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

Other rare childhood cancers include multiple endocrine neoplasia syndromes and Carney complex, skin cancer, chordoma, and cancer of unknown primary site. The prognosis, diagnosis, classification, and treatment of these other rare childhood cancers are discussed below. It must be emphasized that these cancers are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from case series.

MEN syndromes are familial disorders that are characterized by neoplastic changes that affect multiple endocrine organs.[1] Changes may include hyperplasia, benign adenomas, and carcinomas. There are two main types of MEN syndrome: type 1 and type 2. Type 2 can be further subdivided into three subtypes: type 2A, type 2B, and familial medullary thyroid carcinoma (FMTC). The most salient clinical and genetic alterations of the MEN syndromes are shown in Table 1.

Table 1. MEN Syndromes with Associated Clinical and Genetic Alterations

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Syndrome	Clinical Features/Tumors		Genetic Alterations
MEN type 1: Werner syndrome [2]	Parathyroid		11q13 (MEN1 gene)
	Pancreatic islets:	Gastrinoma	11q13 (MEN1 gene)
		Insulinoma
		Glucagonoma
		VIPoma
	Pituitary:	Prolactinoma	11q13 (MEN1 gene)
		Somatotrophinoma
		Corticotrophinoma
	Other associated tumors:	Carcinoid	11q13 (MEN1 gene)
		Adrenocortical
		Lipoma
MEN type 2A: Sipple syndrome	Medullary thyroid carcinoma		10q11.2 (RET gene)
	Pheochromocytoma
	Parathyroid gland
MEN type 2B	Medullary thyroid carcinoma		10q11.2 (RET gene)
	Pheochromocytoma
	Mucosal neuromas
	Intestinal ganglioneuromatosis
	Marfanoid habitus
Familial medullary thyroid carcinoma	Medullary thyroid carcinoma		10q11.2 (RET gene)

The MEN 1 syndrome, also referred to as Werner syndrome, is an autosomal dominant disorder characterized by the presence of tumors in the parathyroid, pancreatic islet cells, and anterior pituitary. Diagnosis of this syndrome should be considered when two of the three endocrine tumors listed in the table above are present. Less common tumors associated with this syndrome include adrenocortical tumors, carcinoid tumors, lipomas, angiofibromas, and collagenomas. The first manifestation of the disease in 90% of patients is hypercalcemia; the most common cause of morbidity and mortality in these patients is the development of gastrinomas, leading to Zollinger-Ellison syndrome.[2,3] Germline mutations of the MEN1 gene located on chromosome 11q13 are found in 70% to 90% of patients; however, this gene has also been shown to be frequently inactivated in sporadic tumors.[4] Mutation testing should be combined with clinical screening for patients and family members with proven at-risk MEN 1 syndrome.[5] There are guidelines that may be followed for screening patients with MEN 1 syndrome.

MEN 2A is characterized by the presence of two or more endocrine tumors (see Table 2) in an individual or in close relatives. RET mutations in these patients are usually confined to exons 10 and 11. MEN 2B is characterized by medullary thyroid carcinomas, parathyroid hyperplasias, adenomas, pheochromocytomas, mucosal neuromas, and ganglioneuromas.[6,7] The medullary thyroid carcinomas that develop in these patients are extremely aggressive. More than 95% of muations in these patients are confined to codon 918 in exon 16, causing receptor autophosphorylation and activation.[8] Patients also have medullated corneal nerve fibers, distinctive faces with enlarged lips, and an asthenic Marfanoid body habitus. A pentagastrin stimulation test can be used to detect the presence of medullary thyroid carcinoma in such patients, although current management of patients is driven primarily by the results of genetic analysis for RET mutations.[8] There are guidelines that may be followed for screening patients with MEN 2 syndromes.

FMTC is diagnosed in families with medullary thyroid carcinoma in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. RET mutations in exons 10, 11, 13, and 14 account for most cases. (See Table 2.)

