Unusual Cancers of Childhood

Table of Contents

Description
HEAD AND NECK CANCERS
Nasopharyngeal Carcinoma
Thyroid Tumors
Oral Cancers
Salivary Gland Cancers
Laryngeal Carcinoma
THORACIC CANCERS
Breast Cancer
Bronchial Adenomas/Carcinoids
Pleuropulmonary Blastoma
Esophageal Tumors
Thymomas
Tumors of the Heart
Mesothelioma
ABDOMINAL CANCERS
Carcinoma of the Adrenal Cortex
Renal Cell Carcinoma
Carcinoma of the Stomach
Cancer of the Pancreas
Colorectal Carcinoma
Carcinoid Tumors
GENITAL/URINARY TUMORS
Carcinoma of the Bladder
Ovarian Cancer
OTHER RARE CHILDHOOD CANCERS
Multiple Endocrine Neoplasia Syndrome
Skin Cancer (Melanoma, Basal Cell and Squamous Cell Carcinoma)
Clear Cell Sarcoma of Tendon Sheaths
Cancer of Unknown Primary Site

Description

GENERAL INFORMATION

Cancer in children and adolescents is rare. 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 incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.1 At these pediatric cancer centers, there are clinical trials available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Much of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI.

The tumors discussed in this summary are diverse; the discussion is arranged in descending anatomic order, from infrequent tumors of the head and neck to rare tumors of the urogenital tract and skin. All of these cancers are rare enough that most pediatric hospitals might see fewer than two in a year. Most of these tumors are more frequent in adults with cancer; thus, much of the information about these tumors may also be sought through sources relevant to adults with cancer.

HEAD AND NECK CANCERS

Head and neck cancers include nasopharyngeal carcinoma, thyroid tumors, mouth cancer, salivary gland cancer, and laryngeal carcinoma. The prognosis, diagnosis, classification, and treatment of these head and neck cancers are discussed below.

Nasopharyngeal Carcinoma

Nasopharyngeal cancer arises in the lining of the nasal cavity and pharynx.2 This tumor accounts for about one-third of all cancers of the upper airways. The incidence of this tumor is approximately one in 100,000 persons under the age of 20 in the United States.3 There is a higher frequency of this tumor in North Africa and Southeast Asia.

Nasopharyngeal carcinoma occurs in association with Epstein-Barr virus (EBV), the virus associated with infectious mononucleosis. The virus can be detected in biopsy specimens of these cancers, and tumor cells can have EBV antigens on their cell surface. Three histologic subtypes are recognized by the World Health Organization. Type 1 is squamous cell carcinoma, type 2 is nonkeratinizing carcinoma, and type 3 is undifferentiated carcinoma.

This cancer most frequently spreads to lymph nodes in the neck, which may alert the patient, parent, or physician to the presence of this tumor. The tumor may also spread to the nose, mouth, and pharynx, causing snoring, epistaxis, obstruction of the eustachian tubes, or hearing loss; it may also invade the base of the skull, causing cranial nerve palsy or difficulty with movements of the jaw (trismus). Distant metastatic sites may include the bones, the lungs, and the liver. The location of the primary tumor can be made by direct inspection of the nasopharynx. A diagnosis can be made from a biopsy of the primary tumor or of enlarged lymph nodes of the neck. Nasopharyngeal carcinomas must be distinguished from all other cancers that can present with enlarged lymph nodes and from other types of cancer in the head and neck area. Thus, diseases such as thyroid cancer, rhabdomyosarcoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and Burkitt's lymphoma must be considered, as should benign conditions such as nasal angiofibroma (which presents with epistaxis) and infections draining into the lymph nodes of the neck.

Diagnostic tests should determine the extent of the primary tumor and whether there are metastases. Visualization of the nasopharynx by an ear-nose-throat specialist using a mirror, examination by a neurologist, and magnetic resonance imaging (MRI) of the head and neck can be used to determine the extent of the primary tumor. Evaluation of the chest and abdomen by computed tomography (CT) and bone scan should also be performed to determine whether there is metastatic disease. The levels of EBV and antibody to EBV should also be measured.2,4

Tumor staging is done by the tumor-node-metastasis (TNM) classification system of the American Joint Committee on Cancer. Various reports have indicated an overall survival rate of at least 75% for patients with early stage disease; there is a lower survival rate for patients with higher stage disease.5 No factors other than extent of tumor have correlated with prognosis.

