder was previously always fatal, but new treatments are extending remissions significantly.

There are key differences in these three disorders in terms of diagnosis, treatment, and prognosis.

Langerhans’ cell histiocytosis is poorly understood, and hence, numerous treatment methods have been tried over the years. The disease has been treated aggressively as an infection and just as aggressively with chemotherapy as a malignancy. Stem cell transplants are sometimes recommended for children with severe, unresponsive disease. Low-dose radiation is sometimes used for bone involvement, with doses ranging from 700 to 1,000 cGy.

Class II histiocytosis is treated with stem cell transplantation. Descriptions of the types of stem cell transplants and their late effects are at the end of this chapter under “Stem cell transplantation.”

Children with Class III malignant histiocytosis are given induction therapy consisting of vincristine (Oncovin ^® ), prednisone, cyclophosphamide (Cytoxan ^® ), and doxorubicin (Adriamycin ^® ). Maintenance drugs used are vincristine, cyclophosphamide, and doxorubicin.

Most survivors of histiocytosis have no long-term side effects from their treatment. For those who had numerous relapses of the disease or were treated with a stem cell transplant, the chances are higher of developing problems later in life. The following are very rare late effects of treatment for histiocytosis.

Heart problems. Heart problems can occur months or years after treatment with high doses of anthracyclines (i.e., doxorubicin, idarubicin, or daunorubicin), high-dose cyclophosphamide, or chest radiation. Symptoms include shortness of breath, fatigue, wheezing, anxiety, poor exercise tolerance, rapid heartbeat, and irregular heartbeat. Survivors often have no symptoms, but problems may be found on cardiac tests such as echocardiograms, electrocardiograms (EKGs), and Holter monitors. For more information, see Chapter 12 .

Hearing loss. Some children with Langerhans’ cell histiocytosis develop hearing loss after years of chronic ear infections. For more information, see Chapter 10 .

Diabetes insipidus. If the disease infiltrated the pituitary gland, diabetes insipidus often develops.

Uncommon problems. Very rare late effects include bladder problems (i.e., hemorrhagic cystitis and bladder fibrosis) from cyclophosphamide, and damaged joints (from osteonecrosis—death of blood vessels that nourish bones) from high-dose steroids. For more information, see Chapter 14 , and Chapter 17 .

Liver tumors

Liver tumors comprise fewer than 5 percent of all childhood cancers. The two most common types of childhood liver cancer are hepatoblastoma and hepatocellular carcinoma. Eighty percent of childhood hepatoblastomas occur before age 3, whereas hepatocellular carcinoma has two common incidence peaks in children: from birth to age 4 and from ages 12 to 15.

Surgery. The primary goal of surgery is to remove as much of the tumor as possible. Generally, surgery occurs soon after diagnosis. In cases where the tumor is very large or if the disease has spread to other organs, chemotherapy sometimes is given before surgery.

Chemotherapy. Chemotherapy almost always is used to treat both types of liver cancer. Chemotherapy can be given systemically (i.e., injected into the bloodstream and reaching all parts of the body) or regionally (i.e., delivered directly to the liver).

For hepatoblastoma, the most commonly used drugs are cisplatin (Platinol ^® ), vincristine (Oncovin ^® ), and fluorouracil (5-FU). Other drugs, such as doxorubicin (Adriamycin ^® ), ifosfamide (Ifex ^® ), carboplatin, and etoposide (VP-16 or Vepesid ^® ) have been used for more advanced stages of the disease.

Initial treatment for hepatocellular carcinoma usually includes cisplatin and doxorubicin.

The following are possible late effects of treatment for liver cancers.

Heart problems. Heart problems can occur months or years after treatment with high doses of anthracyclines (i.e., doxorubicin, idarubicin, or daunorubicin), high-dose cyclophosphamide, or chest radiation. Symptoms include shortness of breath, fatigue, wheezing, anxiety, poor exercise tolerance, rapid heartbeat, and irregular heartbeat. Survivors often have no symptoms, but problems may be found on cardiac tests such as echocardiograms, electrocardiograms (EKGs), and Holter monitors. For more information, see Chapter 12 .

