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Unusual Cancers of Childhood Treatment (PDQ®)

  • Last Modified: 05/02/2014

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Other Rare Childhood Cancers

Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex
        Clinical presentation and diagnostic evaluation of MEN syndromes
        Treatment of MEN syndromes
        Carney complex
Pheochromocytoma and Paraganglioma
        Genetic predisposition
        Clinical presentation
        Paraganglioma and pheochromocytoma in children and adolescents
        Diagnostic evaluation
        Treatment
Skin Cancer (Melanoma, Basal Cell Carcinoma, and Squamous Cell Carcinoma)
        Melanoma
        Basal cell and squamous cell carcinomas
Chordoma
        Incidence
        Prognosis
        Clinical presentation
        Treatment
Cancer of Unknown Primary Site
        Incidence
        Diagnostic evaluation
        Treatment

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.

Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex

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. MEN type 2 can be further subdivided into three subtypes: type 2A, type 2B, and familial medullary thyroid carcinoma. (Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN syndromes.)

Clinical presentation and diagnostic evaluation of MEN syndromes

The most salient clinical and genetic alterations of the MEN syndromes are shown in Table 5.

Table 5. MEN Syndromes with Associated Clinical and Genetic Alterations
Syndrome Clinical Features/Tumors Genetic Alterations 
MEN type 1: Werner syndrome [2]Parathyroid 11q13 (MEN1 gene)
Pancreatic islets: Gastrinoma11q13 (MEN1 gene)
Insulinoma
Glucagonoma
VIPoma
Pituitary: Prolactinoma11q13 (MEN1 gene)
Somatotrophinoma
Corticotropinoma
Other associated tumors: Carcinoid: bronchial and thymic11q13 (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)

  • MEN 1 syndrome: 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] It is recommended that screening for patients with MEN 1 syndrome begin by the age of 5 years and continue for life. The number of tests or biochemical screening is age specific and may include yearly serum calcium, parathyroid hormone, gastrin, glucagon, secretin, proinsulin, chromogranin A, prolactin, and IGF-1. Radiologic screening should include a magnetic resonance imaging of the brain and computed tomography (CT) of the abdomen every 1 to 3 years.[6]

  • MEN 2A and 2B syndromes:

    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.[7-9]

    • MEN 2A is characterized by the presence of two or more endocrine tumors (see Table 6) in an individual or in close relatives.[10] 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.[10-12] The medullary thyroid carcinomas that develop in these patients are extremely aggressive. More than 95% of mutations in these patients are confined to codon 918 in exon 16, causing receptor autophosphorylation and activation.[13] 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 management of patients is driven primarily by the results of genetic analysis for RET mutations.[13,14]

    Guidelines for genetic testing of suspected patients with MEN 2 syndrome and the correlations between the type of mutation and the risk levels of aggressiveness of medullary thyroid cancer, have been published.[14,15]

  • Familial Medullary Thyroid Carcinoma: Familial medullary thyroid carcinoma 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 6.)

Table 6. Clinical Features of MEN 2 Syndromes
MEN 2 Subtype Medullary Thyroid Carcinoma Pheochromocytoma Parathyroid Disease 
MEN 2A95%50%20% to 30%
MEN 2B100%50%Uncommon
Familial medullary thyroid carcinoma100%0%0%

Treatment of MEN syndromes
  • MEN 1 syndrome: Treatment of patients with MEN 1 syndrome is based on the type of tumor. The outcome of patients with the MEN 1 syndrome is generally good provided adequate treatment can be obtained for parathyroid, pancreatic, and pituitary tumors.

  • MEN 2 syndromes: The 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.
    • MEN 2A syndrome: For children with MEN 2A, thyroidectomy is commonly performed by approximately age 5 years or older if that is when a mutation is identified. [9,16-20] 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.[21-23]

      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.[20,24-26]

    • MEN 2B syndrome: 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.[13,17,27]; [28][Level of evidence: 3iiiDii] 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.

    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.[29-31] 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.[31-33]

    (Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN 2A and MEN 2B.)

In a randomized phase III trial for adult patients with unresectable locally advanced or metastatic hereditary or sporadic medullary thyroid carcinoma treated with vandetanib, a selective inhibitor of RET, VEGFR, and EGFR, versus placebo, vandetanib administration was associated with significant improvements in progression-free survival, response rate, disease control rates, and biochemical response.[34]

Carney complex

The Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1A gene, located in chromosome 17.[35] 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.[35-37] There are guidelines that may be followed for screening patients with Carney complex.