Table 2. Clinical Features of MEN 2 Syndromes

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MEN 2 Subtype	Medullary Thyroid Carcinoma	Pheochromocytoma	Parathyroid Disease
MEN 2A	95%	50%	20% to 30%
MEN 2B	100%	50%	Uncommon
FMTC	100%	0%	0%

A germline activating mutation in the RET oncogene (a receptor tyrosine-kinase) on chromosome 10q11.2 is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN 2A and MEN 2B syndromes.[9-11] 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. For children with MEN 2A, thyroidectomy is commonly performed by approximately age 5 years or older if that is when a mutation is identified. [11-16] Relatives of patients with MEN 2A should undergo genetic testing in early childhood, before the age of 5 years. Carriers should undergo total thyroidectomy as described above with autotransplantation of one parathyroid gland by a certain age.[16-19] Because of the increased virulence of medullary thyroid carcinoma in children with MEN 2B and in those with mutations in codons 883, 918, and 922, it is recommended that these children undergo prophylactic thyroidectomy in infancy.[8,13,20] 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 in a small percentage of cases 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.[21-23] 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.[23,24]

The Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1A gene, located in chromosome 17.[25] The syndrome is characterized by cardiac and cutaneous myxomas, pale brown to brown lentigines, blue nevi, primary pigmented nodular adrenocortical disease causing Cushing syndrome, and a variety of endocrine and nonendocrine tumors, including pituitary adenomas, thyroid tumors, and large cell calcifying Sertoli cell tumor of the testis.[25-27] There are guidelines that may be followed for screening patients with Carney complex.

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.[28-30] 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.

Refer to the PDQ summary on Genetics of Medullary Thyroid Cancer for more information about MEN 2A and MEN 2B.

• 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.[31,32]

Melanoma is the most common skin cancer in children, followed by basal cell and squamous cell carcinomas (SCCs).[33-41] There are approximately 425 cases of melanoma diagnosed each year in the United States in patients younger than 20 years, representing about 1% of all new cases of melanoma that are diagnosed annually in this country.[42] Melanoma annual incidence increases with age from 1 to 2 per million in children younger than 10 years, to 4.1 and 16.9 per million in children aged 10 to 14 years and in children aged 15 to 19 years, respectively.[43] Melanoma accounts for about 8% of all cancers seen in children aged 15 to 19 years.[43] The incidence of pediatric melanoma (in children younger than 20 years) increased by 1.7% per year between 1975 and 2006;[43] increased ambient ultraviolet radiation increases the risk of the disease.[44]

Conditions associated with an increased risk of melanoma in children and adolescents include giant melanocytic nevi, xeroderma pigmentosum (a rare recessive disorder characterized by extreme sensitivity to sunlight, keratosis, and various neurologic manifestations),[37] immunodeficiency, immunosuppression, and Werner syndrome.[45] Other phenotypic traits that are associated with an increased risk of melanoma in adults have been documented in children and adolescents with melanoma and include exposure to ultraviolet sunlight, red hair, blue eyes,[46-49] poor tanning ability, freckling, dysplastic nevi, increased number of melanocytic nevi, and family history of melanoma.[50,51] Neurocutaneous melanosis is an unusual condition associated with large or multiple congenital nevi of the skin in association with meningeal melanosis or melanoma; approximately 2.5% of patients with large congenital nevi develop this condition, and those with increased numbers of satellite nevi are at greatest risk.[52,53]

Pediatric melanoma shares many similarities with adult melanoma, and the prognosis is stage dependent. In pediatric melanoma, however, thickness does not appear to correlate with outcome in localized invasive disease.[44,54,55] In addition, pediatric melanoma appears to have a much higher incidence of nodal involvement,[56,57] but this feature does not appear to affect clinical outcome. Children younger than 10 years who have melanoma often present with poor prognostic features, are more often non-white, have head and neck primary tumors, and more often have syndromes that predispose them to melanoma.[44,55]