Treatment combines the use of surgery, radiation therapy, and chemotherapy.6 Nasopharyngeal carcinoma generally has spread to the bones of the skull and to lymph nodes in the neck at the time of diagnosis; thus, the principal role of surgery is to obtain adequate diagnostic material from a biopsy of the involved lymph node or the primary site. Combined modality therapy with radiation and chemotherapy appears to be the most effective treatment for this tumor.7,8 Chemotherapy approaches include neoadjuvant and/or adjuvant therapy with cisplatin, 5-fluorouracil, and methotrexate. Radiation dose to the tumor should be greater than 60 Gy. An overall survival rate of 78% has been reported with this approach.9,10

Thyroid Tumors

Tumors of the thyroid are classified as adenomas or carcinomas.11 Adenomas are benign growths that may cause enlargement of all or part of the gland, which extends to both sides of the neck and can be quite large. Some of these tumors may secrete hormones. Transformation to a malignant carcinoma may occur in some cells, which then may grow and spread to lymph nodes in the neck or to the lungs.

Most thyroid carcinomas occur in girls. Although rare, these cancers represent about 1.5% of all tumors seen in the pediatric age group. There is an excessive frequency of thyroid adenoma and carcinoma in patients who previously received irradiation to the neck.12 Thyroid cancer may be associated with the development of other types of malignant tumors, such as the multiple endocrine neoplasia (MEN) syndromes. Thyroid carcinomas are differentiated tumors, meaning that they tend to grow slowly and are not highly malignant. Thyroid radionuclide scans do not demonstrate the uptake of radioisotope into the area of the suspected neoplasm.

Various histologies account for the general diagnostic category of carcinoma of the thyroid.13 Papillary carcinoma represents 60% to 75% of these tumors,14 follicular carcinoma 10% to 20%, medullary carcinoma 5% to 10%, and anaplastic carcinoma less than 1%. Follicular carcinomas may be sporadic or familial. Follicular carcinoma and papillary carcinoma generally have a benign course, with an approximately 80% 10-year survival rate. Fifty percent of medullary thyroid carcinomas, which may be familial, have hematogenous metastases at diagnosis.15 Follicular carcinoma may also have a high incidence of metastases, whereas papillary carcinomas often have multicentric origin. Patients with medullary carcinoma of the thyroid have a guarded prognosis, unless they have very small tumors ("microcarcinoma," defined as less than 1.0 cm in diameter), which carry a good prognosis.16

Surgery is the treatment required for all thyroid neoplasms. Total thyroidectomy is recommended for medullary cancer, and the resected parathyroid glands generally are autotransplanted to other sites such as the forearm.17 A more conservative approach is recommended for papillary carcinoma, with lymph node dissection leading to near total thyroidectomy. Over the 4 to 6 weeks following surgery, patients may develop hypothyroidism. A radioactive iodine scan is performed to search for residual neoplasm in the functioning thyroid tissue. After the thyroid scan, radioactive iodine (I-131) treatment is given at a dose of 100 to 150 mCu, and the patient is kept in a safe area overnight or until the kidney clears virtually all of the radioactive component. In the postoperative period, hormone replacement therapy must be given to compensate for the lost thyroid hormone.18 I-131 is usually successful in suppressing thyroid function, after which the patient is treated with synthetic thyroid hormones for life. Periodic evaluations are required to determine whether there is metastatic disease involving the lungs. Lifelong follow-up is necessary.19 Thyroglobulin levels, T4, and TSH levels should be evaluated periodically to determine whether replacement hormone is appropriately dosed. Patients with thyroid cancer generally have an excellent survival with relatively few side effects.19 Recurrence is common, however, and is seen more often in children younger than 10 years old.20 Even patients with tumor that has spread to the lungs may expect to have no decrease in life span after appropriate treatment.

Oral Cancers

Cancer of the mouth in children or in adolescents is extremely rare.3 This cancer primarily occurs in adults older than 50 years who have used tobacco for many years; however, it can occur in survivors of other childhood tumors who have had radiation therapy to this area. Evidence suggests that oral cancer at younger ages primarily results from the use of smokeless tobacco products among preadolescent boys.17 Changes in the texture, color, and shape of the mucosal lining of the mouth have been seen, together with degenerative changes of the gingiva, in more than half of all teenagers who use smokeless tobacco.21 Precancerous lesions are common among children. Squamous cell carcinoma, the most frequent type of cancer in these sites, must be distinguished from benign tumors of the pharynx and neck, e.g., dermoid cysts, lipomas, myofibromas, cystic hygroma, and teratomas. Other tumors in this area may include ameloblastoma or adamantinoma, a rare tumor that may arise in the mandible or the maxilla, as well as in the long bones.22 The treatment of ameloblastoma is surgical resection, if possible. Ameloblastoma may be benign or malignant; pulmonary metastases may be discovered many years after treatment for this tumor.

