Pediatric head and neck tumors
2025-06-23 Paola Dal Cin, PhD Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
Keywords
Head and neck tumor , childrenClassification
Definition
Head and neck tumors are uncommon in pediatric patients; however, some tumors occur almost exclusively in the pediatric age group e.g., congenital granular cell epulis, sialoblastoma, and melanotic neuroectodermal tumor of infancy. Benign and malignant pediatric neoplasms largely within the soft tissue compartment of the head and neck region may be associated with cancer predisposition syndromes e.g., odontogenic keratocyst juvenile nasopharyngeal angiofibroma, ossifying fibroma of the jaw, paraganglioma, plexiform neurofibroma, plexiform schwannoma, mucosal neuroma, and nevus sebaceous syndrome; along with malignant tumors such as squamous cell carcinoma.1
Odontogenic tumors are a group of neoplastic growths that originate from the tissues responsible for tooth formation and the periodontal apparatus of the jaw. Some odontogenic tumors demonstrate strong predilection for pediatric patients including the unicystic ameloblastoma, adenomatoid odontogenic tumor, ameloblastic fibroma, ameloblastic fibro-odontoma, odontoma, and primordial odontogenic tumor. 2 Most odontogenic tumors pathogenic mutations affect the MAPK/ERK, WNT/β-catenin, and Sonic Hedgehog (SHH) pathways, 3-5and there is a prevalence of BRAF p.V600E in benign mixed epithelial and mesenchymal and malignant odontogenic tumors. 5
The parotid gland is involved in up to 90 % of all pediatric salivary gland tumors, followed by the submandibular, sublingual, and minor salivary glands, with a female predisposition for both benign and malignant salivary neoplasm. 6 Fine-needle aspiration (FNA) cytology is a basic diagnostic tool for all salivary gland tumors. 7 Pleomorphic adenoma and mucoepidermoid carcinoma as the most common primary benign and malignant neoplasms in childhood, respectively. The vast majority (80%) of salivary gland carcinomas in children and adolescents represent low-grade mucoepidermoid carcinomas followed by acinic cell and adenoid cystic carcinoma. Secretory carcinoma (SC) is rare low grade salivary gland carcinoma in children, characterized by morphological resemblance to mammary secretory carcinoma and a recurrent translocation leading to ETV6::NTRK3 fusion.
| Pediatric head and neck tumors | Genetic marker(s) |
|---|---|
| Benign tumors | |
| Squamous papilloma and papillomatosis | Human papillomaviruses (HPVs) are causative of a group of clinically papillary lesions. HPV6 and HPV11 (identified in 90% of cases) are the genotypes most frequently associated with respiratory papillomatosis papillomatosis (RRP) and solitary oral squamous papilloma (SP).8,9 Most infections in children occur at birth, during passage through the birth canals of contaminated mothers. 10,11 |
| White sponge naevus (WGN) | A rare autosomal dominant disorder, also known as Cannon disease, strongly linked to mutations in KRT4 and KRT13. 12 |
| Congenital granular cell epulis(CGCE) | It is rare neonatal benign congenital growth predominantly in the gingiva of female newborns. 13 Polydactyly, triple X syndrome and neurofibromatosis are among the associated conditions that have been reported. 14 |
| Central giant cell granuloma (CGCG) | Point mutations were identified in TRPV4, KRAS and FGFR1 genes in sporadic cases, and FGFR1 has beeen associated with association with young age. 15 Rarely ,they may occurr in specific syndromes grouped under the umbrella term RASopathies. 16 |
| Some odontogenic tumors demonstrate strong predilection for pediatric patients including the unicystic ameloblastoma, adenomatoid odontogenic tumor, ameloblastic fibroma, ameloblastic fibro-odontoma, odontoma, and primordial odontogenic tumor. 2 Most benign and malignant odontogenic tumors share pathogenic mutations affecting the MAPK/ERK, WNT/β-catenin, and Sonic Hedgehog (SHH) pathways. 3-5 | |
