のガイドライン小児がんセンターおよび小児患者の治療におけるその役割;がんは、アメリカ小児科学会（American Academy of Pediatrics）によって概説されている。これらの小児がんセンターでは、小児および青年に発生するほとんどのタイプのがん、および機会に臨床試験が利用できます。これらの試験に参加することは、ほとんどの患者/家族に提供される。臨床的;癌と診断された小児および青年の試験は、一般的には、潜在的により良い治療と現在の治療とを比較するように設計されている。標準として認められています。治療薬の同定における進歩の大部分は、小児がんの治療は臨床試験を通じて達成されている。進行中の臨床試験に関する情報は、このフォーラムから入手できます。
生存の劇的な改善は、がんのある小児および青年のために達成されている。 1975年から2010年の間に、小児がんの死亡率は50％以上減少した。小児期および青年期のがん生存者は、がん治療の副作用が治療後数週間または数年持続するか、 （小児および青年がん生存者の晩期影響の徴候、タイプ、およびモニタリングに関する具体的な情報については、小児がんの治療の後期効果の要約を参照のこと）。
国際小児腫瘍学会（SociétéInternationale D’OncologiePédiatrique[SIOP]）などのCOGおよび他の国際的なグループによって、珍しい小児がんの研究のためのいくつかの取り組みが開発されている。希少小児腫瘍（TREP）に関するイタリアの協力プロジェクトは、2000年に開始された、ポーランドの小児腫瘍学研究グループ（Polish Pediatric Rare Tumor Study Group）欧州では、フランス、ドイツ、イタリア、ポーランド、英国の珍しい腫瘍研究グループが欧州共同研究小児希少腫瘍グループ（EXPeRT）に参加し、国際協力と特定の稀な腫瘍実体の分析 COG内では、COGレジストリ（現在は小児がん研究ネットワーク/プロジェクトすべての子どもとして知られている）および希な腫瘍バンクに対する発生率の増加、単一アーム臨床試験の開発、成人協同集団試験との協力を増やすことである。このイニシアチブの成果と課題は詳細に記述されている[6、12]
鼻咽頭癌は、エプスタイン・バーウイルス（EBV）感染と強く関連している。 EBV DNAは、鼻咽頭癌細胞においてモノクローナルエピソームとして存在し、腫瘍細胞はその細胞表面上にEBV抗原を有することができる。 EBVの循環レベルEBV感染のDNAおよび血清学的証拠が診断に役立つ可能性がある HLA A2Bsin2ハプロタイプなどの特定のHLAサブタイプは、鼻咽頭癌の高いリスクと関連している
腫瘍ステージングは、腫瘍 – ノード – 転移（TNM）分類システムを用いて行われる。アメリカ合同委員会（AJCC、第7版）
鼻咽頭癌を有する小児および青年の90％以上が進行性疾患（III / IV期またはT3 / T4期）に罹患している〜。サーベイランス、疫学、および最終結果（SEER）プログラムからのデータの遡及的分析では、20歳未満の患者は高齢者よりも進行病の方が高いことが報告されている
SEER研究の症例の28％を占める小児患者における鼻腔の最も一般的な癌であるのは稀であるにもかかわらず、髄様芽細胞腫である SEERデータベースからの511人の患者のシリーズでは、わずかな男性優位性があり、 （81％）、最も一般的な腫瘍部位は鼻腔（72％）および洞様洞洞であった（31）。 13％）。
腫瘍はKadishシステムに従ってステージングされる（表1参照）。カディシュ段階と相関して、予後は90％（ステージA）から40％未満（ステージD）の範囲である。ほとんどの患者は、局所進行病変（Kadish stage BおよびC）を呈し、患者の約3分の1が遠隔部位に腫瘍を示す（Kadish stage D）[29,30]。最近の報告では、PET-CTが病期診断病気。
マルチモーダル治療の使用は生存の機会を最適化し、初期診断後5年以上生存することが期待される小児の70％以上が診断されている21。 5年の無病生存率および73％〜74％のOS  [証拠レベル：3iiiA]
治療の主流は外科手術と放射線療法である。内視鏡下洞手術などの新しい手法は、開頭手術に同様の短期間のアウトカムをもたらす可能性がある。  [証拠レベル：3iiiDii]定位放射線手術や陽子線治療（荷電粒子線治療）などの他の技術も、この腫瘍の管理に重要な役割を果たす可能性がある。
報告は、進行期の病気の患者における術前補助化学療法または補助化学療法の使用が増加していることを示唆する有望な結果を示している[25,36,38,44,45]。  [証拠レベル：3iii]有効性とともに使用された化学療法レジメンには、イホスファミドを含むまたは含まないエトポシドを含むシスプラチン; [39、47]ビンクリスチン、アクチノマイシンD、およびシクロホスファミド（ドキソルビシン有りまたは無し）;イホスファミド/エトポシド;シスプラチン+エトポシドまたはドキソルビシン;ビンクリスチン、ドキソルビシン、およびシクロホスファミド; およびイリノテカン+ドセタキセル [証拠レベル：3iiA]
甲状腺の腫瘍は腺腫または癌腫に分類される[56 – 58]。腺の全部または一部の拡大を引き起こす良性で、よく外接してカプセル化された結節である;頸部の両側に広がり、かなり大きい場合がありますが、一部の腫瘍はホルモンを分泌する可能性があります。悪性癌腫への形質転換が起こりうる。いくつかの細胞では、頸部またはリンパ節に増殖して広がりうる。肺;小児の甲状腺結節のおよそ20％は悪性である[56,59]
研究により、小児期の分化甲状腺癌の遺伝的プロファイリングと成人腫瘍の遺伝的プロファイリングとの間に微妙な相違があることが示されている。 BRAF V600E突然変異は乳頭を有する成人の50％以上に見られる（小児では45％〜65％、成人では3％〜34％である）小児乳頭癌ではRET / PTC再構成の有病率が高くなる甲状腺癌;小児患者ではBRAF V600E変異の存在との相関はないようである。ステージまたは予後に関連している。分化した甲状腺癌は、生殖系列DICER1変異と関連しており、DICER1症候群の一部と考えられている
甲状腺がんの患者は、通常、痛みのない子宮頸部アデノパシーの有無にかかわらず、甲状腺腫瘤を呈する[69 – 71]甲状腺がんは、医学および家族歴および臨床配置に基づいて、MENまたはDICERなどの腫瘍素因症候群-1症候群。
初期診断アプローチとしての細針吸引は、感度が高く有用である。しかし疑わしい場合には、開腹生検または切除術が考慮されるべきである[76 – 79]。
正常な残存切除のためには、血清TSHレベルを最大放射性ヨウ素取り込みを可能にするために上昇させなければならないが、これは通常、甲状腺切除術後3〜4週間、甲状腺ホルモン撤回によって達成することができる。次いで、機能的に活動的な残存腫瘍を検索するために走査が行われる。甲状腺床の外に病気がない場合は、甲状腺全部の破壊のためにアブレーション用量のI-131（約30mCi）を投与する。結節性または播種性疾患の徴候がある場合は、より高い用量（100-200 mCi）のI-131が必要となる [証拠レベル：3iDiv]小児では、I-131用量は体重1-1.5mCi / kg）。[56,86,87]
定期的な評価が必要かどうかを判断する必要があります。肺に関わる転移性疾患がある。生涯監視は、必要とされる。 T4およびTSHレベルが評価される。交換ホルモンが適切に投与されたかどうかを定期的に判断する。一般的な目的は、TSH分泌を0.1mIU / L未満に抑えることである [証拠レベル：1A]
乳頭状甲状腺癌患者におけるBRAF突然変異の高い可能性を考慮して、選択的RAF / MEK阻害剤の使用が研究されている[91,108,109]
髄様甲状腺癌は、一般にMEN2症候群と関連している（詳しくは、この概要のMultiple Endocrine Neoplasia（MEN）Syndromes and Carney Complexのセクションを参照）。彼らはより積極的な臨床経過を提示する。症例の50％が診断時に血行性の転移を有する。甲状腺髄様癌の患者は、予後が良好な非常に小さな腫瘍（直径が1.0cm未満と定義される微小癌腫）がない限り、予後が保証される。 国立がん研究所（NCT01660984）により、甲状腺髄様癌を有する小児および若年成人の自然史研究が行われている。デノボRET突然変異および家族歴がない患者では、腸管神経節腫脹または骨格もしくは眼のスティグマタなどの非内分泌症状が早期診断を容易にし、結果を改善する可能性があります。
髄様甲状腺癌の大部分の症例は、MEN 2A症候群およびMEN 2B症候群の文脈で生じる。家族性の症例では、初期の遺伝子検査とカウンセリングが示されており、RET生殖細胞系突然変異を有する小児には予防手術が推奨される。強い遺伝子型 – 表現型の相関関係は、予防的甲状腺摘出術が行われるべきスクリーニングおよび年齢を含む、介入のためのガイドラインの開発を容易にしている。
局所進行性または転移性の髄様甲状腺癌を有する小児をフェーズI / II試験でバンデタニブで治療した。 16人の患者のうち、1人のみが応答を示さず、7人が部分応答を示し、客観的応答率は44％であった。これらの患者のうちの3人の患者の疾患がその後再発したが、バンデタニブで治療された16人の患者のうち11人が報告時に治療中であった。コホート全体の治療期間の中央値は27ヶ月で、2〜52ヶ月の範囲であった。
口腔内の腫瘍および腫瘍様病変の90％以上が良性である[117 – 120]口腔癌は、小児および青年において極めてまれである[121,122] SEER Stat Fact Sheetsによると、すべての症例の0.6％が20歳未満の患者で診断され、2008年にこの患者の年齢調整された罹患率は100,000人につき0.24ケースであった。
若年成人女性では口腔癌および咽頭癌の発症率が高まっており、このパターンは若年女性およびヒトパピローマウイルス（HPV）感染における肛門生殖器の性交の全国的増加と一致する。現在推定されている米国での経口HPV感染の有病率は14〜69歳の人々で6.9％であり、HPVは約30,000人の口腔咽頭がんを引き起こすことが示されている。さらに、1999年から2008年にかけて、HPV関連口腔咽頭がんの罹患率は、白人男性では年4.4％、白人女性では1.9％増加した[124 – 126]男女ともにHPV予防接種率を高める現行の実践HPV関連の非がん性のがんの負担を軽減することができます。
口腔の悪性病変は、小児で行われた口腔生検の0.1％〜2％、口腔腫瘍生検の3％〜13％で認められた[119,120]。悪性腫瘍の種類には、リンパ腫特にバーキット）および肉腫（横紋筋肉腫および線維肉腫を含む）が含まれる。口腔粘膜表皮腫は、小児および青年期の年齢群ではほとんど報告されていない。ほとんどが低悪性度であり、手術のみで治癒率が高い。  [証拠レベル：3iiiA]
小児年齢群の5年生存率は約95％である。SEERデータベースのレビューでは、耳下腺腫瘍で20歳未満の284例の患者が同定された [証拠レベル：3iA] OSは5年で96％、10年で95％、20年で83％であった。青年は死亡率が高かった（7.1％対15歳未満の子供は1.6％、P = .23）。
ほとんどの唾液腺新生物は耳下腺に発生する[147 – 153]。これらの腫瘍は、顎下腺または軽度の唾液中に生じる。舌と顎の下の腺。これらの腫瘍は最も頻繁に良性ですが、特に幼児では悪性であるかもしれない。
小児における最も一般的な悪性唾液腺腫瘍;粘膜上皮癌であり、その後にacinic cell carcinoma、adenoid cystic carcinomaがみられるが、一般的な悪性腫瘍には横紋筋肉腫、腺癌、未分化癌があまり含まれていない[140,151,153,155〜157]悪性腫瘍が生じる。ある研究では、12の腫瘍のうち12の腫瘍がMECT1 / MAML2融合転写物に対して陽性であった。これは、唾液腺腫瘍の成人に見られる共通の染色体転座t（11,19）（q21、p13）を反映している。粘液表皮癌は、治療に関連する唾液腺腫瘍の最も一般的なタイプであり、 5年生存率は約95％である[153,157,159,160]
ラジカル手術;可能であれば、唾液腺腫瘍の選択治療法であり、追加的に使用する。高悪性度腫瘍または腫瘍を有する放射線療法;リンパ節転移、リンパ血管浸潤、または神経周囲伸展のような非侵襲性の特徴を有する[145,156,161]、 [証拠レベル：3iiiA] 1回の後向き研究で陽子と従来の放射線療法を比較し、良好な急性毒性および線量プロファイル。
シアロバラドーマは、新生児期には通常陽性の腫瘍であり、ほとんど転移することはない。カルボプラチン、エピルビシン、ビンクリスチン、エトポシド、ダクチノマイシン、ドキソルビシン、およびイホスファミドを用いた化学療法レジメンは、  [証拠レベル：3iiiDiv]
Rhabdomyosarcomaは最もです。 common malignant tumor of the larynx in the pediatric age group and is treated with chemotherapy and radiation therapy.[ 169 ] (Refer to the summary on Childhood Rhabdomyosarcoma Treatment) SCC of the larynx is managed in the same manner as in adults with; carcinoma at this site, with surgery and radiation.[ 170 ] Laser surgery may be the; initial treatment utilized for these lesions. (Refer to the summary on Laryngeal Cancer Treatment for more information about treatment of laryngeal cancer in adults.)