Salivary Gland Cancers

Many salivary gland cancers arise in the parotid gland.23,24 About 15% of these tumors may arise in the submandibular glands or in the minor salivary glands under the tongue and jaw. These tumors are most frequently benign, but on very rare occasions, may be malignant. The malignant lesions include adenocarcinoma, undifferentiated carcinoma, acinic cell carcinomas, and mucoepidermoid carcinoma. These tumors may occur after radiation therapy is given for treatment of primary leukemia or solid tumors. Radical surgical removal is the treatment of choice, whenever possible, with additional use of radiation therapy and chemotherapy for high-grade tumors or tumors that have spread from their site of origin.25,26 Prognosis for patients with these tumors is generally good.27

Laryngeal Carcinoma

Benign and especially malignant tumors of the larynx are rare. Malignant tumors may be associated with benign tumors such as polyps and papillomas.28,29 These tumors may cause hoarseness, difficulty swallowing, and enlargement of the lymph nodes of the neck. Rhabdomyosarcoma is the most common malignant tumor of the larynx in the pediatric age group. Squamous cell carcinoma of the larynx should be managed in the same manner as in adults with carcinoma at this site, with surgery and radiation. Laser surgery may be the first type of treatment utilized for these lesions.

Papillomatosis of the larynx is a benign overgrowth of tissues lining the larynx, associated with the human papillomavirus.30 This condition is not cancerous and may be treated with interferon.31 These tumors can cause hoarseness because of their association with wart-like nodules on the vocal cords and may extend into the lung, producing significant morbidity. Malignant degeneration may occur, with development of cancer in the larynx.

THORACIC CANCERS

Thoracic cancers include breast cancer, bronchial adenomas, bronchial carcinoid tumors, pleuropulmonary blastoma, esophageal tumors, thymomas, tumors of the heart and mesothelioma. The prognosis, diagnosis, classification, and treatment of these thoracic cancers are discussed below.

Breast Cancer

Most tumors that involve the breast during childhood are benign, yet carcinomas have been reported in both males and females younger than 21 years.32-35 There is an increased lifetime risk of breast cancer in female survivors of Hodgkin's disease who were treated with radiation to the chest area.35 Carcinomas are more frequent than sarcomas. Mammograms should start at age 25 for any patient who has had radiation therapy to the chest. Treatment options include radiation, chemotherapy, and surgery for children and adolescents with breast cancer. Breast tumors may also occur as metastatic deposits from leukemia, rhabdomyosarcoma, or other sarcomas.

Bronchial Adenomas/Carcinoids

Bronchial adenomas, which are slow-growing neoplasms, are also called carcinoid tumors.36-38 Primary treatment of these tumors is surgical resection. For bronchial carcinoid tumors, nuclear scans may demonstrate uptake of radioactivity by the tumor or lymph nodes, suggesting metastatic spread. Neither chemotherapy nor radiation therapy is indicated for bronchial carcinoid, unless evidence of metastasis is documented.

Pleuropulmonary Blastoma

Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy in children. The tumor usually is located in lung periphery, but it may be extrapulmonary with involvement of the mediastinum, diaphragm, and/or pleura.39 The tumors may recur or metastasize, in spite of primary resection.40 Responses to chemotherapy have been reported with agents similar to those used for the treatment of rhabdomyosarcoma.41 Chemotherapeutic agents may include vincristine, cyclophosphamide, dactinomycin, and doxorubicin. Radiation, either external beam or p32, may be used when the tumor cannot be surgically removed. A family history of cancer in close relatives has been noted for many young patients affected by this tumor.42

Esophageal Tumors

Esophageal cancer is rare in the pediatric age group, although it is relatively common in older adults.43 Symptoms are related to difficulty in swallowing and associated weight loss. Most of these tumors are squamous cell carcinomas, although sarcomas can also arise in the esophagus. The most common benign tumor is leiomyoma. Diagnosis is made by histologic examination of biopsy tissue.

Treatment options for esophageal carcinoma include either external beam, intracavitary radiation therapy, or chemotherapy with the platinum derivatives, paclitaxel, and etoposide, agents commonly used to treat carcinomas. Prognosis generally is poor for this cancer, which rarely can be completely resected.

Thymomas

A cancer of the thymus is not considered a thymoma unless there are neoplastic changes of the epithelial cells that cover the organ.44 Other tumors that involve the thymus gland include lymphoma, germ cell tumors, carcinomas, carcinoid, and thymoma. Hodgkin's disease and non-Hodgkin's lymphoma may also involve the thymus and must be differentiated from true thymomas.