For patients with the Carney complex, prognosis depends on the frequency of recurrences of cardiac and skin myxomas and other tumors.

Pheochromocytoma and Paraganglioma

Pheochromocytoma and paraganglioma are rare catecholamine-producing tumors with a combined annual incidence of three cases per 1 million individuals. Tumors arising within the adrenal gland are known as pheochromocytomas, whereas morphologically identical tumors arising elsewhere are termed paragangliomas. Paragangliomas are further divided into: (1) sympathetic paragangliomas that predominantly arise from the intra-abdominal sympathetic trunk and usually produce catecholamines, and (2) parasympathetic paragangliomas that are distributed along the parasympathetic nerves of the head, neck, and mediastinum and are rarely functional.[38,39]

Genetic predisposition

It is now estimated that up to 30% of all pheochromocytomas and paragangliomas are familial; several susceptibility genes have been described (see Table 7). The median age at presentation in most familial syndromes is 30 to 35 years, and up to 50% of subjects have disease by age 26 years.[40-43]

Table 7. Characteristics of Paraganglioma (PGL) and Pheochromocytoma (PCC) Associated with Susceptibility Genesa
Germline Mutation  Syndrome Proportion of all PGL/PCC (%) Mean Age at Presentation (y) Penetrance of PGL/PCC (%) 
RET MEN25.335.650
VHL VHL9.028.610–26
NF1 NF12.941.60.1–5.7
SDHD PGL17.135.086
SDHFA2 PGL2<132.2100
SDHC PGL3<142.7Unknown
SDHB PGL45.532.777
SDHA -<340.0Unknown
KIF1B-beta -<146.0Unknown
EGLN1 -<143.0Unknown
TMEM127 -<242.8Unknown
MAX [43]-<234Unknown
UnknownCarney triad<127.5-
SDHB, C, D Carney-Stratakis<133Unknown
MEN1 MEN1<130.5Unknown
No mutationSporadic disease7048.3-

MEN1 = multiple endocrine neoplasia type 1; MEN2 = multiple endocrine neoplasia type 2; NF1 = neurofibromatosis type 1; VHL = von Hippel-Lindau.
aAdapted from Welander et al.[40]

  1. Von Hippel-Lindau (VHL) syndrome—Pheochromocytoma and paraganglioma occur in 10% to 20% of patients with VHL.

  2. Multiple Endocrine Neoplasia (MEN) Syndrome Type 2—Codon-specific mutations of the RET gene are associated with a 50% risk of development of pheochromocytoma in MEN 2A and MEN 2B. Somatic RET mutations are also found in sporadic pheochromocytoma and paraganglioma.

  3. Neurofibromatosis type 1 (NF1)—Pheochromocytoma and paraganglioma are a rare occurrence in patients with NF1, and typically have characteristics similar to those of sporadic tumors, with a relatively late mean age of onset and rarity in pediatrics.

  4. Familial pheochromocytoma/paraganglioma syndromes, associated with germline mutations of mitochondrial succinate dehydrogenase (SDH) complex genes (see Table 7). They are all inherited in an autosomal dominant manner but with varying penetrance.
    • PGL1—Associated with SDHD mutations, manifests more commonly with head and neck paragangliomas, and has a very high penetrance, with more than 80% of carriers developing disease by age 50 years.
    • PGL2—Associated with SDHAF2 mutations, is very rare, and generally manifests as parasympathetic paraganglioma.
    • PGL3—Associated with SDHC mutations, is very rare, and usually presents with parasympathetic paraganglioma, often unifocal, benign, and in the head and neck location.
    • PGL4—Associated with SDHB mutations and usually manifests with intra-abdominal sympathetic paraganglioma. The neoplasms associated with this mutation have a much higher risk of malignant behavior, with more than 50% of patients developing metastatic disease. There is also an increased risk of renal cell carcinoma and gastrointestinal stromal tumor (GIST).