Recurrent respiratory papillomatosis is the most common benign laryngeal tumor in children and is associated with HPV infection, most commonly HPV-6 and HPV-11.[ 171 ] The presence of HPV-11 appears to correlate with a more aggressive clinical course than HPV-6.[ 172 ] These tumors can cause; hoarseness because of their association with wart-like nodules on the vocal; cords and may rarely extend into the lung, producing significant morbidity.[ 173 ] Malignant; degeneration may occur with development of cancer in the larynx and squamous cell lung cancer.
Papillomatosis is not; cancerous, and primary treatment is surgical ablation with laser vaporization.[ 174 ] Frequent recurrences are common. Lung involvement, although rare, can occur.[ 173 ] If a patient requires more than four surgical procedures per year, other interventions may be necessary, including the following
The effectiveness of intralesional cidofovir has not been conclusively demonstrated.[ 178 ]
NUT midline carcinoma is a very rare and aggressive malignancy genetically defined by rearrangements of the gene NUT. In the majority (75%) of cases, the NUT gene on chromosome 15q14 is fused with BRD4 on chromosome 19p13, creating chimeric genes that encode the BRD-NUT fusion proteins. In the remaining cases, NUT is fused to BRD3 on chromosome 9q34 or to NSD3 on chromosome 8p11,[ 179 ] these tumors are termed NUT -variant.[ 180 ]
The tumors arise in midline epithelial structures, typically mediastinum and upper aerodigestive track, and present as very aggressive undifferentiated carcinomas, with or without squamous differentiation.[ 181 ] Although the original description of this neoplasm was made in children and young adults, individuals of all ages can be affected.[ 180 ] A retrospective series with clinicopathologic correlation found that the median age at diagnosis of 54 patients was 16 years (range, 0.1–78 years).[ 182 ]
The outcome is very poor, with an average survival of less than 1 year. Preliminary data seem to indicate that NUT -variant tumors may have a more protracted course.[ 180, 181 ]
Treatment includes a multimodal approach with systemic chemotherapy, surgery, and radiation therapy. Cisplatin, taxanes, and alkylating agents have been used with some success; however, while early response is common, tumors progress early in the course of the disease.[ 182 ][ Level of evidence: 3iiiB ]
Preclinical studies have shown that NUT-BRD4 is associated with globally decreased histone acetylation and transcriptional repression; studies have also shown that this acetylation can be restored with histone deacetylase inhibitors, resulting in squamous differentiation and arrested growth in vitro and growth inhibition in xenograft models. Response to vorinostat has been reported in two separate cases of children with refractory disease, thus suggesting a potential role for this class of agents in the treatment of this malignancy.[ 183, 184 ] The BET bromodomain inhibitors represent a promising class of agents that is being investigated for adults with this malignancy.[ 179 ]
The following are examples of national and/or institutional clinical trials that are currently being conducted.進行中の臨床試験に関する情報は、このフォーラムから入手できます。
Thoracic cancers include the following
The prognosis, diagnosis, classification, and; treatment of these thoracic cancers are discussed below.これらの癌は15歳未満の患者ではまれにしか見られないことが強調されなければならず、その証拠のほとんどは症例シリーズに由来する
The most frequent breast tumor seen in children is a fibroadenoma.[ 2, 3 ] These tumors can be observed and many will regress without a need for surgical resection.しかし、葉状腫に至るまれな悪性形質転換が報告されている。疑わしい線維腺腫の突然の急速な拡大は、針生検または切除の適応症である。
Breast cancer has been reported in both males and females younger than 21 years.[ 5 – 10 ] A review of the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute shows that 75 cases of malignant breast tumors in females aged 19 years or younger were identified from 1973 to 2004.[ 11 ] Fifteen percent of these patients had in situ disease, 85% had invasive disease, 55% of the tumors were carcinomas, and 45% of the tumors were sarcomas—most of which were phyllodes tumors.癌腫群の3例のみが転移性疾患を示し、11例（27％）は局所進行性疾患を有していた。肉腫患者全員が限局性疾患を呈した。癌腫患者のうち、85％が外科的切除を受け、10％が補助放射線療法を受けた。肉腫患者のうち、97％が外科的切除を有し、9％が放射線を受けた。 The 5- and 10-year survival rates for patients with sarcomatous tumors were both 90%; for patients with carcinomas, the 5-year survival rate was 63% and the 10-year survival rate was 54%.
Breast tumors may also occur as metastatic deposits from; leukemia, rhabdomyosarcoma, other sarcomas, or lymphoma (particularly in patients who are infected with the human immunodeficiency virus).
Risk factors for breast cancer in adolescents and young adults include the following
Mammograms with adjunctive breast magnetic resonance imaging (MRI) start at age 25; years or 10 years postexposure to radiation therapy (whichever came last). (Refer to the summary on the Late Effects of Treatment for Childhood Cancer for more information about secondary breast cancers.)
Breast cancer is the most frequently diagnosed cancer among AYA women aged 15 to 39 years, accounting for about 14% of all AYA cancer diagnoses.[ 17 ] Breast cancer in this age group has a more aggressive course and worse outcome than in older women. Expression of hormone receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2) on breast cancer in the AYA group is also different from that in older women and correlates with a worse prognosis.[ 12, 18 ]
Treatment of the AYA group is similar to that of older women. However, unique aspects of management must include attention to genetic implications (i.e., familial breast cancer syndromes) and fertility.[ 19, 20 ]
(Refer to the summary on; adult Breast Cancer Treatment)
Primary lung tumors are rare in children and histologically quite diverse.[ 1 ] When epithelial cancers of the lung occur, they tend to be of advanced stage, with prognosis dependent on both histology and stage.[ 21 ] Most primary lung tumors are malignant. In a review of 383 primary pulmonary neoplasms in children, 76% were malignant and 24% were benign.[ 22 ] A review of primary malignant epithelial lung tumors using the National Cancer Data Base found that the most common primary malignant pediatric lung neoplasms were carcinoid tumors (63%) followed by mucoepidermoid carcinoma of the lung (18%).[ 23 ]
Most pulmonary malignant neoplasms in children are due to metastatic disease, with an approximate ratio of primary malignant tumors to metastatic disease of 1:5.[ 24 ]
The most common malignant primary tumors of the lung are bronchial tumors and pleuropulmonary blastoma.
Bronchial tumors are a heterogeneous group of primary endobronchial lesions, and although adenoma implies a benign process, all varieties of bronchial tumors on occasion display malignant behavior. The following three histologic types have been identified:[ 25 – 30 ]
Bronchial tumors of all histologic types are associated with an excellent prognosis after surgical resection in children, even in the presence of local invasion.[ 31, 32 ]; [ 33 ][ Level of evidence: 2A ]
The presenting symptoms of a bronchial tumor are usually caused by an incomplete bronchial obstruction and include the following
Because of difficulties in diagnosis, symptoms are frequently present for months, and, occasionally, children with wheezing have been treated for asthma, with delays in diagnosis for as long as 4 to 5 years.[ 34 ]
Metastatic lesions are reported in approximately 6% of carcinoid tumors, and recurrences are reported in 2% of cases. Atypical carcinoid tumors are rare but more aggressive, with 50% of patients presenting with metastatic disease at diagnosis.[ 21, 35 ] There is a single report of a child with a carcinoid tumor and metastatic disease who developed the classic carcinoid syndrome.[ 36 ] Octreotide nuclear scans may demonstrate uptake of; radioactivity by the tumor or lymph nodes, suggesting metastatic spread.