Thymomas are rare in adults and children.45 Various diseases and syndromes are associated with thymoma, including myasthenia gravis, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, thyroiditis, and pure red cell aplasia.46 Endocrine (hormonal) disorders including hyperthyroidism, Addison's disease, and panhypopituitarism can also be associated with a diagnosis of thymoma.47

Thymomas are usually located in the front part of the chest, and are usually discovered during a routine chest x-ray. Symptoms can include cough, difficulty with swallowing, tightness of the chest, chest pain, and shortness of breath although nonspecific symptoms may occur. These tumors generally are slow-growing, but are potentially invasive, with metastases to distant organs or lymph nodes. Staging is related to invasiveness. Surgery is performed with the goal of a complete resection.

Radiation therapy is necessary for patients with invasive thymoma, whether or not there has been a complete resection.47 Chemotherapy is usually reserved for patients with advanced stage disease who have not responded to radiation therapy or corticosteroids. Agents that have been effective include doxorubicin, cisplatin and paclitaxel.47-49 The prognosis for patients with invasive thymoma usually is poor, although significantly higher rates of survival have been reported for patients with tumors that are not locally invasive. Thymic carcinoma, which microscopically resembles undifferentiated nasopharyngeal carcinoma, is associated with Epstein-Barr virus infection, as is nasopharyngeal carcinoma. This tumor is responsive to chemotherapy and is potentially curable.

Tumors of the Heart

The most common tumors of the heart are benign and include myxomas and neurofibromas, i.e., tumors of the nerves that innervate the muscles.50 Other tumors of the heart can include metastatic spread of rhabdomyosarcoma, melanoma, leukemia, and carcinoma of other sites. Primary tumors of the heart may include benign and malignant teratoma, rhabdomyosarcoma, hemangioma, and chondrosarcoma. Symptoms include abnormalities of heart rhythm, enlargement of the heart, fluid in the pericardial sac, and congestive heart failure. Successful treatment requires surgery, which may include transplantation, and chemotherapy appropriate for the type of cancer that is present.51

Mesothelioma

This tumor can involve the membranous coverings of the lung, the heart, or the abdominal organs.52 These tumors can spread over the surface of organs, without invading far into the underlying tissue, and may spread to regional or distant lymph nodes. Mesothelioma may develop after successful treatment of an earlier cancer, especially after treatment with radiation.53,54 In adults, these tumors have been associated with exposure to asbestos, which was used as building insulation.55 The amount of exposure required to develop cancer is unknown, and there is no information about the risk for children exposed to asbestos.

Benign and malignant mesotheliomas cannot be differentiated using histologic criteria. A poor prognosis is associated with lesions that are diffuse and invasive or for those that recur. In general, the course of the disease is slow, and long-term survival is common. Treatment with various chemotherapeutic agents used for carcinomas or sarcomas may result in partial responses. Pain is an infrequent symptom; however, radiation therapy may be used for palliation of pain.

Papillary serous carcinoma of the peritoneum is sometimes mistaken for mesothelioma.56 This tumor generally involves all surfaces lining the abdominal organs, including the surfaces of the ovary. Treatment includes surgical resection whenever possible and use of chemotherapy with agents such as cisplatin, carboplatin, and paclitaxel.

ABDOMINAL CANCERS

Abdominal cancers include adrenocortical tumors, renal cell carcinoma, carcinoma of the stomach, cancer of the pancreas, colorectal carcinoma, carcinoid tumors, and multiple endocrine neoplasia syndrome. The prognosis, diagnosis, classification, and treatment of these abdominal cancers are discussed below.

Carcinoma of the Adrenal Cortex

Adrenocortical tumors are classified as carcinomas and adenomas.57 Adrenocortical tumors may be hormonally active or inactive. Adenomas are generally benign, whereas adrenocortical carcinomas frequently secrete hormones and may cause the patient to develop masculine traits, irrespective of the patient's gender. Pediatric patients with adrenocortical carcinoma often have Li-Fraumeni syndrome, which is an inherited condition that predisposes family members to multiple cancers, including breast cancer, rhabdomyosarcoma, and osteosarcoma.58

These tumors spread locally to the lymph nodes and can also involve the kidneys, lungs, and bones. Surgical removal should be attempted but may not always be possible if the tumor has spread widely. Additional treatment may include the use of an artificial hormone that blocks the masculinizing effects of the tumor 59 or chemotherapy using cisplatin, 5-fluorouracil, and etoposide.60 The prognosis for patients who have small, completely resected tumors generally is excellent, but prognosis can be poor for patients who have large primary tumors or metastatic disease at diagnosis.61

