Multiple Endocrine Neoplasia Syndrome
        Treatment options under clinical evaluation
Skin Cancer (Melanoma, Basal Cell, and Squamous Cell Carcinoma)
        Treatment options under clinical evaluation
Chordoma
Cancer of Unknown Primary Site

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

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

The MEN 1 syndrome, also referred to as Werner syndrome, may involve tumors of the pituitary gland, the parathyroid, and adrenal, gastric, and pancreatic structures, which may secrete hormones such as insulin. The gene for this syndrome is located on chromosome 11q13. Mutation testing should be combined with clinical screening for patients and family members with proven "at risk" MEN 1.[3] 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 carcinomas, parathyroid hyperplasias, adenomas, and pheochromocytomas, mucosal neuromas, and ganglioneuromas.[4,5] 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.

A germline mutation in the ret oncogene (tyrosine-kinase receptor) on chromosome 10q11.2 is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN 2a and MEN 2b syndromes.[6-8] The current management of medullary thyroid cancer in children from families having the MEN 2 syndromes relies on presymptomatic detection of the ret proto-oncogene mutation responsible for the disease. Children with MEN 2a should undergo prophylactic total thyroidectomy between the ages of 5 and 8 years.[8-12] Relatives of patients with MEN 2a should undergo genetic testing in early childhood, before the age of 5 years. Carriers should undergo total thyroidectomy with autotransplantation of one parathyroid gland by a certain age, depending on the type of mutation found.[13-15] Because of the increased virulence of medullary thyroid carcinoma in children with MEN 2b, it is recommended that these children undergo prophylactic thyroidectomy in infancy.[10,16] Complete removal of the thyroid gland is the recommended procedure for surgical management of medullary thyroid cancer in children, since there is a high incidence of bilateral disease.

Hirschsprung disease has been associated with the development of neuroendocrine tumors such as medullary thyroid carcinoma. RET germline inactivating mutations have been detected in up to 50% of patients with familial Hirschsprung disease and less often in the sporadic form. Cosegregation of Hirschsprung disease and medullary thyroid carcinoma phenotype is infrequently reported, but these individuals usually have a mutation in RET exon 10. It has been recommended that patients with Hirschsprung disease be screened for mutations in RET exon 10 and consideration be given to prophylactic thyroidectomy if such a mutation is discovered.[17]

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 nonendocrine tumors. There may be myxomas of the heart, skin, or breast and tumors of peripheral nerve sheath origin.[2,18] Head and neck manifestations are not uncommon.[18]

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.[19-21] Patients who have the MEN 2b syndrome have a worse outcome primarily due to more aggressive medullary thyroid carcinoma. Prophylactic thyroidectomy has the potential to improve the outcome in MEN 2b, but there are no long-term outcome reports published to date. For patients with the Carney complex, prognosis depends on the frequency of recurrences of cardiac and skin myxomas and other tumors.

• NCI-07-C-0189: This phase I/II NCI trial is investigating vandetanib, an orally available tyrosine kinase receptor inhibitor, for patients aged 5 years to 18 years, with hereditary thyroid medullary carcinoma.[22,23]

Melanoma is thought to be the most common skin cancer in children, followed by basal cell and squamous cell carcinomas (SCCs).[24-31] 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 most instances, melanoma in the pediatric population is similar to that of adults in relation to site of presentation, symptoms, description, spread, and prognosis, but thickness does not appear to have prognostic significance.[30,32] Melanoma may grow more rapidly in prepubescent children than in older individuals and may present with more atypical clinical features in children than in adults.[33,34] Analysis of the National Cancer Data Base identified 3,159 patients aged 1 year to 19 years with melanoma. Most of the patients (90%) were age 10 years or older. More girls (56%) were seen than boys. Younger age and higher stage conferred a worse prognosis.[32]

The greatest cause of skin cancer of any type is exposure to the ultraviolet portion of sunlight.[35-38] 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.[27] They are sometimes associated with large congenital black spots known as melanocytic nevi,[39] which may cover the trunk and thigh.[40-42] 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 SCCs and basal cell carcinomas.[28] 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.[28] Individuals with atypical moles, which include raised lesions that may bleed and various color hues (e.g., 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.[43] Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is a rare disorder with a predisposition to the development of early-onset neoplasms, including basal cell carcinoma, ovarian fibroma, and desmoplastic medulloblastoma.[44-47] SCCs are usually reddened lesions with varying degrees of scaling or crusting, and they have an appearance similar to eczema, infections, trauma, or psoriasis.