The management of bronchial tumors is somewhat controversial because bronchial tumors are usually visible endoscopically. Biopsy of these lesions may be hazardous because of the risk of hemorrhage. New endoscopic techniques have allowed biopsy to be performed safely; [ 30, 37 ] however, endoscopic resection is not recommended except in highly selected cases.[ 37, 38 ] Bronchography or computed tomography scan may be helpful to determine the degree of bronchiectasis distal to the obstruction since the degree of pulmonary destruction may influence surgical therapy.[ 39 ]
Conservative pulmonary resection, including sleeve segmental resection, when feasible, with the removal of the involved lymphatics, is the treatment of choice.[ 40, 41 ]; [ 33 ][ Level of evidence: 2A ] Adenoid cystic carcinomas (cylindroma) have a tendency to spread submucosally, and late local recurrence or dissemination has been reported. In addition to en bloc resection with hilar lymphadenectomy, a frozen section examination of the bronchial margins is performed in children with this lesion.
Neither chemotherapy nor radiation therapy is indicated for bronchial tumors, unless evidence of metastasis is documented.
(Refer to the Neuroendocrine Tumors (Carcinoid Tumors) section of this summary for information about neuroendocrine carcinoid tumors.)
Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy; that can present as a pulmonary or pleural mass. The International Pleuropulmonary Blastoma Registry is a valuable resource for information on this rare malignancy.[ 42 ]
The following three subtypes of pleuropulmonary blastoma have been identified
Histologically, these tumors appear as a multilocular cyst with variable numbers of primitive mesenchymal cells beneath a benign epithelial surface, with skeletal differentiation in one-half of the cases.[ 44 ] This form of disease can be clinically and pathologically deceptive because of its resemblance to some developmental lung cysts.
The Pleuropulmonary Blastoma Registry reported on 350 centrally reviewed and confirmed cases of pleuropulmonary blastoma over a 50 year period.[ 45 ]
Prognostic factors for pleuropulmonary blastoma include the following:[ 45 ]
Of the 97 patients who were tested, 66% had a heterozygous germline DICER1 mutation, confirming that this is a familial cancer syndrome.[ 45 ] In this subset, DICER1 mutation status was not related to outcome.
Approximately one-third of families of children with pleuropulmonary blastoma manifest a number of dysplastic and/or neoplastic conditions comprising the pleuropulmonary blastoma family tumor and dysplasia syndrome. Germline mutations in the DICER1 gene are considered the major genetic determinant of the complex.[ 51 – 53 ] Importantly, while DICER1 mutations cause a wide range of phenotypes, pleuropulmonary blastoma does not occur in all families with DICER1 mutations; therefore, the term DICER1 syndrome is generally used for these families. Also, most mutation carriers are unaffected, indicating that tumor risk is modest.[ 52 ] Conversely, approximately 40% of patients with pleuropulmonary blastoma tumors do not have DICER1 germline mutations.[ 45 ]
The most relevant association is with cystic nephroma; up to 10% of pleuropulmonary blastoma cases have been reported to develop cystic nephroma or Wilms tumor, malignaes that are also more prevalent among family members.[ 54 ] Germline DICER1 mutations have also been associated with ovarian sex cord–stromal tumors (especially Sertoli-Leydig cell tumor), multinodular goiter, uterine cervix embryonal rhabdomyosarcoma, cervical primitive neuroectodermal tumor, Wilms tumor, pulmonary sequestration, juvenile intestinal polyps, ciliary body medulloepithelioma, medulloblastoma, and seminoma.[ 46, 53 – 59 ]
DICER1 mutations appear to have a low penetrance, with pleuropulmonary blastoma, cystic nephroma, and multinodular goiter being the most frequently reported manifestations, not all families include pleuropulmonary blastoma, and most mutation carriers do not develop tumors. Most associated conditions occur in children younger than 10 years, although ovarian tumors and multinodular goiters are described in children and adults aged up to 30 years.[ 53 ]
Presenting symptoms are not specific, and commonly include the following
Up to 50% of patients with type I disease have multiple lesions, and in 33% of the cases lesions are bilateral.[ 44 ]
The tumor is usually located in the lung periphery, but it may be; extrapulmonary with involvement of the heart/great vessels, mediastinum, diaphragm, and/or; pleura.[ 50, 60 ] The International Pleuropulmonary Blastoma Registry identified 11 cases of Type II and Type III pleuropulmonary blastoma with tumor extension into the thoracic great vessels or the heart. Radiographic evaluation of the central circulation is performed in children with suspected or diagnosed pleuropulmonary blastoma to identify potentially fatal embolic complications.[ 61 ]
There are no standard treatment options. Current treatment regimens for these rare tumors have been informed by consensus opinion.
A complete surgical resection is the most important prognostic factor; [ 50 ] however, surgery alone results in high relapse rates.[ 44, 49 ]
Data from the International Pleuropulmonary Blastoma Registry and from the European Cooperative Study Group in Pediatric Rare Tumors (EXPeRT) suggest that adjuvant chemotherapy may reduce the risk of recurrence.[ 48 ], [ 60 ][ Level of evidence: 3iiiA ] Responses to chemotherapy have been reported with agents; similar to those used for the treatment of rhabdomyosarcoma.[ 45, 48, 62, 63 ]
High-dose chemotherapy with stem cell rescue has been used without success.[ 64 ]
Some general treatment considerations from the Pleuropulmonary Blastoma Registry include the following:[ 42 ]
Radiation therapy may be used in patients with type III pleuropulmonary blastoma, although this has no impact on survival.[ 45 ]
Esophageal cancer is rare in the pediatric age group, although it is relatively; common in older adults.[ 67, 68 ] Most of these tumors are squamous cell carcinomas; although sarcomas can also arise in the esophagus. The most common benign; tumor is leiomyoma.
Symptoms are related to difficulty in swallowing; and associated weight loss. Diagnosis is made by histologic examination of biopsy; tissue.
Treatment options for esophageal carcinoma include the following
予後; is generally poor for this cancer, which rarely can be completely resected.
(Refer to the summary on adult Esophageal Cancer Treatment for more; information.)
A cancer of the thymus is not considered a thymoma or a thymic carcinoma unless there are neoplastic; changes of the epithelial cells that cover the organ.[ 69 – 71 ] The term thymoma is customarily used to describe neoplasms that show no overt atypia of the epithelial component. Thymic carcinomas have a higher idence of capsular invasion and metastases. A thymic epithelial tumor that exhibits clear-cut cytologic atypia and histologic features no longer specific to the thymus is known as thymic carcinoma, also known as type C thymoma. Other tumors that; involve the thymus gland include lymphomas, germ cell tumors, carcinomas; carcinoids, and thymomas. Hodgkin lymphoma and non-Hodgkin lymphoma may also; involve the thymus and must be differentiated from true thymomas and thymic carcinomas.
Thymoma and thymic carcinomas are very rare in children.[ 72 – 74 ] In the Tumori Rari in Età Pediatrica registry, only eight cases were identified over a 9-year period.[ 72 ] A review of 73 cases of anterior mediastinal tumors using the SEER registry identified thymic epithelial tumors as having the worst survival rate at 10 years from diagnosis; better survival rates occurred in patients with lymphomas and germ cell tumors.[ 73 ] A review of 48 published cases of thymoma in patients younger than 18 years, excluding thymic carcinoma, found an association between stage of disease and survival; it also suggested guidelines for treatment. The overall 2-year survival in this series was 71%.[ 74 ]
Various diseases and syndromes; are associated with thymoma, including the following:[ 75 – 77 ]
These neoplasms are usually located in the anterior mediastinum and are usually; discovered during a routine chest x-ray. Symptoms can include the following:[ 74 ]
Nonspecific symptoms may also occur.
These tumors generally are; slow growing but are potentially invasive, with metastases to distant organs; or lymph nodes. Staging is related to invasiveness. Most children present with low-stage disease.[ 74 ]
Treatment options for thymoma and thymic carcinoma include the following
Sunitinib has yielded clinical responses in four adult patients with thymic carcinoma.[ 84 ]
(Refer to the adult Thymoma and Thymic Carcinoma Treatment summary for more information on the treatment of thymoma and thymic carcinoma.)
Cardiac tumors are rare, with an autopsy frequency of 0.001% to 0.30%; [ 85 ] in one report, the percentage of cardiac surgeries performed as a result of cardiac tumors was 0.093%.[ 86 ] The most common primary tumors of the heart are benign and include the following:[ 87 – 89 ]
Other benign tumors include histiocytoid cardiomyopathy tumors, hemangiomas, and neurofibromas (i.e., tumors of the nerves that innervate the muscles).[ 87, 90 – 93 ]
Myxomas are the most common noncutaneous finding in Carney complex, a rare syndrome characterized by lentigines, cardiac myxomas or other myxoid fibromas, and endocrine abnormalities.[ 94 – 96 ]; A mutation of the PRKAR1A gene is noted in more than 90% of the cases of Carney complex.[ 94, 97 ]
Primary malignant pediatric heart tumors are rare but; may include the following:[ 87, 98, 99 ]
Secondary tumors of the heart include metastatic spread of rhabdomyosarcoma; other sarcomas, melanoma, leukemia, thymoma, and carcinomas of various sites.[ 85, 87 ]
The distribution of cardiac tumors in the fetal and neonatal period is different from that in older patients, with two-thirds of teratomas occurring during this period of life.[ 90 ] Multiple cardiac tumors noted in the fetal or neonatal period are highly associated with a diagnosis of tuberous sclerosis.[ 90, 100 ] A retrospective review of 94 patients with cardiac tumors detected by prenatal or neonatal echocardiography showed that 68% of the patients exhibited features of tuberous sclerosis.[ 101 ] In another study, 79% of patients (15 of 19) with rhabdomyomas discovered prenatally had tuberous sclerosis, while 96% of those diagnosed postnatally had tuberous sclerosis. Most rhabdomyomas, whether diagnosed prenatally or postnatally, will spontaneously regress.[ 102 ]
Patients may be asymptomatic and present with sudden death,[ 103 ][ Level of evidence: 3iiiA ] but about two-thirds of patients have symptoms that may include the following
The utilization of new cardiac MRI techniques can identify the likely tumor type in most children.[ 104 ] However, histologic diagnosis remains the standard for diagnosing cardiac tumors.
Successful treatment may require surgery, debulking for progressive symptoms, cardiac transplantation, and; chemotherapy that is appropriate for the type of cancer that is present:[ 105 – 107 ], [ 108 ][ Level of evidence: 3iiA ]
In one series, 95% of patients were free from cardiac tumor recurrence at 10 years.[ 89 ]
Mesothelioma is extremely rare in childhood, with only 2% to 5% of patients presenting during the first two decades of life.[ 110 ] Fewer than 300 cases in children have been reported.[ 111 ]
Mesothelioma may develop after successful treatment of an; earlier cancer, especially after treatment with radiation.[ 112, 113 ] In adults; these tumors have been associated with exposure to asbestos, which was used as; building insulation.[ 114 ] The amount of exposure required to develop cancer is; unknown, and there is no information about the risk for children exposed to; asbestos.