Renal Cell Carcinoma

Renal cell carcinoma is the most common primary malignancy of the kidney in adults; however, it occurs rarely in children.62,63 The annual incidence rate is approximately 4 per 1 million children, compared to an incidence of Wilms' tumor of the kidney that is at least 29-fold higher. Renal cell carcinoma may be associated with von Hippel-Lindau disease, a hereditary condition in which blood vessels within the retina and cerebellum grow excessively.64 The gene for von Hippel-Lindau is on chromosome 3p14 and is a tumor-suppressor gene whose function is lost in patients with the syndrome. Renal cell carcinoma has also been associated with tuberous sclerosis, a hereditary disease characterized by benign fatty cysts in the kidney.65-67 Familial renal cell carcinoma has been associated with an inherited chromosome translocation involving chromosome 3.66 A high incidence of chromosome 3 abnormalities has also been demonstrated in nonfamilial renal tumors.

Renal cell carcinoma usually presents as an abdominal mass, and there may be discomfort, pain, and/or blood in the urine.65 The tumor can metastasize to the lungs, bones, liver, and lymph nodes and often has spread before the diagnosis is made. This tumor should be considered whenever a patient presents with a kidney mass and is older than 5 years of age.

The primary treatment includes total surgical removal of the kidney and associated lymph nodes. Consideration should also be given to treatment with irradiation, chemotherapy, or both. Treatment of metastatic disease is presently unsatisfactory but usually includes the use of immune system modulators such as interferon-alfa and interleukin-2.68 Rare spontaneous regression of pulmonary metastasis may occur with resection of the primary tumor.

Carcinoma of the Stomach

The frequency and death rate from stomach cancer has declined worldwide over the past 50 years with the introduction of food preservation practices such as refrigeration.69 The tumor must be distinguished from other conditions such as non-Hodgkin's lymphoma, malignant carcinoid, leiomyosarcoma, and various benign conditions or tumors of the stomach. Symptoms include vague upper abdominal pain, which can be associated with poor appetite, and weight loss. Many individuals become anemic but otherwise show no symptoms before the development of metastatic spread. Other symptoms may include nausea, vomiting, change in bowel habits, poor appetite, weakness, and Helicobacter pylori infection.70 Fiberoptic endoscopy can be used to visualize the tumor or to take a biopsy sample to ensure the correctness of diagnosis. Confirmation can also involve an x-ray examination of the upper gastrointestinal tract.

Treatment should include surgical excision with wide margins. For individuals who cannot have a complete surgical resection, radiation therapy may be used along with chemotherapeutic agents such as 5-fluorouracil and irinotecan.71 Other agents that may be of value are the nitrosoureas, with or without cisplatin, etoposide, doxorubicin or mitomycin C.

Prognosis depends on the extent of the disease at the time of diagnosis and the success of treatment that is appropriate for the clinical situation.72 Because of the rarity of stomach cancer in the pediatric age group, little information regarding the treatment outcomes of children exists.

Cancer of the Pancreas

Pancreatic tumors are rare in children and adolescents.3 Tumors included in the general category can arise at any site within the pancreas. Cancers of the pancreas may be classified as adenocarcinoma, squamous cell carcinoma, acinic cell carcinoma, liposarcoma, lymphoma, papillary-cystic carcinoma, pancreaticoblastoma, malignant insulinoma, glucagonoma, and gastrinoma.73 Most pancreatic tumors do not secrete hormones, although some tumors secrete insulin, which can lead to symptoms of weakness, fatigue, hypoglycemia, and coma.73 If tumor interferes with the normal function of the islet cells, patients may have watery diarrhea or abnormalities of salt balance. Both carcinoma of the pancreas and pancreaticoblastoma can produce active hormones and can be associated with abdominal mass, wasting, and pain.74-76 At times, there is obstruction of the head of the pancreas, which is associated with jaundice and gastrointestinal bleeding.