  5. Other susceptibility genes recently discovered include KIF1B-beta, EGLN1/PHD2, TMEM127, SDHA, and MAX.[43]

  6. Other syndromes:
    • Carney triad syndrome is a condition that includes three tumors: paraganglioma, GIST, and pulmonary chondromas. Pheochromocytomas and other lesions such as esophageal leiomyomas and adrenocortical adenomas have also been described. The syndrome primarily affects young women, with a mean age of 21 years at time of presentation. Approximately one-half of the patients present with paraganglioma or pheochromocytoma, although multiple lesions occur in approximately only 20% of the cases. About 20% of the patients have all three tumor types; the remainder have two of the three, most commonly GIST and pulmonary chondromas. This triad doesn’t appear to run in families and no responsible gene has been discovered.[44]

    • Carney-Stratakis syndrome (Carney dyad syndrome) is a condition that includes paraganglioma and GIST, but no pulmonary chondromas. It is inherited in an autosomal dominant manner with incomplete penetrance. It is equally common in men and women, with an average age of 23 years at presentation. The majority of patients with this syndrome have been found to carry germline mutations in the SDHB, SDHC, or SDHD genes.[44]

Immunohistochemical SDHB staining may help triage genetic testing; tumors of patients with SDHB, SDHC, and SDHD mutations have absent or very weak staining, while sporadic tumors and those associated with other constitutional syndromes have positive staining.[45,46] Therefore, immunohistochemical SDHB staining can help identify potential carriers of a SDH mutation early, thus obviating the need for extensive and costly testing of other genes.

Clinical presentation

Patients with pheochromocytoma and sympathetic extra-adrenal paraganglioma usually present with symptoms of excess catecholamine production, including hypertension, headache, perspiration, palpitations, tremor, and facial pallor. These symptoms are often paroxysmal, although sustained hypertension between paroxysmal episodes occurs in more than one-half the patients. These symptoms can also be induced by exertion, trauma, labor and delivery, induction of anesthesia, surgery of the tumor, foods high in tyramine (e.g., red wine, chocolate, cheese), or urination (in cases of primary tumor of the bladder). Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines and usually present as a neck mass with symptoms related to compression, but also may be asymptomatic and diagnosed incidentally.[38]

Paraganglioma and pheochromocytoma in children and adolescents

Paraganglioma and pheochromocytoma are exceedingly rare in the pediatric and adolescent population, accounting for only approximately 20% of all cases.[47,48]

Younger patients have a higher incidence of bilateral adrenal pheochromocytoma and extra-adrenal paraganglioma, and a germline mutation can be identified in close to 60% of patients.[48] Therefore, genetic counseling and testing is always recommended in young patients. The pediatric and adolescent patient appears to present with symptoms similar to those of the adult patient, although with a more frequent occurrence of sustained hypertension.[49] The clinical behavior of paraganglioma and pheochromocytoma appears to be more aggressive in children and adolescents and metastatic rates of up to 50% have been reported.[39,48,49]

In a study of 49 patients younger than 20 years with a paraganglioma or pheochromocytoma, 39 (79%) had an underlying germline mutation that involved the SDHB (n = 27; 55%), SDHD (n = 4; 8%), VHL (n = 6; 12%), or NF1 (n = 2; 4%) genes.[48] The germline mutation rates for patients with nonmetastatic disease were lower than those observed in patients who had evidence of metastases (64% vs. 87.5%). Furthermore, among patients with metastatic disease, the incidence of SDHB mutations was very high (72%) and most presented with disease in the retroperitoneum; five died of their disease. All patients with SDHD mutations had head and neck primary tumors. In another study, the incidence of germline mutations involving RET, VHL, SDHD and SDHB in patients with nonsyndromic paraganglioma was 70% for patients younger than 10 years and 51% among those aged 10 to 20 years.[50] In contrast, only 16% of patients older than 20 years had an identifiable mutation.[50] It is important to remember that these two studies did not include systematic screening for other genes that have been recently described in paraganglioma and pheochromocytoma syndromes such as KIF1B-beta, EGLN1/PHD2, TMEM127, SDHA, and MAX (see Table 7).

These findings suggest that younger patients with extra-adrenal nonsyndromic pheochromocytoma and paraganglioma are at high risk for harboring SDHB mutations and that this phenotype is associated with an earlier age of onset and a high rate of metastatic disease. Early identification of young patients with SDHB mutations using radiographic, serologic, and immunohistochemical markers could potentially decrease mortality and identify other family members who carry a germline SDHB mutation. In addition, approximately 12% of pediatric GIST patients have germline SDHB, SDHC, or SDHD mutations in the context of Carney-Stratakis syndrome.

Diagnostic evaluation

The diagnosis of paraganglioma and pheochromocytoma relies on the biochemical documentation of excess catecholamine secretion coupled with imaging studies for localization and staging.