| Odontogenic tumors | PTCH1 mutations have been reported in a high proportion of odontogenic keratocysts, when multiple can be associated with nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome) OMIM:109400 and in sporadic forms. However, other rare scattered mutations (~20%) can occur independent of the SHH pathway. 17 BRAF p.V600E mutations have been reported in all variants of ameloblastoma e.g.conventional, unicystic (mainly pediatric) and and extraosseous, as well as, in the malignant counterpart, ameloblastic carcinoma, but in lower frequency. 3 However, less frequent mutations have been also detected in other components of the MAPK pathway e.g., KRAS and FGFR2 , and as well as , in non-MAPK pathway mutations e.g .SMO p.Leu412Phe in the Hedgehog pathway. 18 Gain-of-function KRAS mutations,specifically p.G12V/R , have bee reported in sporadic adenomatoid odontogenic tumors. 3 Multiple lesions in patients with Schimmelpenning syndrome OMIM:163200. Odontomas occur in patients with syndromes caused by genetic mutations: familial adenomatous polyposis OMIM:175100; Schimmelpenning syndrome OMIM:163200; odontoma-dysphagia syndrome OMIM:164330 and encephalocraniocutaneous lipomatosis OMIM:613001 So far,sporadic odontomas did not harbourBRAF p.V600E mutation, so far. BRAF p.V600E mutation has been detected in all benign variants of ameloblastic fibroma, and, as well as in ameloblastic fibrosarcoma, the malignant counterpartof ameloblastic fibroma.19 |
| Ossifying fibroma(OF) | Ossifying fibromas of the head and neck region are classified as cemento-ossifying fibroma (COF), and two types of juvenile ossifying fibromas as trabecular (JTOF), and psammomatous (JPOF). CDC73/CDC73 mutations identified in sporadic ossifying fibromas as well as, in multiple ossifying fibromas in patients with hyperparathyroidism–jaw tumour syndrome OMIM:145001 . 20,21 MDM2 amplification and MDM2 and CDK4 expression are rare finfings in OF of craniofacial bones.22 Identical chromosomal breakpoints at bands Xq26 and 2q33 were described in 3 cases of JPOF located in the orbita.which were subsequently mapped to AL51348 and SATB2, respectivey. 23,24 The involvement of SATB2 at 2q33 was demonstrated to be specific to JPOF, suggesting that PsOF is not only morphologically and clinically but also genetically distinct from JTOF and COF. 25 However, whole-RNA-sequencing showed two frameshift SATB2::EXOC6B fusions as the result of complex rearrangements at 2q33.1 (SATB2) and 2p13.2 EXOC6B in a single case of JTOF. 26 |
| Sinonasal tract myxoma | Infantile sinonasal myxomas represent clinically, morphologically, and genetically distinctive neoplasm, different from the other myxomas. APC and CTNNB1 alterations were frequently observed.27 However, the CTNNB1 alterations were exclusively point mutations to the ubiquitination domain (residues D32-S37),and none harbored alterations to the phosphorylation sites T41 and S45 that are altered in 99% of CTNNB1-mutant desmoid fibromatoses. 27 |
| Nasal dermoid cyst (NCD) | No genetic markers so far |
| Nasopharyngeal dermoid | No genetic markers so far |
| Sinonasal chondromesenchymal hamartoma | Both germline and somatic DICER1 mutations have been reported in nasal chondromesenchymal hamartomas,commonly affecting infants. 28 Nasal chondromesenchymal hamartomas arise secondary to germline and somatic mutations of DICER1 in the pleuropulmonary blastoma tumor-predisposition disorder. 29 A single case with t(12;17)(q24.1;q21) has been reported. 30 |
| Pleomorphic adenoma (PA) | It is the most frequent benign salivary neoplasms, however there is very limited molecular work on PA in pediatric patients, and even less information regarding the PLAG1 (8q12) and HMGA2 (12q13.4) histochemical staining. 31 |
| Malignant tumors | |
| Mucoepidermoid carcinoma (MEC) | Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy in children., without sex predilection, and a better overall survival than in adults. 32 The t(11;19)(q21;p13)/ CRTC1::MAML2 fusion seems to be more frequent than t(11;15)(q21;q26)/ CRTC3::MAML2 fusion.33 |