The diagnosis is usually established by biopsy, using laparotomy or a minimally invasive surgery (laparoscopy). A diagnosis can only be achieved after ruling out various benign and cancerous lesions. Treatment includes various surgical procedures to remove the pancreas and duodenum or removal of part of the pancreas. For pediatric patients, the effectiveness of radiation therapy is not known. Chemotherapy may be useful for treatment of localized or metastatic pancreatic carcinoma, although few cases have been successfully treated. Agents that may be of value include 5-fluorouracil, streptozotocin, mitomycin C, doxorubicin, carboplatin, gemcitabine, and irinotecan. Response rates and survival rates generally are not good.75,76

Colorectal Carcinoma

Carcinoma of the large bowel is rare in the pediatric age group, as it is seen in only 1 person per 1 million younger than 20 years in the United States annually.77 These tumors can occur anywhere in the colon or rectum and are often associated with a family cancer syndrome.78 There is an increasing risk of colorectal carcinoma in members of families with a family history of intestinal polyposis, which can lead to the development of multiple adenomatous polyps.79 Juvenile polyps are not associated with an increased incidence or risk of cancer.

Familial polyposis is inherited as a dominant trait, which confers a high degree of risk. Early diagnosis and surgical removal of the colon eliminate the risk of developing carcinomas of the large bowel.80 Some colorectal carcinomas in young people, however, may be associated with a mutation of the adenomatous polyposis coli (APC) gene, which also is associated with an increased risk of brain tumors and hepatoblastoma.81 The familial APC syndrome is caused by mutation of a gene on chromosome 5q, which normally suppresses proliferation of cells lining the intestine and later development of polyps.82 Another tumor suppressor gene on chromosome 18 is associated with progression of polyps to malignant form. Multiple colon carcinomas have also been associated with progression of polyps to a malignant form. Multiple colon carcinomas have been associated with neurofibromatosis type I (NF-1) and several other rarer syndromes.83

The histologic types of colorectal cancer include adenocarcinoma, mucinous or colloid adenocarcinomas, signet-ring adenocarcinoma, and scirrhous tumors. Most tumors in the pediatric age group are mucin-producing carcinomas,84 whereas only about 15% of adult lesions are of this histology. The tumors of younger patients with this histologic variant may be less responsive to chemotherapy. These tumors arise from the surface of the bowel, usually at the site of an adenomatous polyp. The tumor may extend into the muscle layer surrounding the bowel, or the tumor may perforate the bowel entirely and seed through the spaces around the bowel, including intra-abdominal fat, lymph nodes, liver, ovaries, and the surface of other loops of bowel. A high incidence of metastasis involving the pelvis, ovaries, or both may be present in girls.85

Colorectal carcinoma usually presents with symptoms related to the site of the tumor. Changes in bowel habits are associated with tumors of the rectum or lower colon. Tumors of the right colon may cause more subtle symptoms, but are often associated with an abdominal mass, weight loss, decreased appetite, and blood in the stool. Any tumor that causes complete obstruction of the large bowel can cause bowel perforation and spread of the tumor cells within the abdominal cavity.

Because of its rarity, colorectal carcinoma is rarely diagnosed in a pediatric patient; however, vague gastrointestinal symptoms should alert the physician to investigate this possibility. Diagnostic studies that may be of value include examination of the stool for blood, studies of liver and kidney function, measurement of carcinoembryonic antigen, and various medical imaging studies, including direct examination using colonoscopy to detect polyps in the large bowel. Other conventional radiographic studies include barium enema followed by CT of the chest and bone scans.84,85

Most patients present with evidence of metastatic disease, either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs. Complete surgical excision should be the primary aim of the surgeon, but in most instances this is impossible; removal of large portions of tumor provides little benefit for the individuals with extensive metastatic disease. Most patients with microscopic metastatic disease generally develop gross metastatic disease, and few individuals with metastatic disease at diagnosis become long-term survivors.

Current therapy includes the use of radiation for rectal and lower colon tumors, in conjunction with chemotherapy using 5-fluorouracil with leucovorin.86 Other agents that may be of value include irinotecan and oxaliplatin. No significant benefit has been determined for interferon-alfa given in conjunction with 5-fluorouracil/leucovorin.87

Carcinoid Tumors

These tumors, like bronchial adenomas, may be benign or malignant and can involve the lining of the lung or the large or small bowel.88,89 Most lung lesions are benign, however, some metastasize.90 It has become accepted practice to remove the entire right colon in patients with large carcinoid tumors of the appendix (greater than 2 cm in diameter) or with tumors that have spread to the nodes. Treatment of metastatic carcinoid tumors of the large bowel or stomach becomes more complicated and requires treatment similar to that given for colorectal carcinoma. The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver.90 Symptoms may be lessened by giving somatostatin analogues, which are available in short- and long-acting forms.

GENITAL/URINARY TUMORS

Genital/urinary tumors include carcinoma of the bladder and ovarian cancer. The prognosis, diagnosis, classification, and treatment of these genital/urinary tumors are discussed below.