This tumor can involve the membranous coverings of the lung, the heart, or the; abdominal organs.[ 115 – 117 ] 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.
Benign and malignant mesotheliomas cannot be differentiated using histologic; criteria. A poor prognosis is associated with lesions that are diffuse and; invasive and with those that recur. In general, the course of the disease is; slow, and long-term survival is common.
Diagnostic thoracoscopy should be considered in suspicious cases to confirm diagnosis.[ 110 ]
Radical surgical resection has been attempted with mixed results.[ 118 ] In adults, a multimodal therapy including extrapleural pneumonectomy and radiation therapy after combination chemotherapy with pemetrexed-cisplatin may achieve durable responses.[ 119 ][ Level of evidence: 2A ] However, this approach remains highly controversial.[ 120 ] In children, treatment with various; chemotherapeutic agents used for carcinomas or sarcomas may result in partial; responses.[ 117, 121 – 123 ]
Pain is an infrequent symptom, however, if pain occurs, radiation therapy may be; used for palliation.
Papillary serous carcinoma of the peritoneum may be mistaken for; mesothelioma.[ 124 ] 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.
(Refer to the summary on adult; Malignant Mesothelioma Treatment)
Abdominal cancers include the following
The prognosis; diagnosis, classification, and treatment of these abdominal 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.; (Refer to the summary on Wilms Tumor and Other Childhood Kidney Tumors for information about kidney tumors.)
The idence of adrenocortical tumors in children is extremely low (only 0.2% of pediatric cancers).[ 1 ] Adrenocortical tumors appear to follow a bimodal distribution, with peaks during the first and fourth decades.[ 2, 3 ] Childhood adrenocortical tumors typically present during the first 5 years of life (median age, 3–4 years), although there is a second, smaller peak during adolescence.[ 4 – 8 ]
In children, 25 new cases are expected to occur annually in the United States, for an estimated annual idence of 0.2 to 0.3 cases per 1 million individuals.[ 9 ] Internationally, however, the idence of adrenocortical tumors appears to vary substantially. It is particularly high in southern Brazil, where it is approximately 10 to 15 times that observed in the United States.[ 10 – 13 ]
Female gender is consistently predominant in most studies, with a female to male ratio of 1.6 to 1.0.[ 8, 14 ]
生殖系列TP53突然変異は、ほとんど常に素因となる因子である。 The likelihood of a TP53 germline mutation is highest in the first years of life and diminishes with age. Predisposing genetic factors have been implicated in more than 50% of the cases in North America and Europe and in 95% of the Brazilian cases. [ 15 ]
Patients with Beckwith-Wiedemann and hemihypertrophy syndromes have a predisposition to cancer, and as many as 16% of their neoplasms are adrenocortical tumors.[ 18 ] Hypomethylation of the KCNQ1OT1 gene has also been associated with the development of adrenocortical tumors in patients without the phenotypic features of Beckwith-Wiedemann syndrome.[ 19 ] However, less than 1% of children with adrenocortical tumors have these syndromes.[ 20 ]
The distinctive genetic features of pediatric adrenocortical carcinoma have been reviewed.[ 21 ]
Unlike adult adrenocortical tumors, histologic differentiation of pediatric adenomas and carcinomas is difficult. However, approximately 10% to 20% of pediatric cases are adenomas.[ 2, 5 ] The distinction between benign (adenomas) and malignant (carcinomas) tumors can be problematic. In fact, adenomas and carcinomas appear to share multiple genetic aberrations and may represent points on a continuum of cellular transformation.[ 22 ]
Macroscopically, adenomas tend to be well defined and spherical, and they never invade surrounding structures. They are typically small (usually <200 cm 3), and some studies have included size as a criterion for adenoma. By contrast, carcinomas have macroscopic features suggestive of malignancy; they are larger, and they show marked lobulation with extensive areas of hemorrhage and necrosis. Microscopically, carcinomas comprise larger cells with eosinophilic cytoplasm, arranged in alveolar clusters. Several authors have proposed histologic criteria that may help to distinguish the two types of neoplasm.[ 23, 24 ] Morphologic criteria may not allow reliable distinction of benign and malignant adrenocortical tumors. Mitotic rate is consistently reported as the most important determinant of aggressive behavior.[ 25 ] IGF2 expression also appears to discriminate between carcinomas and adenomas in adults, but not in children.[ 26, 27 ] Other histopathologic variables are also important, and risk groups may be identified on the basis of a score derived from tumor characteristics, such as tumor necrosis, mitotic rate, the presence of atypical mitoses, and venous, capsular, or adjacent organ invasion.[ 13, 25 ] Because pediatric adrenocortical tumors are almost universally functional, they cause endocrine disturbances, and a diagnosis is usually made 5 to 8 months after the first signs and symptoms emerge.[ 3, 5 ] Because of the hormone hypersecretion, it is possible to establish an endocrine profile for each particular tumor, which may facilitate the evaluation of response to treatment and monitor for tumor recurrence.[ 13 ] Nonfunctional tumors are rare (<10%) and tend to occur in older children.[ 3 ] In patients with localized disease, younger age (<4 years), virilization alone, normal blood pressure, disease stage I, absence of spillage during surgery, and tumor weight no greater than 200 grams are associated with a greater probability of survival.[ 31 ] In a Cox regression model analysis, only stage I, virilization alone, and age 0 to 3 years were independently associated with a better outcome.[ 3 ] Available data suggest that tumor size is especially important in children; patients with small tumors have an excellent outcome with surgery alone, regardless of histologic features.[ 32 ] A low expression of the HLA class II antigens HLA-DRA, HLA-DPA1, and HLA-DPB1 has been associated with older age, larger tumor size, presence of metastatic disease, and worse outcome.[ 33 ] The overall probability of 5-year survival for children with adrenocortical tumors is reported to be 54% to 74%.[ 3, 5, 6, 8, 30 - 32 ] At the time of diagnosis, two-thirds of pediatric patients have limited disease (tumors can be completely resected), and the remaining patients have either unresectable or metastatic disease.[ 3 ] Treatment of childhood adrenocortical tumors has evolved from the data derived from the adult studies, and the same guidelines are used. Surgery is the most important mode of therapy, and mitotane and cisplatin-based regimens, usually incorporating doxorubicin and etoposide, are recommended for patients with advanced disease.[ 12, 13, 34, 35 ]; [ 8 ][ Level of evidence: 3iiiA ] Treatment options for childhood adrenocortical tumors include the following The use of radiation therapy in pediatric patients with adrenocortical tumors has not been consistently investigated. Adrenocortical tumors are generally considered to be radioresistant. Furthermore, because many children with adrenocortical tumors carry germline TP53 mutations that predispose to cancer, radiation may increase the idence of secondary tumors. One study reported that three of five long-term survivors of pediatric adrenocortical tumors died of secondary sarcoma that arose within the radiation field.[ 13, 41 ] Primary gastric tumors in children are rare, and carcinoma of the stomach is even more unusual.[ 42 ] In one series, gastric cancer in children younger than 18 years accounted for 0.11% of all gastric cancer cases seen over an 18-year period.[ 43 ] The frequency and death rate from stomach cancer has declined worldwide for; the past 50 years with the introduction of food preservation practices such as; refrigeration.[ 44 ] The tumor must be distinguished from other conditions such; as non-Hodgkin lymphoma, malignant carcinoid, leiomyosarcoma, and various; benign conditions or tumors of the stomach.[ 42 ] Symptoms of carcinoma of the stomach include the following Fiberoptic endoscopy can be used to visualize the tumor or to; take a biopsy sample to confirm the diagnosis. Confirmation can; also involve an x-ray examination of the upper gastrointestinal tract. Treatment includes 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 fluorouracil (5-FU) and irinotecan.[ 46 ]; 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.[ 43 ]; Because of the rarity of stomach cancer in the pediatric age group, little; information exists regarding the treatment outcomes of children. (Refer to the; summary on adult Gastric Cancer Treatment) Malignant pancreatic tumors are rare in children and adolescents, with an idence of 0.46 cases per 1 million individuals younger than 30 years.[ 47 - 50 ] The primary pancreatic tumors of childhood can be classified into the following four categories Solid pseudopapillary tumor of the pancreas, also known as Frantz tumor, is the most common pediatric pancreatic tumor, accounting for up to 70% of cases in most institutional series.[ 49, 51 ] This tumor has low malignant potential and most commonly affects females of reproductive age (median age, 21 years), with a predilection for blacks and East Asians.[ 47, 49, 52 ] There is no known genetic or hormonal factor to explain the strong female predilection, although it has been noted that all tumors express progesterone receptors.[ 53 ] Solid pseudopapillary tumor of the pancreas is a very friable tumor, and tumor rupture and hemoperitoneum have been reported.[ 47, 49, 52 ] Tumors can occur throughout the pancreas and are often exophytic. On imaging, the mass shows typical cystic and solid components, with intratumoral hemorrhage and a fibrous capsule.[ 47 ] Histologically, the tumors are characterized by a combination of solid, pseudopapillary, and cystic changes. The fragility of the vascular supply leads to secondary degenerative changes and cystic areas of hemorrhage and necrosis. The cells surrounding the hyalinized fibrovascular stalks form the pseudopapillae.[ 47 ] A highly specific paranuclear dot-like immunoreactivity pattern for CD99 has been described.[ 54 ] The outcome of solid pseudopapillary tumors of the pancreas is excellent, with 10-year survival rates in excess of 95%.[ 53 ] Treatment of solid pseudopapillary tumor of the pancreas is surgical; however, preoperative and operative spillage is not unusual. Surgery is usually curative, although local recurrences occur in 5% to 15% of the cases.[ 52 ] Metastatic disease, usually in the liver, may occur in up to 15% of the cases.[ 47, 49, 52 - 54 ] Single-agent gemcitabine has been reported to be effective in cases of unresectable or metastatic disease.[ 55 ] Pancreatoblastoma accounts for 10% to 20% of all pancreatic tumors during childhood. It is the most common pancreatic tumor of young children and typically presents in the first decade of life, with a median age at diagnosis of 5 years.[ 47, 56 ] Patients with Beckwith-Wiedemann syndrome have an increased risk of developing pancreatoblastoma; this syndrome is identified in up to 60% of cases of pancreatoblastoma developing during early infancy and in 5% of children developing pancreatoblastoma later in life.[ 57 ] Pancreatoblastoma has also been associated with familial adenomatous polyposis syndromes.[ 58 ] This tumor is thought to arise from the persistence of the fetal analog of pancreatic acinar cells. Pathology shows an epithelial neoplasm with an arrangement of acinar, trabecular, or solid formations separated by dense stromal bands.