Hearing loss. Cisplatin can result in mild to profound hearing loss in some children. For more information, see Chapter 10 .

Second cancers. A rare side effect from treatment with etoposide is developing second cancers. For more information, see Chapter 19 .

Soft tissue sarcomas

Childhood soft tissue sarcoma is a disease in which cancer arises in the body’s soft tissues. Soft tissues include muscles, tendons (which connect muscles to bones), fat, blood vessels, nerves, and synovia (tissues around joints). Forty-seven percent of all childhood soft tissue sarcomas have a histology (which is how the cells look under a microscope) that is different from rhabdomyosarcoma (discussed later in this chapter). These soft tissue sarcomas include the following:

• Synovial sarcoma.  This is the most common non-rhabdomyosarcoma soft tissue sarcoma in childhood. Synovial sarcoma is found most often in older children and is very rarely diagnosed in children younger than age 10. The disease occurs most frequently in the lower extremities, most often in the thigh or knee area. The second most common sites are the upper extremities, followed by the head, neck, and trunk.

• Fibrosarcoma.  This soft tissue sarcoma occurs most often in infants and children younger than age 5 and in children between ages 10 and 15. These tumors usually develop in the extremities, and the majority of children diagnosed have localized disease. Infants diagnosed with this disease tend to respond to treatment better than do older children.

• Malignant peripheral nerve sheath tumor . (also known as neurofibrosarcoma or malignant schwannoma). This is an aggressive malignancy that accounts for approximately 5 to 10 percent of all non-rhabdomyosarcoma soft tissue sarcomas of childhood. The disease often occurs in association with neurofibromatosis. The most common sites of origin are the extremities.

• Malignant fibrous histiocytoma.  This form of soft tissue sarcoma most frequently occurs in the lower extremities and the trunk area. Other sites include the upper limbs, scalp, and kidneys.

The following are extremely rare forms of childhood soft tissue sarcomas. Young children with these diseases are generally treated on protocols based on those used for childhood rhabdomyosarcoma. Teens are usually treated on protocols similar to those used for adults with soft tissue sarcomas.

• Leiomyosarcoma.  Leiomyosarcoma, which arises from smooth muscle, most often occurs in the gastrointestinal tract, especially the stomach.

• Liposarcoma.  Liposarcoma arises in fatty tissue and is found most frequently in early adolescence. The most common sites of origin are the legs or trunk.

• Hemangiopericytoma.  Hemangiopericytoma is a tumor of the blood and lymph vessels that occurs most frequently in infants.

• Alveolar soft part sarcoma.  This rare soft tissue sarcoma, found most often in older children, arises from skeletal muscles of the extremities, head, and neck.

Treatment for non-rhabdomyosarcoma soft tissue sarcomas usually is with surgery and sometimes radiation therapy. Chemotherapy may be used to shrink large tumors to make them operable.

Although medical science has made advances in treating soft tissue sarcomas while reducing the side effects and long-term impact to the child, amputation is sometimes necessary. Limb-sparing procedures have made this less common.

Surgery. Surgery is the cornerstone of treatment for soft tissue sarcomas. The surgeon attempts to completely remove the mass with wide margins (i.e., removing a portion of the surrounding tissue) to ensure that no microscopic disease remains. This is often followed by 4000 to 5500 cGy of radiation. Investigational use of brachytherapy (which is implanting radioactive seeds for continuous low-level administration of radiation) is ongoing for children with rare soft tissue sarcomas. Another newer therapy used in current studies is intraoperative electron radiation. Radiation is directed at the site during surgery when the tumor and the surrounding areas are exposed.

Because these malignancies are so rare in children, treatment for non-rhabdomyosarcoma soft tissue sarcomas is based on experience with adults. However, children with non-rhabdomyosarcoma soft tissue sarcomas usually have a better outcome than do adults with the same diseases.

Chemotherapy. The use of chemotherapy after surgery is controversial. Patients with tumors too large to remove or whose disease has spread may be treated with vincristine, dactinomycin, and cyclophosphamide.