| Acinic cell carcinoma (AciCC) | Acinic cell carcinoma (AciCC) is the 2nd most common pediatric malignant salivary gland tumor,with a female predominance. 34 It is characterized by a recurrent t(4;9)(q13;q31) , leading to enhancer hijacking and upregulation of the NR4A3. 35 NR4A3 is a highly sensitive and specific immunohistochemical marker for AciCC . 36 So far no HTN3::MSANTD fusion or NR4A2 rearrangement have been reported in pediatric cases. |
| Secretory carcinoma (SC) of salivary glands | Secretory carcinoma (SC) of salivary glands is a rare malignacy in childred with morphologic and molecular similarities to SC of the breast e,g, recurrent t(12;15)(p13;q25)} / ETV6::NTRK3 gene fusion, with excellent prognosis following surgical resection. The detection of the this gene fusion was is of great importance for the possibility to administer a target therapy, Larotrectinib 37 A single pediatric case harboring a ETV6::RET fusion has been sofar reported.38 |
| Sialoblastoma (SBL) | Sialoblastoma is a rare congenital epithelial malignant tumor of the salivary glands, usually diagnosed at birth or shortly thereafter with less aggressive behavior for submandibular sialoblastoma in comparison with other sites reported in chidren. 39 Only a few studies have investigated the genetic characteristics of SBLs, but FGFR2 C382R mutation is the most common mutation so far reported in solid pattern SBL umors, with increased risk of recurrence and metastasis.40 A synchronous occurrence of sialoblastoma and hepatoblastoma has been also reported in literature. 41 Single cytogentic investigation have been reported .42 |
| Nasopharyngeal carcinoma (NPC) | There are striking ethnic differences in the prevalance of nasopharyngeal carcinomas (NPCs).EBV is especially associated with undifferentiated type which is the most frequent in children, and age distribution is also different in these endemic regions,e.g., Southern parts of China, Southeast Asia, Alaska, and in the Mediterranean Basi.43 People with certain HLA class I genes have a higher risk of developing NPC.44 |
| NUT carcinoma | NUT carcinoma is poorly differentiated carcinoma originating from midline locations such as the head, neck or mediastinum. It is characterized by NUTM1 a.k.a. NUTM1 rearrangement mainly with BRD4 but addtional partner genes e.g. BRD3, NSD3 , ZNF532, ZNF592 or other unidentified genes.45 Among all NUT carcinomas, pediatric salivary gland tumors may represent a distinct clinical subset associated with male predilection and comparatively prolonged survival. 46 NUT immunohistochemistry /FISH for NUTM1 play an important role in diagnosis.47 |
| Melanotic neuroectodermal tumour of infancy (MNTI) | Melanotic neuroectodermal tumor of infancy (MNTI) is a rare osteoliytic locally aggressive neoplasm primarily affecting the jaws of the new-born infant. 48 No BRAF V600E mutations have been reported 49. A single case without apparent copy number variations but both germ-line CDK2A heterozygous mutation and mutiple gene fusions, including RPLP1:: C19MC wereere also been observed . 50 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 33723760 | 2021 | Review of Pediatric Head and Neck Neoplasms that Raise the Possibility of a Cancer Predisposition Syndrome. | Cortes-Santiago N et al |
| 2 | 38032744 | 2023 | Pediatric Odontogenic Tumors. | Liu Y et al |
| 3 | 35048058 | 2021 | The Molecular Pathology of Odontogenic Tumors: Expanding the Spectrum of MAPK Pathway Driven Tumors. | Guimarães LM et al |
| 4 | 36378285 | 2022 | Molecular diagnostics in odontogenic tumors. | Buettner R et al |
| 5 | 38057461 | 2023 | Prevalence of BRAF p.V600E and Detection Methods in Benign Mixed and Malignant Odontogenic Tumors: A Systematic Review. | Severino-Lazo RJG et al |
| 6 | 37352681 | 2023 | Pediatric primary salivary gland tumors. | Jesberg P et al |
| 7 | 38228123 | 2024 | Efficacy of Fine-Needle Aspiration Cytology in Diagnosing Secretory Carcinoma of Salivary Gland: A Systematic Review and Meta-Analysis. | Kala PS et al |