[ 47 ]; CTNNB1 gene mutations have been described in some cases, suggesting that pancreatoblastoma might result from alterations in the normal pancreas differentiation.[ 59 ] Although approximately one-half of the cases originate in the head of the pancreas, jaundice is uncommon. Close to 80% of the tumors secrete alpha-fetoprotein, which can be used to measure response to therapy and monitor for recurrence.[ 56 ] In some cases, the tumor may secrete adrenocorticotropic hormone (ACTH) or antidiuretic hormone, and patients may present with Cushing syndrome and syndrome of inappropriate antidiuretic hormone secretion.[ 57 ] Metastases are present in 30% to 40% of the patients, usually involving liver, lungs, and lymph nodes.[ 56 ] Using a multimodality approach, close to 80% of patients can be cured.[ 56 ] Surgery is the mainstay in the treatment of pancreatoblastoma, and a complete surgical resection is required for cure. Because of the common origin in the head of the pancreas, a Whipple procedure is usually required. For large, unresectable, or metastatic tumors, preoperative chemotherapy is indicated; pancreatoblastoma commonly responds to chemotherapy, and a cisplatin-based regimen is usually recommended. The PLADO regimen, which includes cisplatin and doxorubicin, is the most commonly used regimen, and treatment is modeled after the management of hepatoblastoma, with two to three cycles of preoperative therapy, followed by resection and adjuvant chemotherapy.[ 49, 56, 58, 60 ] Although radiation therapy has been used in unresectable or relapsed cases, its role in the treatment of microscopic disease after surgery has not been defined.[ 58 ] High-dose chemotherapy with autologous hematopoietic stem cell rescue has been reported to be effective in selected cases.[ 49, 61 ] Islet cell tumors represent approximately 15% of pediatric pancreatic tumors in most series.[ 49, 51, 62 ] These tumors usually present in middle age and may be associated with multiple endocrine neoplasia type 1 (MEN1) syndrome; less than 5% of islet cell tumors occur in children.[ 47 ] The most common type of functioning islet cell tumor is insulinoma, followed by gastrinoma. Patients with insulinoma present with fasting hyperinsulinic hypoglycemia; in young children, presentation may include behavioral problems, seizures, or coma. Gastrinoma presents with Zollinger-Ellison syndrome, with recurrent peptic ulcers in uncommon locations, and diarrhea due to gastric hypersecretion. While most insulinomas are benign, a significant proportion of gastrinomas are malignant.[ 62 ] Other less common tumors seldom seen in children are the ACTHoma, which presents as Cushing syndrome, and the VIPoma, which presents as Verner-Morrison syndrome. Nonfunctioning tumors are extremely rare in pediatrics, except when associated with MEN1. Islet cell tumors are typically solitary; when multiple tumors are present, the diagnosis of MEN1 syndrome should be considered. On imaging, these tumors are usually small and well defined. Somatostatin receptor scintigraphy is useful for the location of islet cell tumors; however, only 60% to 70% express somatostatin receptor.[ 47 ] Treatment of islet cell tumors includes medical therapy for control of the syndrome and complete surgical resection. For patients with malignant tumors and unresectable or metastatic disease, chemotherapy and mammalian target of rapamycin (mTOR) inhibitors are recommended. The management of these tumors in children follows the consensus guidelines established for adult patients.[ 62, 63 ] (Refer to the summary on adult Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment) Pancreatic carcinomas (acinar cell carcinoma and ductal adenocarcinoma) are extremely rare in children. These malignaes represent less than 5% of pediatric pancreatic tumors and include the following:[ 49, 51 ] Presenting symptoms are nonspecific and are related to local tumor growth. However, 4% to 15% of adult patients with acinar cell carcinoma may present with a lipase hypersecretion syndrome, manifesting as peripheral polyarthropathy and painful subcutaneous nodules. (Refer to the summary on adult Pancreatic; Cancer Treatment for information about the treatment of pancreatic carcinoma.) Carcinoma of the large bowel is rare in the pediatric age group. It is seen in one case per 1 million persons younger than 20 years in the United States annually; fewer than 100 cases are diagnosed in children each year in the United States.[ 66 ] From 1973 to 2006, the Surveillance, Epidemiology, and End Results database recorded 174 cases of colorectal cancer in patients younger than 19 years.[ 67 ] Colorectal tumors can occur in any location in the large bowel. Larger series and reviews suggest that ascending and descending colon tumors are each seen in approximately 30% of cases, with rectal tumors occurring in approximately 25% of cases.[ 68 - 70 ] Signs and symptoms in children with descending colon tumors include the following The median duration of symptoms before diagnosis was about 3 months in one series.[ 66, 71 ] Changes in bowel habits may be associated with tumors of the rectum or lower colon. Tumors of the right colon may cause more subtle symptoms but are often associated with the following Any tumor that causes complete obstruction of the large bowel can cause bowel perforation and spread of the tumor cells within the abdominal cavity. Diagnostic studies include the following:[ 72, 73 ] There is a higher idence of mucinous adenocarcinoma in the pediatric and adolescent age group (40%–50%), with many lesions being the signet ring cell type,[ 66, 71, 75 ] 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. In the adolescent and young adult population with the mucinous histology, there is a higher idence of signet ring cells, microsatellite instability, and mutations in the mismatch repair genes.[ 76 ] 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 idence of metastasis involving the pelvis, ovaries, or both may be present in girls.[ 73 ] Colorectal cancers in younger patients with noninherited sporadic tumors often lack KRAS mutations and other cytogenetic anomalies seen in older patients.[ 77 ] Most reports also suggest that children present with more advanced disease than do adults, with 80% to 90% of patients presenting with Dukes stage C/D or TNM stage III/IV disease (refer to the Stage Information for Colon Cancer section of the summary on adult Colon Cancer Treatment for more information about staging).[ 66, 68 - 72, 75, 78 - 84 ] Most patients present with evidence of metastatic disease,[ 71 ] either as gross; tumor or as microscopic deposits in lymph nodes, on the surface of the bowel; or on intra-abdominal organs.[ 75, 78 ] Treatment options for childhood colorectal cancer include the following A recent review of nine clinical trials comprising 138 patients younger than 40 years demonstrated that the use of combination chemotherapy improved progression-free survival and overall survival (OS) in these patients. Furthermore, OS and response rates to chemotherapy were similar to those observed in older patients.[ 87 ][ Level of evidence: 2A ] Other active agents used in adults include oxaliplatin, bevacizumab, panitumumab, cetuximab, aflibercept, and regorafenib.[ 88 - 91 ] Survival is consistent with the advanced stage of disease observed in most children with colorectal cancer, with an overall mortality rate of approximately 70%. For patients with a complete surgical resection or for those with low-stage/localized disease, survival is significantly prolonged, with the potential for cure.[ 68 ] About 20% to 30% of adult patients with colorectal cancer have a significant history of familial cancer; of these, about 5% have a well-defined genetic syndrome.[ 92 ] The idence of these genetic syndromes in children has not been well defined, as follows The most common genetic syndromes associated with the development of colorectal cancer are shown in Tables 5 and 6. Familial polyposis is inherited as a dominant trait, which confers a high; degree of risk. Early diagnosis and surgical removal of the colon eliminates; the risk of developing carcinomas of the large bowel.[ 96 ] 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.[ 97 ] Familial adenomatous polyposis (FAP); 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.[ 98 ] A double-blind, placebo-controlled, randomized phase I trial in children aged 10 to 14 years with FAP reported that celecoxib at a dose of 16 mg/kg per day is safe for administration for up to 3 months. At this dose, there was a significant decrease in the number of polyps detected on colonoscopy.[ 99 ][ Level of evidence: 1iiDiv ] The role of celecoxib in the management of FAP is not clear. Another tumor suppressor gene on chromosome 18 is associated with; progression of polyps to malignant form. Multiple colon; carcinomas have been associated with neurofibromatosis type I and; several other rare syndromes.[ 100 ] (Refer to the summary on Genetics of Colorectal Cancer for more information about the genetic syndromes associated with childhood colorectal cancer.) These tumors, like bronchial adenomas, may be benign or malignant and can; involve the lining of the lung, large or small bowel, or liver.[ 101 - 106 ] Most lung; lesions are benign, however, some metastasize.[ 107 ] The carcinoid syndrome of; excessive excretion of somatostatin is characterized by flushing, labile blood; pressure, and metastatic spread of the tumor to the liver.[ 107 ] Symptoms may be; lessened by giving somatostatin analogs, which are available in short-acting and; long-acting forms.[ 108 ] Occasionally, carcinoids may produce ectopic ACTH and cause Cushing disease.[ 109 ] Most carcinoid tumors of; the appendix are discovered identally at the time of appendectomy, and are small, low-grade, localized tumors, simple appendectomy is the therapy; of choice.[ 110 - 112 ] For larger (>2 cm) tumors or tumors that have spread to local; nodes, cecectomy or rarely, right hemicolectomy, is the usual treatment.それ; has become accepted practice to remove the entire right colon in patients with; large carcinoid tumors of the appendix (>2 cm in diameter) or with; tumors that have spread to the nodes, however, this practice remains controversial.[ 113 ]
There are no reported cases of recurrence of appendiceal carcinoid tumors in children and adolescents after surgical resection without right hemicolectomy.
Overall, the prognosis for patients with appendiceal carcinoids is excellent. The Italian cooperative project on rare pediatric tumors (Tumori Rari in Eta Pediatrica [TREP] enrolled 113 children younger than 18 years with appendiceal neuroendocrine tumors between 2000 and 2013.[ 115 ][ Level of evidence: 3iiiA ] They found no relapses or deaths in this cohort after appendectomy for incompletely resected tumors. These data support the conclusion that observation alone is adequate follow-up after resection of appendiceal carcinoid tumors. A MEDLINE search did not find any documented cases of childhood localized appendiceal carcinoid in children younger than 18 years with complete resection who relapsed.[ 116 ]
Nonappendiceal neuroendocrine tumors in the abdomen can occur in the pancreas, stomach, and liver. The most common clinical presentation is an unknown primary site. Nonappendiceal neuroendocrine tumors are more likely to be larger, higher grade, or present with metastases.[ 117 ]
In one retrospective, single-institution study, the 5-year relapse-free survival rate of nonappendiceal neuroendocrine tumors was 41% and the overall survival rate was 66%. Chemotherapy for these tumors was largely ineffective.[ 117 ]
(Refer to the Bronchial tumors section of this summary for information about bronchial carcinoid tumors.)