Biochemical testing

Measurement of plasma-free fractionated metanephrines (metanephrine and normetanephrine) is usually the diagnostic tool of choice when the diagnosis of a secreting paraganglioma or pheochromocytoma is suspected. A 24-hour urine collection for catecholamines (epinephrine, norepinephrine, and dopamine) and fractionated metanephrines can also be performed for confirmation.[51,52]

Catecholamine metabolic and secretory profiles are impacted by hereditary background; both hereditary and sporadic paraganglioma and pheochromocytoma differ markedly in tumor contents of catecholamines and corresponding plasma and urinary hormonal profiles. About 50% of secreting tumors produce and contain a mixture of norepinephrine and epinephrine, while most of the rest produce norepinephrine almost exclusively, with occasional rare tumors producing mainly dopamine. Patients with epinephrine-producing tumors are diagnosed later (median age, 50 years) than those with tumors lacking appreciable epinephrine production (median age, 40 years). Patients with MEN2 and NF1 syndromes, all with epinephrine-producing tumors, are typically diagnosed at a later age (median age, 40 years) than patients with tumors that lack appreciable epinephrine production secondary to mutations of VHL and SDH (median age, 30 years). These variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of paraganglioma and pheochromocytoma for different progenitor cells with variable susceptibility to disease-causing mutations.[53,54]

Imaging

Imaging modalities available for the localization of paraganglioma and pheochromocytoma include CT, magnetic resonance imaging, iodine I-123 or iodine I-131–labeled metaiodobenzylguanidine (123/131I-mIBG) scintigraphy, and fluorine F-18 6-fluorodopamine (6-[18F]FDA) positron emission tomography (PET). For tumor localization, 6-[18F]FDA PET and 123/131I-mIBG scintigraphy perform equally well in patients with nonmetastatic paraganglioma and pheochromocytoma, but metastases are better detected by 6-[18F]FDA PET than by 123/131I-mIBG.[55] Other functional imaging alternatives include indium In-111 octreotide scintigraphy and fluorodeoxyglucose F-18 PET, both of which can be coupled with CT imaging for improved anatomic detail.

Treatment

Treatment of paraganglioma and pheochromocytoma is surgical. For secreting tumors, alpha and beta adrenergic blockade must be optimized prior to surgery. For patients with metastatic disease, responses have been documented to some chemotherapeutic regimens such as gemcitabine and docetaxel or vincristine, cyclophosphamide, and dacarbazine.[56,57] Chemotherapy may help alleviate symptoms and facilitate surgery, although its impact in overall survival is less clear. Responses have also been obtained to high-dose 131I-mIBG.[58]

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

Melanoma

Incidence

Melanoma, although rare, is the most common skin cancer in children, followed by basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs).[59-66] In a retrospective study of 22,524 skin pathology reports in patients younger than 20 years, investigators identified 38 melanomas, 33 of which occurred in patients aged 15 to 19 years. Study investigators reported that the number of lesions that needed to be excised in order to identify one melanoma was 479.8, which is 20 times higher than the adult population.[67]

In patients younger than 20 years, there are approximately 425 cases of melanoma diagnosed each year in the United States, representing about 1% of all new cases of melanoma.[68] Melanoma annual incidence in the United States (2002–2006) increases with age, from 1 to 2 per 1 million in children younger than 10 years to 4.1 per 1 million in children aged 10 to 14 years and 16.9 per 1 million in children aged 15 to 19 years.[69,70] Melanoma accounts for about 8% of all cancers in children aged 15 to 19 years.[69,70] The incidence of pediatric melanoma increased by an average of 2% per year between 1973 and 2009.[70] The increased incidence was especially notable in females between the ages of 15 and 19 years. Increased exposure to ambient ultraviolet radiation increases the risk of the disease.