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.[28] Wide excision with skin grafting may become necessary. The current recommendation is 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 lymph node [SLN] biopsy technique).[48,49] 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-alpha-2b alone may be recommended for a period of 1 year.[28,50,51] Finding the tumor-involved regional lymph node (via SLN biopsy) may clarify the suspicion of melanoma in diagnostically difficult situations such as Spitz nevus with significant atypia at the primary site.[48] However, on the basis of reports of clinically benign melanocytic lesions involving regional lymph nodes, the prognostic value of SLN biopsy is unclear.[52] SLN biopsies have shown an increased frequency of benign nodal nevi, which might mimic metastasis of melanoma and, therefore, may raise potential diagnostic and therapeutic issues.[53] For individuals with metastatic disease, a combination of cisplatin, vinblastine, imidazole carboxamide, interleukin-2 (IL-2), and interferon-alpha-2b has been proposed.[28]

Overall 5-year survival of children and adolescents with melanoma is approximately 91%.[54] Most children and adolescents present with localized disease (68%–78%) and have an excellent outcome (96% 5-year survival). In a Surveillance, Epidemiology, and End Results (SEER) study, the 5-year survival for those with nodal or distant metastases was 77% and 57%, respectively.[54] The prognosis of children and adolescents with melanoma has been previously reported to be similar to that of adults with similar stage disease, with the prognosis depending on the tumor thickness and the extent of spread at the time of diagnosis.[55,56] However, the outcomes for children and adolescents noted in the SEER study are substantially better for those with nodal or distant metastases than the outcomes for adults in similar stages. One study compared young patients (≤20 years) with adult patients and found a higher incidence of lymph node metastases in the younger patients versus case-matched adult patients (18% vs. 10%), but, the 10-year cause-specific survival rates were similar between the two groups (89% and 79%, respectively).[57] The reason for this difference is unknown, though it is speculated that in children some cases were classified as stage III on the basis of what may have been an intranodal nevus.[52] Factors associated with worse survival from melanoma include male gender, unfavorable location of primary tumor, and regional or distant metastases.[54] Refer to the PDQ summary on adult Skin Cancer Treatment for more information.

There are two melanoma trials available to patients aged 10 years or older. Both of these trials are combination adult/pediatric trials.

• E1697 (ECOG):[58] Phase III trial of 4 weeks of high-dose interferon-alpha-2b in stages T3 to T4 or N1 melanoma.



• S0008 (SWOG):[59] Phase III trial of high-dose interferon-alpha-2b versus cisplatin, vinblastine, and dacarbazine plus IL-2 in patients with high-risk melanoma.

Chordoma is a rare tumor that arises from remnants of the notochord within the clivus, spinal vertebrae, or sacrum. The incidence in the United States is approximately one case per 1 million people per year. In American children and adolescents, chordomas are more likely to arise in the clivus, especially in females, rather than in the sacrum, which is more common among adult males.[60] Patients usually present with pain, with or without neurologic deficits such as cranial or other nerve impairment. Diagnosis is straightforward when the typical physaliferous (soap-bubble-bearing) cells are present. Differential diagnosis is sometimes difficult and includes dedifferentiated chordoma and chondrosarcoma. Standard treatment includes surgery, which is not commonly curative because of difficulty in obtaining clear margins, and external radiation therapy. The best results have been obtained using proton-beam therapy,[61,62] but this is currently available only in Loma Linda, California, and Boston, Massachusetts. Recurrences are usually local but can include distant metastases to lungs or bone. Children younger than 5 years may have a worse outlook than older patients.[63,64] The survival rate in children and adolescents is about 50% at 4 years from diagnosis.[64] There is no known effective cytotoxic agent or combination chemotherapy for this disease, but there is a report of temporary regression after ifosfamide and doxorubicin therapy in a 19-month-old child.[65]

These cancers present as a metastatic cancer for which a precise primary tumor site cannot be determined.[66] 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 adenocarcinomas, melanomas, and embryonal tumors such as rhabdomyosarcomas and neuroblastomas may have such a presentation. Because of the age-related incidence of tumor types, embryonal histologies are more common in children.

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.[66] 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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