Carcinoma of the Bladder

Carcinoma of the bladder is extremely rare in children. The most common carcinoma to involve the bladder is transitional cell carcinoma, which generally presents with hematuria.91 The diagnosis and treatment of this tumor are the same for children, adolescents, and adults. Adolescents who develop this tumor are often prone to the development of other cancers, including other bladder cancers. Bladder cancer in adolescents may develop as a consequence of alkylating-agent chemotherapy given for other childhood tumors or leukemia.92,93 The association between cyclophosphamide and bladder cancer is the only established relationship between a specific anticancer drug and a solid tumor.92 One of the most important risk factors for bladder cancer in adults is cigarette smoking, which may be associated with up to 50% of these cancers in men and 33% in women.93

Ovarian Cancer

Most cancers that affect the ovaries are of germ cell origin, which are more common in children than adults, in whom adenocarcinomas are more frequently encountered. Ovarian carcinomas of nongerm-cell origin include tumors derived from malignant epithelial elements, including adenocarcinoma,94 cystadenocarcinoma, endometrioid tumors, clear cell tumors, and undifferentiated carcinomas. Treatment is stage related and may include radiation and chemotherapy with cisplatin, carboplatin, etoposide, topotecan, taxol, and other agents.

OTHER RARE CHILDHOOD CANCERS

Other rare childhood cancers include multiple endocrine neoplasia syndrome, skin cancer, clear cell sarcoma of tendon sheaths, and cancer of unknown primary site. The prognosis, diagnosis, classification, and treatment of these other rare childhood cancers are discussed below.

Multiple Endocrine Neoplasia Syndrome

These syndromes are familial disorders that are characterized by neoplastic changes in more than one endocrine organ.80 Changes may include hyperplasia, benign adenomas, and carcinomas. There are distinct genetic disorders with characteristic clinical presentations referred to as MEN-1, MEN-2a, and MEN-2b. An additional complex is referred to as the Carney complex, which is an association of multiple endocrine neoplasia associated with heart and skin tumors.95-97

The MEN-1 syndrome, also referred to as Werner's syndrome,98 may involve tumors of the pituitary gland, the parathyroid, adrenal, and gastric and pancreatic structures, which may secrete hormones such as insulin. The gene for this syndrome is located on chromosome 11q13. The MEN-2a syndrome (Sipple syndrome) is associated with medullary thyroid carcinoma, parathyroid hyperplasia, adenomas, and pheochromocytoma. The MEN-2b syndrome is associated with medullary thyroid carcinoma, parathyroid hyperplasia, adenomas, and pheochromocytoma, mucosal neuromas, and ganglioneuromas.99 Patients with the MEN-2b syndrome may have a slender body build, long and thin extremities, a high arch palate, and pectus excavatum or pes cavus. The face may be characterized by thick lips because of mucosal neuromas. Such patients can also be identified by performing a pentagastrin stimulation test or by genetic screening in families known to be affected. In this syndrome, medullary thyroid carcinoma may be particularly aggressive; therefore, the thyroid should be removed by age 5 or 6 years in affected individuals.100,101

The Carney complex includes the association of primary pigmented nodular adrenocortical disease with blue nevi of the skin and mucosa and a variety of additional endocrine or non-endocrine tumors. There may be myxomas of the skin or breast and tumors of peripheral nerve sheath origin.95-97 The outcome of patients with the MEN-1 syndrome is generally good provided adequate treatment can be obtained for parathyroid, pancreatic, and pituitary tumors. The outcome for patients with the MEN-2a syndrome is also generally good, yet the possibility exists for recurrence of medullary thyroid carcinoma and pheochromocytoma.100-102 For patients with the Carney complex, prognosis depends on the frequency of recurrences of cardiac and skin myxomas and other tumors.

Skin Cancer (Melanoma, Basal Cell and Squamous Cell Carcinoma)

Melanoma is thought to be the most common skin cancer in children, followed by basal cell and squamous cell carcinomas.103-107 The incidence of melanoma in children and adolescents represents approximately 1% of the new cases of melanoma that are diagnosed annually in this country. In all instances, melanoma in the pediatric population is similar to that of adults in relation to site of presentation, symptoms, description, spread, and prognosis.

The greatest cause of skin cancer of any type is exposure to the ultraviolet (UV) portion of sunlight.108-111 Other causes may be related to chemical carcinogenesis, radiation exposure, immunodeficiency, or immunosuppression. The person who is most likely to develop a melanoma is easily sunburned, has poor tanning ability, and generally has light hair, blue eyes, and pale skin. Worldwide, there is an increasing incidence of both melanoma and nonmelanoma skin cancers. Melanoma presents as a relatively flat, dark-colored lesion, which may enlarge, penetrate the skin, or metastasize.