Risk factors

Conditions associated with an increased risk of developing 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),[62] immunodeficiency, immunosuppression, history of retinoblastoma, and Werner syndrome.[71,72] 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,[73-76] poor tanning ability, freckling, dysplastic nevi, increased number of melanocytic nevi, and family history of melanoma.[77-79] 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.[80,81]

Prognosis

Pediatric melanoma shares many similarities with adult melanoma, and the prognosis is stage dependent.[82] Similar to adults, most pediatric cases (about 75%) are localized and have an excellent outcome.[70,76] More than 90% of children and adolescents with melanoma are expected to be alive 5 years after their initial diagnosis.[76,82-84]

The outcome for patients with nodal disease is intermediate, with about 60% expected to survive long term.[76,83] In one study, the outcome for patients with metastatic disease was favorable,[76] but this result was not duplicated in another study from the National Cancer Database.[83]

Prepubescent children with melanoma are more often non-white, have head and neck primary tumors, thicker primary lesions, and a higher incidence of spitzoid morphology, vascular invasion, and nodal metastases.[76,82,83,85]

The use of sentinel node biopsy for staging pediatric melanoma has become widespread, and the thickness of the primary tumor, as well as ulceration, have been correlated with a higher incidence of nodal involvment.[86] Younger patients appear to have a higher incidence of nodal involvement; this finding does not appear to significantly impact clinical outcome in this population.[85] In other series of pediatric melanoma, a higher incidence of nodal involvement did not appear to impact survival.[87-89] The association of thickness with clinical outcome is controversial in pediatric melanoma.[76,83,90-92] In addition, it is unclear why some variables that correlate with survival in adults are not replicated in children. One possible explanation for this difference might be the inclusion of patients who have lesions that are not true melanomas in the adult series; these patients are not included in pediatric trials.[93,94]

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.[76,82,83,85]

Diagnostic evaluation

Biopsy or excision is necessary to determine the diagnosis of any skin cancer. Diagnosis is necessary for decisions regarding additional treatment. Although BCCs and SCCs are generally curable with surgery alone, 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.[62] 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 biopsy has become routine in many centers [95,96] 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.[95,97,98]

Lymph node dissection is recommended if sentinel nodes are involved with tumor, and adjuvant therapy with high-dose interferon alfa-2b for a period of 1 year should be considered in these patients.[62,95,99-101] Clinically benign melanocytic lesions can sometimes pose a significant diagnostic challenge, especially when they involve regional lymph nodes.[102-104]

The diagnosis of pediatric melanoma may be difficult and many of these lesions may be confused with the so-called melanocytic tumors of unknown metastatic potential.[105] These lesions are biologically different from melanoma and benign nevi.[105,106] The term Spitz nevus and Spitzoid melanoma are also commonly used, creating additional confusion. One retrospective study found that children aged 10 years or older were more likely to present with amelanotic lesions, bleeding, uniform color, variable diameter, and elevation (such as a de novo bump).[107][Level of evidence: 3iiA]

Novel diagnostic techniques are actively being used by various centers in an attempt to differentiate melanoma from these challenging melanocytic lesions. For example, the absence of BRAF mutations or the presence of a normal chromosomal complement with or without 11p gains strongly argues against the diagnosis of melanoma.[108,109] In contrast, the use of fluorescence in situ hybridization (FISH) probes that target four specific regions in chromosomes 6 and 11 can help classify melanoma correctly in more than 85% of cases; however, 24% of atypical Spitzoid lesions will have chromosomal alterations on FISH analysis and 75% will have BRAF V600E mutations.[110,111] HRAS mutations have been described in some cases of Spitz nevi but they have not been described in Spitzoid melanoma. The presence of a HRAS mutation may aid in the differential diagnosis of Spitz nevus and Spitzoid melanoma.[112] Some of the characteristic genetic alterations seen in various melanocytic lesions are summarized in the table below:[113,114]

Table 8. Characteristics of Melanocytic Lesions
Tumor  Affected Gene  
MelanomaBRAF, NRAS, KIT
Spitz nevusHRAS; BRAF and NRAS (uncommon)
Acquired nevusBRAF
Dysplastic nevusBRAF, NRAS
Blue nevusGNAQ
Ocular melanomaGNAQ
Congenital neviBRAF, NRAS

Treatment

Surgery is the treatment of choice for patients with localized melanoma. Current guidelines recommend margins of resection as follows:

  1. 0.5 cm for melanoma in situ.
  2. 1.0 cm for melanoma thickness under 1 mm.
  3. 1 cm to 2 cm for melanoma thickness of 1.01 mm to 2 mm.
  4. 2 cm for tumor thickness greater than 2 mm.