Treatment of metastatic carcinoid tumors; of the large bowel, pancreas, or stomach becomes more complicated and requires treatment; similar to that given for adult high-grade neuroendocrine tumors. (Refer to the summary on adult Gastrointestinal Carcinoid Tumors for treatment options in patients with malignant carcinoid tumors.)
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract in adults.[ 118 ] These tumors are rare in children.[ 119 ] Approximately 2% of all GIST occur in children and young adults.[ 120 – 122 ] In one series, pediatric GIST accounted for 2.5% of all pediatric nonrhabdomyosarcomatous soft tissue sarcomas.[ 123 ] Previously, these tumors were diagnosed as leiomyomas, leiomyosarcomas, and leiomyoblastomas.
In pediatric patients, GIST are most commonly located in the stomach and almost exclusively affect adolescent females.[ 122, 124, 125 ]
Histologically, pediatric GIST have a predominance of epithelioid or epithelioid/spindle cell morphology and, unlike adult GIST, their mitotic rate does not appear to accurately predict clinical behavior.[ 124, 126 ] The majority of GIST in the pediatric age range have loss of the succinate dehydrogenase (SDH) complex and consequently, lack SDHB expression by immunohistochemistry.[ 127, 128 ] In addition, these tumors have minimal large-scale chromosomal changes and overexpress the insulin-like growth factor 1 receptor.[ 129, 130 ]
Activating mutations of KIT and PDGFA, which are seen in 90% of adult GIST, are present in only a small fraction of pediatric GIST.[ 124, 129, 131 ] The lack of SDHB expression in most pediatric GIST implicates cellular respiration defects in the pathogenesis of this disease and supports the notion that this disease is better classified as SDH-deficient GIST. Furthermore, about 50% of patients with SDH-deficient GIST have germline mutations of the SDH complex, most commonly involving SDHA,[ 127 ] supporting the notion that SDH-deficient GIST is a cancer predisposition syndrome and testing of affected patients for constitutional mutations for the SDH complex should be considered.[ 132 ] A small percentage of SDH-deficient GIST lack somatic or germline mutations of the SDH complex and are characterized by SDHC promoter hypermethylation and gene sileng and are categorized as SDH epimutant tumors.[ 133 ]
Most pediatric patients with GIST are diagnosed during the second decade of life with anemia-related gastrointestinal bleeding. In addition, pediatric GIST have a high propensity for multifocality (23%) and nodal metastases.[ 122, 124, 131 ] These features may account for the high idence of local recurrence seen in this patient population. Despite these features, patients have an indolent course characterized by multiple recurrences and long survival.[ 131 ]
SDH-deficient GIST can arise within the context of the following two syndromes:[ 124, 134 ]
Once the diagnosis of pediatric GIST is established, referral to medical centers with expertise in the treatment of GIST should be considered, and that all samples be evaluated for mutations of KIT (exons 9, 11, 13, 17), PDGFR (exons 12, 14, 18), and BRAF (V600E).[ 137, 138 ]
Treatment of GIST depends on whether a mutation is detected, as follows
Responses to imatinib and sunitinib in pediatric patients with SDH-deficient GIST are uncommon and consist mainly of disease stabilization.[ 124, 139, 140 ] In a review of ten patients who were treated with imatinib mesylate, one patient experienced a partial response and three patients had stable disease.[ 124 ] In another study, sunitinib appeared to show more activity, with one partial response and five cases of stable disease in six children with imatinib-resistant GIST.[ 141 ] Unlike the adult recommendations, the use of adjuvant imatinib cannot be recommended in children with SDH-deficient GIST.[ 142 ]
Genital/urinary tumors include the following
The prognosis, diagnosis, classification, and treatment of these; genital/urinary tumors are discussed below.これらの腫瘍は15歳未満の患者ではまれにしか見られないことが強調されなければならず、ほとんどの証拠は症例シリーズに由来する。
Urothelial bladder neoplasms are extremely rare in children.
Histologic classification of these neoplasms includes urothelial papillomas, papillary neoplasms of low malignant potential, low-grade urothelial carcinoma, and high-grade urothelial carcinoma. An alternative designation is transitional cell carcinoma of the bladder.最も一般的な; histology is papillary urothelial neoplasm of low malignant potential, while high-grade, invasive urothelial carcinomas are extremely rare in young patients.[ 1 – 5 ]
Bladder cancer in adolescents may develop as; a consequence of alkylating-agent chemotherapy given for other childhood tumors; or leukemia.[ 4, 6, 7 ] The association between cyclophosphamide and bladder; cancer is the only established relationship between a specific anticancer drug; and a solid tumor.[ 6 ]
In contrast to adults, most pediatric bladder carcinomas are low grade, superficial, and have an excellent prognosis after transurethral resection.[ 2, 3, 5, 8 ] Squamous cell carcinoma and more aggressive carcinomas, however, have been reported and may require a more aggressive surgical approach.[ 3, 9 – 11 ]
(Refer to the summary on; adult Bladder Cancer Treatment)
Testicular tumors are very rare in young boys and account for an idence of 1% to 2% of all childhood tumors.[ 12, 13 ] The most common testicular tumors are benign teratomas followed by malignant nonseminomatous germ cell tumors. (Refer to the summary on Childhood Extracranial Germ Cell Tumors)
Non–germ cell tumors such as sex cord–stromal tumors are exceedingly rare in prepubertal boys. In a small series, gonadal stromal tumors accounted for 8% to 13% of pediatric testicular tumors.[ 14, 15 ] In newborns and infants, juvenile granulosa cell and Sertoli cell tumors are the most common stromal cell tumor.[ 16 ] Juvenile granulosa cell tumors usually present in infancy (median age, 6 days) and Sertoli cell tumors present later in infancy (median age, 7 months). The prognosis for sex cord–stromal tumors is usually excellent after orchiectomy.[ 17 ][ Level of evidence: 3iiiA ] In older males, Leydig cell tumors are more common. Stromal cell tumors have been described as benign in young boys.[ 18 – 20 ]
There are conflicting data about malignant potential in older males. Most case reports suggest that in the pediatric patients, these tumors can be treated with surgery alone.[ 18 ][ Level of evidence: 3iii ]; [ 21 ][ Level of evidence: 3iiiA ]; [ 20 ][ Level of evidence: 3iiiDii ] It is prudent to check alpha-fetoprotein (AFP) levels before surgery. Elevated AFP levels are usually indicative of a malignant germ cell tumor. However, AFP levels and decay in levels are often difficult to interpret in infants younger than 1 year.[ 22 ]
However, given the rarity of this tumor, the surgical approach in pediatrics has not been well defined.
The majority of ovarian masses in children are not malignant.
The most common neoplasms are germ cell tumors, followed by epithelial tumors, stromal tumors, and then other tumors such as Burkitt lymphoma.[ 26 – 29 ] The majority of malignant ovarian tumors occur in girls aged 15 to 19 years.[ 30 ]
Ovarian tumors derived; from malignant epithelial elements include adenocarcinomas; cystadenocarcinomas, (mucinous) borderline tumors, endometrioid tumors, clear cell tumors, and; undifferentiated carcinomas.[ 31 ] In one series of 19 patients younger than 21 years with epithelial ovarian neoplasms, the average age at diagnosis was 19.7 years. Dysmenorrhea and abdominal pain were the most common presenting symptoms, 79% of the patients had stage I disease with a 100% survival rate, and only those who had small cell anaplastic carcinoma died.[ 32 ]
Girls with ovarian carcinoma (epithelial ovarian neoplasia) fare better than do adults with similar histology, probably because girls usually present with low-stage disease.[ 32 ]
Treatment is stage-related and may include; surgery, radiation, and chemotherapy with cisplatin, carboplatin, etoposide, topotecan; paclitaxel, and other agents.
Ovarian surface epithelial neoplasms comprise a small subset of ovarian epithelial neoplasms; in children, most of the cases are of serous or mucinous histology and have a low malignant potential. Surgery and chemotherapy have been used to treat ovarian surface epithelial neoplasms.[ 33 ]
Ovarian sex cord–stromal tumors are a heterogeneous group of rare tumors that derive from the gonadal non–germ cell component.[ 34 ] Histologic subtypes display some areas of gonadal differentiation and include juvenile granulosa cell tumors, Sertoli-Leydig cell tumors, and sclerosing stromal tumors. Ovarian Sertoli-Leydig cell tumors in children and adolescents are commonly associated with the presence of germline DICER1 mutations and may be a manifestation of the familial pleuropulmonary blastoma syndrome.[ 35 ]
The clinical presentation and prognosis of sex cord–stromal tumors varies by histology. In all entities, metastatic spread occurs rarely and if present, is usually limited to the peritoneal cavity.[ 34 ] Distant metastases may rarely occur, mostly in relapse situations.[ 36 ]
In the United States, these tumors may be registered in the Testicular and Ovarian Stromal Tumor registry.[ 37 ] In Europe, patients are prospectively registered in the national rare tumor groups.[ 37, 38 ] The recommendations regarding diagnostic work-up, staging, and therapeutic strategy have been harmonized between these registries.[ 37 ]
A French registry identified 38 girls younger than 18 years with ovarian sex cord tumors.[ 23 ] Complete surgical resection was achieved in 23 of 38 girls who did not receive adjuvant treatment. Two patients recurred, one patient’s tumor responded to chemotherapy, and the other patient died. Fifteen girls had tumor rupture and/or ascites. Eleven of the 15 patients received chemotherapy and did not recur; of the four who did not receive chemotherapy, all recurred and two died.
The most common histologic subtype in girls younger than 18 years is juvenile granulosa cell tumors (median age; 7.6 years, range, birth to 17.5 years).[ 39, 40 ] Juvenile granulosa cell tumors represent about; 5% of ovarian tumors in children and adolescents and are distinct from the; granulosa cell tumors seen in adults.[ 34, 41 – 43 ]
患者; with juvenile granulosa cell tumors present with the following:[ 44, 45 ]
Juvenile granulosa cell tumors have been reported in children with; Ollier disease and Maffucci syndrome.
As many as 90% of children with juvenile granulosa cell tumors will have; low-stage disease (stage I) by International Federation of Gynecology and Obstetrics (FIGO); criteria and are usually curable with unilateral salpingo-oophorectomy alone.