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.[58] 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.[59-62] 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. The width of surgical margins in melanoma is dictated by the site, size, and thickness of the lesion and ranges from 0.5 cm for in situ lesions to 2 cm or more for thicker lesions.[37] To achieve negative margins in children, wide excision with skin grafting may become necessary in selected cases. Examination of regional lymph nodes using sentinel lymph node (SLN) biopsy has become routine [63] and is recommended in patients with lesions measuring more than 1 mm in thickness or in those whose lesions are 1 mm or less in thickness and have unfavorable features such as ulceration, Clark level of invasion IV or V, or mitosis rate of 1 per mm² or higher.[63-65] Lymph node dissection is recommended if sentinel nodes are involved with tumor, and adjuvant therapy with high-dose interferon-alpha-2b for a period of 1 year should be considered in these patients.[37,63,66-68] Clinically benign melanocytic lesions can sometimes pose a significant diagnostic challenge, especially when they involve regional lymph nodes.[69,70]

Novel diagnostic techniques may be used to try to differentiate melanoma from atypical spitzoid lesions. For example, the absence of BRAF mutations or the presence of a normal chromosomal complement with or without 11p gains strongly favors a diagnosis other than melanoma.[71,72] For patients with metastatic disease, prognosis is poor and single-agent chemotherapy with dacarbazine, temozolomide, sorafenib,[73] interleukin 2, or biochemotherapy may be used.[74,75]

Overall 5-year survival of children and adolescents with melanoma is approximately 90%.[44,55] Approximately three-fourths of all children and adolescents present with localized disease and have an excellent outcome (>90% 5-year survival). The outcome for patients with nodal disease is intermediate, with about 60% expected to survive long term.[44,55] In one study, the outrcome for patients with metastatic disease was favorable,[44] but this figure was not duplicated in another study from the National Cancer Database.[55] (Refer to the PDQ summary on adult Skin Cancer Treatment for more information.)

There is one melanoma trial available to patients aged 10 years or older in cooperation with the adult cooperative group, Eastern Cooperative Oncology Group (ECOG).

• ECOG-1697: ECOG-1697 Phase III trial of 4 weeks of high-dose interferon-alpha-2b in stages T2N0, T3a-bN0, T4a-bN0, and T1-4N1a, N2a (microscopic) melanoma.

Chordoma is a very rare tumor of bone 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 one million people per year, and only 5% of all chordomas occur in patients younger than 20 years.[76] In children and adolescents, chordomas are more likely to arise in the skull base rather than in the sacrum, making them relatively inaccessible to complete surgical excision. Most pediatric patients have the conventional or chondroid variant of chordoma.[76,77] 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.[78-80][Level of evidence: 3iiiDiii] Recurrences are usually local but can include distant metastases to lungs or bone. Children younger than 5 years appear to have a worse outlook than older patients.[76,81,82] The survival rate in children and adolescents ranges from about 50% to 80%.[76,82] There is no known effective cytotoxic agent or combination chemotherapy for this disease. Imatinib mesylate has been shown to have antitumor activity in adults with chordoma,[83] and its effect might be the result of inhibition of phosphorylation and activation of PDGFR alpha, beta, and KIT receptors.[84] This therapy has not been tested in children with chordoma.

Cancers of unknown primary site (CUPs) present as a metastatic cancer for which a precise primary tumor site cannot be determined.[85] 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, treatment should be directed toward the specific histopathology of the tumor and should be age appropriate for the general type of cancer initiated, irrespective of the site or sites of involvement.[85] Studies in adults suggest that positron emission tomography (PET) imaging can be helpful in identifying CUPs, particularly in patients whose tumors arise in the head and neck area.[86] In addition, molecular assignment of tissue of origin using molecular profiling techniques is feasible and can aid in identifying the putative tissue of origin in about 60% of patients with CUPs.[87] It is still unclear, however, whether these techniques can improve the outcomes or response rates of these patients, and no pediatric studies have been conducted.[88]

Chemotherapy and radiation therapy treatments appropriate and relevant for the general category of carcinoma or sarcoma (depending on the histologic findings, symptoms, and extent of tumor) should be initiated as early as possible.

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