Melanomas may be congenital.106 They are sometimes associated with large congenital black spots known as melanocytic nevi, which may cover the trunk and thigh. Melanomas can also develop in individuals with xeroderma pigmentosum, a rare recessive disorder characterized by extreme sensitivity to sunlight, keratosis, and various neurologic manifestations. Individuals with xeroderma pigmentosum may also develop other skin cancers, including squamous and basal cell carcinomas.107 Children with hereditary immunodeficiencies have an increased lifetime risk of developing melanoma.

Neurocutaneous melanosis is an unusual condition associated with large or multiple congenital nevi of the skin and melanin deposits within the central nervous system. These deposits may be detected by magnetic resonance imaging of the brain or spinal cord. Dysplastic nevi occur in about 5% of the U.S. population and are potential precursors of melanoma.107 Individuals with atypical moles, which include raised lesions (that may bleed) and various color hues (brown, tan, pink, black), are at an increased risk of having melanoma and of having children affected by these premalignant lesions.

Basal cell carcinomas generally appear as raised lumps or ulcerated lesions, usually in areas with previous sun exposure. These tumors may be multiple and exacerbated by radiation therapy as delivered for medulloblastoma.112,113 Squamous cell carcinomas are usually reddened lesions with varying degrees of scaling or crusting, and they have an appearance similar to eczema, infections, trauma, or psoriasis.114

Biopsy or excision is necessary to determine the diagnosis of any skin cancer. Diagnosis is necessary for decisions regarding additional treatment. Basal and squamous cell carcinomas are generally curable with surgery alone, but the treatment of melanoma requires greater consideration because of its potential for metastasis. Surgery for melanoma depends on the size, site, level of invasion, and metastatic extent or stage of the tumor.107 Wide excision with skin grafting may become necessary. It is currently recommended that surgical resection include a 2-cm-deep margin for melanoma lesions, with examination of the regional lymph nodes draining the site of the melanoma. This procedure may require the injection of a radioisotope, following its distribution, and then performing excision of the associated regional lymph nodes (sentinel node biopsy technique). This requires injection of a vital blue stain and radioisotope into the skin to characterize the pattern of lymph node drainage. Lymph node dissection is necessary if sentinel nodes are involved with the tumor; however, if there is no spread of the disease beyond the lymph nodes, adjuvant therapy with interferon alfa-2b alone may be recommended for a period of 1 year.107 For individuals with metastatic disease, a combination of cisplatin, vinblastine, imidazole carboxamide, interleukin-2, and interferon alfa-2b has been proposed.107 Prognosis for melanoma in children and adolescents is similar to that for adults with similar stage disease, with the prognosis depending on the tumor thickness and the extent of spread at the time of diagnosis.115,116 Survival decreases with greater depth of invasion and with metastases to lymph nodes.

Clear Cell Sarcoma of Tendon Sheaths

Malignant melanoma of soft parts has been described as "clear cell sarcoma of tendons and aponeuroses."117 Because of its association with tenosynovial structures and its derivation from neuroectoderm, malignant melanoma of soft parts shares a number of features with cutaneous melanoma, as has been shown by immunophenotyping and structural similarities. More than 95% of these tumors present in the extremities. Survival with this tumor has been correlated with tumor size and other microscopic features. Cytogenetic studies of these tumors have noted a specific chromosome abnormality. Treatment includes surgical removal, radiation therapy, and chemotherapy similar to that given for soft tissue sarcomas.

Cancer of Unknown Primary Site

These cancers present as a metastatic cancer for which a precise primary tumor site cannot be determined.118 As an example, lymph nodes at the base of the skull may enlarge in relationship to a tumor that may be on the face or the scalp but is not evident by physical examination or by radiographic imaging. Thus, modern imaging techniques may indicate the extent of the disease but not a primary site. Tumors such as adenocarcinoma, melanoma, and embryonal tumors such as rhabdomyosarcoma and neuroblastoma may have such a presentation.

For all patients who present with tumors from an unknown primary site, the treatment should be considered in relation to the pathology of the tumor and should be appropriate for the general type of cancer initiated, irrespective of the site or sites of involvement.118 Chemotherapy and radiation therapy treatments appropriate and relevant for the general category of carcinoma or sarcoma (depending upon the histologic findings, symptoms, and extent of tumor) should be initiated as early as possible.

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