Patients with spontaneous tumor rupture or malignant ascites (FIGO stage Ic), advanced disease (FIGO stage II–IV), and those with high mitotic; activity tumors have a poorer prognosis and require chemotherapy.[ 23, 38 ] Use of a cisplatin-based chemotherapy; regimen has been reported in both the adjuvant and recurrent disease settings; with some success.[ 38, 39, 43, 46, 47 ]
Sertoli-Leydig cell tumors are rare in young girls and are more frequently seen in adolescents. They may present with virilization [ 48 ] or precocious puberty.[ 49 ] These tumors may also be associated with Peutz-Jeghers syndrome, but more frequently are a part of the DICER-1 tumor spectrum.[ 35, 50 ]
A study of 44 patients from the European Cooperative Study Group on Pediatric Rare Tumors showed that prognosis of Sertoli-Leydig tumors was determined by stage and histopathologic differentiation.[ 51 ]
Surgery is the primary treatment for Sertoli-Leydig cell tumors and is the only treatment for low-stage disease (FIGO stage Ia), with essentially 100% event-free survival.[ 23 ]
Patients with Sertoli-Leydig tumors with abdominal spillage during surgery, spontaneous tumor rupture, or metastatic disease (FIGO stages IC, II, III, and IV) are treated with cisplatin-based combination chemotherapy, although the impact of chemotherapy has not been studied in clinical trials.[ 23, 51 ] An additional study reported on 40 women with FIGO stage I or Ic Sertoli-Leydig cell tumors of the ovary, with an average age of 28 years.[ 52 ][ Level of evidence: 3iiA ] Of 34 patients with intermediate or poor differentiation, 23 patients received postoperative chemotherapy (most regimens included cisplatin); none recurred. Of the 11 patients who did not receive postoperative chemotherapy, two recurred; both had tumors that were salvaged with chemotherapy.
Small cell carcinomas of the ovary are exceedingly rare and aggressive tumors and may be associated with hypercalcemia.[ 53 ] Successful treatment with aggressive therapy has been reported in a few cases.[ 53, 54 ][ Level of evidence: 3iiB ]; [ 55, 56 ][ Level of evidence: 3iiiA ]
Adenocarcinoma of the cervix and vagina is rare in childhood and adolescence, with fewer than 50 reported cases.[ 29, 57 ] Two-thirds of the cases are related to exposure to diethylstilbestrol in utero.
The median age at presentation is 15 years, with a range of 7 months to 18 years, and most patients present with vaginal bleeding. Adults with adenocarcinoma of the cervix or vagina will present with stage I or stage II disease 90% of the time. In children and adolescents, there is a high idence of stage III and stage IV disease (24%). This difference may be explained by the practice of routine pelvic examinations in adults and the hesitancy to perform pelvic exams in children.
The treatment of choice is surgical resection,[ 58 ] followed by radiation therapy for residual microscopic disease or lymphatic metastases. The role of chemotherapy in management is unknown, although drugs commonly used in the treatment of gynecologic malignaes, carboplatin and paclitaxel, have been used.
The 3-year event-free survival (EFS) for all stages is 71% ± 11%; for stage I and stage II, the EFS is 82% ± 11%, and for stage III and stage IV, the EFS is 57% ± 22%.[ 57 ]
Other rare childhood cancers include the following
The prognosis, diagnosis, classification, and treatment of these; other rare childhood cancers are discussed below.;これらの癌は15歳未満の患者ではまれにしか見られないことが強調されなければならず、ほとんどの証拠は症例シリーズに由来する。
MEN syndromes are familial disorders 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
(Refer to the summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN syndromes.)
The most salient clinical and genetic alterations of the MEN syndromes are shown in Table 7.
The first manifestation of disease in 90% of patients is hypercalcemia; the most common cause of morbidity and mortality in these patients is the development of gastrinomas that lead to Zollinger-Ellison syndrome.[ 2, 3 ]
Primary hyperparathyroidism is very rare in children and, unlike adults, has an equal sex distribution. Nephrolithiasis is the leading cause of objective symptoms. In a review of 38 cases, 28 children were found to have familial disease; of those children, 26 patients were diagnosed with MEN1 syndrome.[ 4 ] Modern genetic testing can detect approximately 70% to 95% of patients with hyperparathyroidism that is secondary to MEN1 syndrome. A series of 160 patients with MEN1 syndrome was the first large study of patients diagnosed before age 21 years. Four patients had a malignant tumor, and one of these patients died.[ 5 ]
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.[ 6 ] Mutation testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.[ 7 ]
It is recommended that screening for patients with MEN1 syndrome begin by the age of 5 years and continue for life.試験または生化学的スクリーニングの回数は、年齢に依存し、毎年の血清カルシウム、副甲状腺ホルモン、ガストリン、グルカゴン、セクレチン、プロインシュリン、クロモグラニンA、プロラクチン、およびIGF-1を含み得る。 Radiologic screening should include a magnetic resonance imaging of the brain and computed tomography (CT) of the abdomen every 1 to 3 years.[ 8 ]
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 MEN2A and MEN2B syndromes.[ 9 – 11 ]
A pentagastrin stimulation test can be used to detect the presence of medullary thyroid carcinoma in these patients, although management of patients is driven primarily by the results of genetic analysis for RET mutations.[ 15, 16 ]
Guidelines for genetic testing of suspected patients with MEN2 syndrome and the correlations between the type of mutation and the risk levels of aggressiveness of medullary thyroid cancer have been published.[ 16, 17 ]
The most-recent literature suggests that this entity should not be identified as a form of hereditary medullary thyroid carcinoma that is separate from MEN2A and MEN2B. Familial medullary thyroid carcinoma should be recognized as a variant of MEN2A, to include families with only medullary thyroid cancer who meet the original criteria for familial disease. The original criteria includes families of at least two generations with at least two, but less; than ten, patients with RET germline mutations, small families in which two or fewer members in a single generation have germline RET mutations, and single individuals with a RET germline mutation.[ 16, 18 ]
The standard approach to patients who present with hyperparathyroidism and MEN1 syndrome is genetic testing and treatment with a cervical resection of at least three parathyroid glands and transcervical thymectomy.[ 4 ]
Relatives of patients with MEN2A undergo genetic testing in early childhood, before the age of 5 years. Carriers undergo total thyroidectomy as described above with autotransplantation of one parathyroid gland by a certain age.[ 23, 27 – 29 ]
Complete removal of the thyroid gland is the recommended procedure for surgical management of medullary thyroid cancer in children because there is a high idence 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.[ 33 – 35 ] 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.[ 35 – 37 ]
(Refer to the summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN2A and MEN2B.)
In a randomized phase III trial for adult patients with unresectable locally advanced or metastatic hereditary or sporadic medullary thyroid carcinoma treated with either vandetanib (a selective inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor) or placebo, vandetanib administration was associated with significant improvements in progression-free survival, response rate, disease control rates, and biochemical response.[ 38 ] Children with locally advanced or metastatic medullary thyroid carcinoma were treated with vandetanib in a phase I/II trial. Of 16 patients, only one had no response and seven had a partial response. Disease in three of those patients subsequently recurred, but 11 of 16 patients treated with vandetanib remained on therapy at the time of the report.[ 39 ]
Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1A gene, located in chromosome 17.[ 40 ] 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.[ 40 – 42 ] There are published surveillance guidelines for patients with Carney complex that include cardiac, testicular, and thyroid ultrasound.
For patients with the Carney complex, prognosis; depends on the frequency of recurrences of cardiac and skin myxomas and other; tumors.
Pheochromocytoma and paraganglioma are rare catecholamine-producing tumors with a combined annual idence of three cases per 1 million individuals. Paraganglioma and pheochromocytoma are exceedingly rare in the pediatric and adolescent population, accounting for approximately 20% of all cases.[ 43, 44 ]
Tumors arising within the adrenal gland are known as pheochromocytomas, whereas morphologically identical tumors arising elsewhere are termed paragangliomas. Paragangliomas are further divided into the following subtypes:[ 45, 46 ]
It is now estimated that up to 30% of all pheochromocytomas and paragangliomas are familial; several susceptibility genes have been described (refer to Table 9). 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.[ 47 – 50 ]
Genetic factors and syndromes associated with an increased risk of pheochromocytoma and paraganglioma include the following
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.[ 53, 54 ] Therefore, immunohistochemical SDHB staining can help identify potential carriers of a SDH mutation early, obviating the need for extensive and costly testing of other genes.
Younger patients have a higher idence of bilateral adrenal pheochromocytoma and extra-adrenal paraganglioma, and a germline mutation can be identified in close to 60% of patients.[ 44 ] Therefore, genetic counseling and testing is always recommended in young patients.
Patients with pheochromocytoma and sympathetic extra-adrenal paraganglioma usually present with the following symptoms of excess catecholamine production
These symptoms are often paroxysmal, although sustained hypertension between paroxysmal episodes occurs in more than one-half of patients. These symptoms can also be induced by exertion, trauma, induction of anesthesia, resection of the tumor, consumption of foods high in tyramine (e.g., red wine, chocolate, cheese), or urination (in cases of primary tumor of the bladder).[ 45 ]
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 identally.[ 45 ]
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.[ 55 ] 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.[ 44, 46, 55 ]
Studies of germline mutations in young patients with pheochromocytoma or paraganglioma have further characterized this group of neoplasms, as follows
It is important to note 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 (refer to Table 9).
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.
The diagnosis of paraganglioma and pheochromocytoma relies on the biochemical documentation of excess catecholamine secretion coupled with imaging studies for localization and staging
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 are 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.[ 60, 61 ]
For tumor localization, 6-[ 18 F]FDA PET and 123/131 I-mIBG scintigraphy perform equally well in patients with nonmetastatic paraganglioma and pheochromocytoma, but metastases are better detected by 6-[ 18 F]FDA PET than by 123/131 I-mIBG.[ 62 ] 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 of paraganglioma and pheochromocytoma is surgical. For secreting tumors, alpha- and beta-adrenergic blockade must be optimized before surgery.
For patients with metastatic disease, responses have been documented to some chemotherapeutic regimens such as gemcitabine and docetaxel or different combinations of vincristine, cyclophosphamide, doxorubicin, and dacarbazine.[ 63 – 65 ] Chemotherapy may help alleviate symptoms and facilitate surgery, although its impact on overall survival is less clear.
Responses have also been obtained to high-dose 131 I-mIBG and sunitinib.[ 66, 67 ]
(Refer to the summary on Genetics of Skin Cancer for more information about specific gene mutations and related cancer syndromes.)