Sentinel node biopsy should be offered to patients with thin lesions (≤1 mm) and ulceration, mitotic rate greater than 1 mm2, young age, and to patients with lesions greater than 1 mm with or without adverse features. Young patients have a higher incidence of sentinel node positivity and this feature adversely affects clinical outcomes.[86,89] If the sentinel node is positive, patients should be offered the option to undergo a complete lymph node dissection. Patients with high-risk primary cutaneous melanoma, such as those with regional lymph node involvement, should be offered the option to receive adjuvant interferon alfa-2b, a therapy that is well tolerated in children.[99,100,115]

For patients with metastatic disease, prognosis is poor and various agents such as interferon, dacarbazine, temozolomide, sorafenib, or interleukin-2, and biochemotherapy can be used.[116-118] The results of pediatric trials that incorporate newer therapies such as vemurafenib and ipilimumab are not yet available.[119,120] Vemurafenib is used only in the treatment of patients with a BRAF mutation.[119]

(Refer to the PDQ summary on adult Melanoma Treatment for more information.)

Basal cell and squamous cell carcinomas

Clinical presentation

Basal cell carcinomas (BCCs) generally appear as raised lumps or ulcerated lesions, usually in areas with previous sun exposure.[121] These tumors may be multiple and exacerbated by radiation therapy.[122] Nevoid BCC syndrome (Gorlin syndrome) is a rare disorder with a predisposition to the development of early-onset neoplasms, including BCC, ovarian fibroma, and desmoplastic medulloblastoma.[123-126] SCCs are usually reddened lesions with varying degrees of scaling or crusting, and they have an appearance similar to eczema, infections, trauma, or psoriasis.

Diagnostic evaluation and treatment

Biopsy or excision is necessary to determine the diagnosis of any skin cancer. Diagnosis is necessary for decisions regarding additional treatment. BCCs and SCCs are generally curable with surgery alone and further diagnostic workup is not indicated.

Most BCCs have activation of the hedgehog pathway, generally resulting from mutations in PTCH1.[127] Vismodegib (GDC-0449), a hedgehog pathway inhibitor, has been approved for the treatment of adult patients with BCC.[128,129] It was approved by the U.S. Food and Drug Administration for the treatment of adults with metastatic BCC or with locally advanced BCC that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. This drug also reduces the tumor burden in patients with basal cell nevus syndrome.[130]

(Refer to the PDQ summary on adult Skin Cancer Treatment for more information.)

Chordoma

Incidence

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.[131] Most pediatric patients have the conventional or chondroid variant of chordoma.[131,132]

Prognosis

Younger children appear to have a worse outlook than older patients.[131,133-136] The survival rate in children and adolescents ranges from about 50% to 80%.[131,134,136]

Clinical presentation

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. Childhood chordoma has been associated with tuberous sclerosis complex.[137]

Treatment

Standard treatment includes surgery and external radiation therapy, often proton-beam radiation.[136] Surgery is not commonly curative in children and adolescents because of difficulty obtaining clear margins and the likelihood of the chordoma arising in the skull base, rather than in the sacrum, making them relatively inaccessible to complete surgical excision. The best results have been obtained using proton-beam therapy (charged-particle radiation therapy).[138,139]; [136,140][Level of evidence: 3iiA]; [141][Level of evidence: 3iiiDiii]

There is no known effective cytotoxic agent or combination chemotherapy for this disease, with only anecdotal reports published. Imatinib mesylate has been studied in adults with chordoma on the basis of the overexpression of PDGFR alpha, beta, and KIT in this disease.[142,143] Among 50 adults with chordoma treated with imatinib and evaluable by RECIST, there was one partial response and 28 additional patients had stable disease at 6 months.[143] The low rate of RECIST responses and the potentially slow natural course of the disease complicate the assessment of the efficacy of imatinib for chordoma.[143] Other tyrosine kinase inhibitors and combinations involving kinase inhibitors have been studied.[144-146]

Recurrences are usually local but can include distant metastases to lungs or bone.

Cancer of Unknown Primary Site

Incidence

Cancers of unknown primary site present as a metastatic cancer for which a precise primary tumor site cannot be determined.[147] 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 the above-mentioned presentation. Children represent less than 1% of all solid cancers of unknown primary site and because of the age-related incidence of tumor types, embryonal histologies are more common in this age group.[148]

Diagnostic evaluation

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.[147] Studies in adults suggest that PET imaging can be helpful in identifying cancers of unknown primary site, particularly in patients whose tumors arise in the head and neck area.[149] A report in adults using fludeoxyglucose PET-CT identified 42.5% of primary tumors in a group of cancers of unknown primary site.[150] 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 cancers of unknown primary site.[151] 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.[152]

Treatment

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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