Melanoma, although rare, is the most common skin cancer in children, followed by; BCCs and SCCs.[ 68 – 75 ] 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 to identify one melanoma was 479.8, which is 20 times higher than in the adult population.[ 76 ]
It is estimated that approximately 400 cases of melanoma are diagnosed each year in patients younger than 20 years in the United States, accounting for less than 1% of all new cases of; melanoma.[ 77 ] Melanoma annual idence in the United States (2002–2006) increases with age, as follows:[ 78, 79 ]
Melanoma accounts for about 6% of all cancers in children aged 15 to 19 years.[ 80 ]
The idence of pediatric melanoma increased by an average of 2% per year between 1973 and 2009.[ 79 ] The increased idence was especially notable in females between the ages of 15 and 19 years. Increased exposure to ambient ultraviolet (UV) radiation increases the risk of the disease. However, a review of United States Surveillance, Epidemiology, and End Results data from 2000 to 2010 suggested that the idence of melanoma in children and adolescents decreased over that interval.[ 81 ]
Conditions associated with an increased risk of developing melanoma in children and adolescents include the following
Phenotypic traits that are associated with an increased risk of melanoma in adults have been documented in children and adolescents with melanoma and include the following:[ 87 – 93 ]
Pediatric melanoma shares many similarities with adult melanoma, and the prognosis is dependent on stage.[ 94 ] As in adults, most pediatric cases (about 75%) are localized and have an excellent outcome.[ 79, 90, 95 ] More than 90% of children and adolescents with melanoma are expected to be alive 5 years after their initial diagnosis.[ 90, 94, 96, 97 ]
The outcome for patients with nodal disease is intermediate, with about 60% expected to survive long term.[ 90, 95, 96 ] In one study, the outcome for patients with metastatic disease was favorable,[ 90 ] but this result was not duplicated in another study from the National Cancer Database.[ 96 ]
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, thicker primary lesions, a higher idence of spitzoid morphology vascular invasion and nodal metastases, and more often have syndromes that predispose them to melanoma.[ 90, 94, 96, 98 ]
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 idence of nodal involvement.[ 99 ] Younger patients appear to have a higher idence of nodal involvement; this finding does not appear to significantly impact clinical outcome in this population.[ 98, 100 ] In other series of pediatric melanoma, a higher idence of nodal involvement did not appear to impact survival.[ 101 – 103 ]
The association of thickness with clinical outcome is controversial in pediatric melanoma.[ 90, 95, 96, 104 – 108 ] 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, considering the problematic histological distinction between true melanoma and melanocytic lesions with unknown malignant potential (MELTUMP); these patients are not included in pediatric trials.[ 109, 110 ]
The diagnostic evaluation of melanoma includes the following
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.[ 71, 111, 116 – 118 ] Clinically benign melanocytic lesions can sometimes pose a significant diagnostic challenge, especially when they involve regional lymph nodes.[ 119 – 121 ]
The diagnosis of pediatric melanoma may be difficult and many of these lesions may be confused with the so-called MELTUMP.[ 122 ] These lesions are biologically different from melanoma and benign nevi.[ 122, 123 ] The terms 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).[ 124 ][ 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.[ 125, 126 ] In contrast, the use of fluorescence in situ hybridization (FISH) probes that target four specific regions in chromosomes 6 and 11 can help distinguish melanoma from common nevi; however, atypical Spitzoid lesions will also have chromosomal alterations on FISH analysis and some will also have BRAF V600E mutations and BAP1 loss.[ 127 – 130 ]
Patients with atypical Spitzoid neoplasm tumors that harbored a 9p21 homozygous deletion had the highest risk for developing locoregional and distant disease.[ 131 ] However, in another study, 9p21 deletion was not associated with an unfavorable clinical outcome.[ 132 ] HRAS mutations have been described in some cases of Spitz nevi but they have not been described in Spitzoid melanoma. The presence of an HRAS mutation may aid in the differential diagnosis of Spitz nevus and Spitzoid melanoma.[ 133 ] Some of the characteristic genetic alterations seen in various melanocytic lesions are summarized in Table 10 below.[ 134, 135 ]
A study demonstrated that there are three distinct genomic subtypes of childhood melanocytic lesions. Conventional melanomas had a high burden of somatic single nucleotide variations, TERT promoter mutations, and activating BRAF V600 mutation, as well as a signature consistent with UV damage; two-thirds had MC1R variants associated with an increased susceptibility to melanoma. In contrast, melanomas that developed in a congenital melanocytic nevus contained activating NRAS Q61 mutations. About 40% of Spitzoid melanomas had kinase fusions involving various genes including RET, ROS1, NTRK1, ALK, and BRAF and were absent TERT mutations, except in cases of Spitzoid melanomas with fatal outcome.[ 132 ] MET fusions have also been recently described in atypical Spitzoid tumors and Spitzoid melanoma.[ 136 ] These studies emphasize the need to promote sun protection practices in early life, to individualize therapy based on the type of melanocytic lesion, and to improve access to therapeutic agents being explored in adults in young patients.[ 132, 137 ]
Surgery is the treatment of choice for patients with localized melanoma. Current guidelines recommend margins of resection as follows
Sentinel node biopsy should be considered in patients with thin lesions (≤1 mm) and ulceration, mitotic rate greater than 1 mm 2, young age, and in patients with lesions greater than 1 mm with or without adverse features. Young patients have a higher idence of sentinel node positivity and this feature adversely affects clinical outcomes.[ 99, 103 ] If the sentinel node is positive, the option to undergo a complete lymph node dissection should be considered. Patients with high-risk primary cutaneous melanoma, such as those with regional lymph node involvement, can be offered the option to receive adjuvant interferon alfa-2b, a therapy that is well tolerated in children.[ 116, 117, 138 ] Trials of other adjuvant therapies, such as BRAF and MEK inhibitors and checkpoint inhibitors, are currently not available for pediatric patients.
For patients with metastatic, recurrent, or progressive disease, prognosis is poor. Various agents such as interferon, dacarbazine, temozolomide, sorafenib, or; interleukin-2, and biochemotherapy can be used.[ 139 – 141 ] The results of pediatric trials that incorporate newer therapies such as vemurafenib and checkpoint inhibitors including ipilimumab and PD-1 inhibitors are not yet available.[ 142, 143 ]
(Refer to the summary on adult Melanoma Treatment)
The following are examples of national and/or institutional clinical trials that are currently being conducted.進行中の臨床試験に関する情報は、このフォーラムから入手できます。
BCCs generally appear as raised lumps or ulcerated lesions; usually in areas with previous sun exposure.[ 144 ] These tumors may be multiple and; exacerbated by radiation therapy.[ 145 ] 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.[ 146 – 149 ] 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. 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.[ 150 ] Vismodegib (GDC-0449), a hedgehog pathway inhibitor, has been approved for the treatment of adult patients with BCC.[ 151, 152 ] 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 after 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.[ 153 ]
(Refer to the summary on adult Skin Cancer; Treatment)
Chordoma is a very rare tumor of bone that arises from remnants of the notochord within the clivus, spinal vertebrae, or sacrum. The idence 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.[ 154 ] Most pediatric patients have the classical or chondroid variant of chordoma, while the dedifferentiated variant is rare in children.[ 154, 155 ]
Younger children appear to have a worse outlook than do older patients.[ 154, 156 – 160 ] The survival rate in children and adolescents ranges from about 50% to 80%.[ 154, 157, 159 ]
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.[ 161 ]
Standard treatment includes surgery and external radiation therapy, often proton-beam radiation.[ 159, 162 ] 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) because these tumors are relatively radiation resistant, and radiation-dose conformality with protons allows for higher tumor doses while sparing adjacent critical normal tissues.[ 163, 164 ]; [ 159, 165 ][ Level of evidence: 3iiA ]; [ 166 ][ Level of evidence: 3iiiDiii ]
There are only a few anecdotal reports of the use of cytotoxic chemotherapy after surgery alone or surgery plus radiation therapy. Treatment with ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide has been reported with some success.[ 167, 168 ] The role for chemotherapy in the treatment of this disease is uncertain.
Imatinib mesylate has been studied in adults with chordoma on the basis of the overexpression of PDGFR alpha, beta, and KIT in this disease.[ 169, 170 ] Among 50 adults with chordoma treated with imatinib and evaluable by Response Evaluation Criteria In Solid Tumors (RECIST) guidelines, there was one partial response and 28 additional patients had stable disease at 6 months.[ 170 ] 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.[ 170 ] Other tyrosine kinase inhibitors and combinations involving kinase inhibitors have been studied.[ 171 – 173 ]
Recurrences are usually local but can include distant metastases to lungs or bone.
Children represent less than 1% of all solid cancers of unknown primary site and because of the age-related idence of tumor types, embryonal histologies are more common in this age group.[ 174 ]
Cancers of unknown primary site present as a metastatic cancer for which a precise primary tumor; site cannot be determined.[ 175 ] 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 present in this way.
For all patients who present with tumors from an unknown primary site; treatment is directed toward the specific histopathology of the tumor and; is age-appropriate for the general type of cancer initiated, irrespective of; the site or sites of involvement.[ 175 ]
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.[ 176 ] A report in adults using 2-deoxy-2-[18F]-fluoro-D-glucose (18 F-FDG) PET-CT identified 42.5% of primary tumors in a group of cancers of unknown primary site.[ 177 ]
The use of gene expression profiling and next-generation sequeng can enhance our ability to identify the putative tissue of origin and guide in the selection of targeted agents for specific mutations.[ 178 – 182 ] No pediatric studies have been conducted to date.
Chemotherapy, targeted therapy, 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); is initiated as early as possible.[ 183 ]
(Refer to the summary on adult Carcinoma of Unknown Primary Treatment for more; information.)
This summary is written and maintained by the Pediatric Treatment Editorial Board, which is;編集者から独立しています。この要約は、独立したレビューを反映しています。文学は、またはの政策声明を表すものではありません。もっと;サマリーポリシーに関する情報と編集委員会の役割要約の維持については、この概要および包括的な癌データベースのページをご覧ください。
This cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of unusual cancers of childhood.それは、がん患者を看護する臨床医に通知し支援するためのリソースとして意図されています。ヘルスケアの意思決定を行うための正式なガイドラインや推奨事項はありません。
This summary is reviewed regularly and updated as necessary by the Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute ().この要約は、文献の独立したレビューを反映しており、National Institutes of Health（）の政策声明を表すものではない。
この要約の引用文献には、証拠レベルの指定が付いています。これらの指定は、読者が特定の介入またはアプローチの使用を支持する証拠の強さを評価するのを助けるためのものです。 The Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
小児科医編集委員会。 Unusual Cancers of Childhood Treatment. Bethesda, MD: /types/childhood-cancers/hp/unusual-cancers-childhood-. 。 [PMID: 26389315]
入手可能な証拠の強さに基づいて、治療オプションは「標準」または「臨床評価中」のいずれかと記載することができます。これらの分類は、保険払い戻しの決定の基礎として使用すべきではありません。保険の範囲についての詳細は、Cancer Care Managing Managingページを参照してください。