| 8 | 15514560 | 2004 | Recurrent respiratory papillomatosis: a longitudinal study comparing severity associated with human papilloma viral types 6 and 11 and other risk factors in a large pediatric population. | Wiatrak BJ et al |
| 9 | 30693456 | 2019 | HPV-Related Papillary Lesions of the Oral Mucosa: A Review. | Betz SJ et al |
| 10 | 20553530 | 2010 | Current concepts on human papillomavirus infections in children. | Syrjänen S et al |
| 11 | 28427542 | 2017 | Recurrent respiratory papillomatosis: A state-of-the-art review. | Fortes HR et al |
| 12 | 29047160 | 2018 | Mutations in the genes for keratin-4 and keratin-13 in Swedish patients with white sponge nevus. | Westin M et al |
| 13 | 30888637 | 2020 | Congenital Granular Cell Epulis: Classic Presentation and Its Differential Diagnosis. | Cheung JM et al |
| 14 | 20964807 | 2010 | Spontaneous regression of congenital epulis: a case report and review of the literature. | Ritwik P et al |
| 15 | 36428107 | 2023 | Significant association between FGFR1 mutation frequency and age in central giant cell granuloma. | Niada S et al |
| 16 | 38347383 | 2024 | Multiple central giant cell granuloma of the jaws: diagnostic signposts of Noonan syndrome and RASopathy. | Friedrich RE et al |
| 17 | 31162759 | 2019 | PTCH1 alterations are frequent but other genetic alterations are rare in sporadic odontogenic keratocysts. | Qu J et al |
| 18 | 24859340 | 2014 | Identification of recurrent SMO and BRAF mutations in ameloblastomas. | Sweeney RT et al |
| 19 | 31899815 | 2020 | Ameloblastic fibrosarcoma: clinicopathological and molecular analysis of seven cases highlighting frequent BRAF and occasional NRAS mutations. | Agaimy A et al |
| 20 | 27658992 | 2016 | CDC73 gene mutations in sporadic ossifying fibroma of the jaws. | Chen Y et al |
| 21 | 31929790 | 2019 | Clinical Features, Treatment, and Surveillance of Hyperparathyroidism-Jaw Tumor Syndrome: An Up-to-Date and Review of the Literature. | Torresan F et al |
| 22 | 35546651 | 2022 | MDM2 Gene Amplification and Expression of MDM2 and CDK4 are Rare in Ossifying Fibroma of Craniofacial Bones. | Bahceci DH et al |
| 23 | 8625058 | 1995 | Nonrandom chromosome breakpoints at Xq26 and 2q33 characterize cemento-ossifying fibromas of the orbit. | Sawyer JR et al |
| 24 | 15022060 | 2004 | Cytogenetic distinction among benign fibro-osseous lesions of bone in children and adolescents: value of karyotypic findings in differential diagnosis. | Parham DM et al |
| 25 | 36788065 | 2023 | Psammomatoid Ossifying Fibroma Is Defined by SATB2 Rearrangement. | Cleven AHG et al |
| 26 | 38890784 | 2024 | SATB2-rearrangement in a case of juvenile trabecular ossifying fibroma, expanding the spectrum of SATB2-rearranged neoplasia. | Perret R et al |
| 27 | 37678343 | 2023 | Infantile Sinonasal Myxoma Is Clinically and Genetically Distinct From Other Myxomas of the Craniofacial Bones and From Desmoid Fibromatosis. | Odintsov I et al |
| 28 | 32462280 | 2020 | Nasal Chondromesenchymal Hamartoma. | Thirunavukkarasu B et al |
| 29 | 25118636 | 2014 | Nasal chondromesenchymal hamartomas arise secondary to germline and somatic mutations of DICER1 in the pleuropulmonary blastoma tumor predisposition disorder. | Stewart DR et al |
| 30 | 22356457 | 2012 | Translocation t(12;17)(q24.1;q21) as the sole anomaly in a nasal chondromesenchymal hamartoma arising in a patient with pleuropulmonary blastoma. | Behery RE et al |
| 31 | 20055685 | 2010 | Pediatric epithelial salivary gland tumors: spectrum of histologies and cytogenetics at a children's hospital. | Craver RD et al |
| 32 | 36612247 | 2022 | Mucoepidermoid Carcinoma of the Salivary Gland: Demographics and Comparative Analysis in U.S. Children and Adults with Future Perspective of Management. | Ullah A et al |
| 33 | 26221861 | 2016 | Mucoepidermoid Carcinoma in Children: A Single Institutional Experience. | Techavichit P et al |
| 34 | 32083250 | 2019 | Are demographics associated with mucoepidermoid or acinic cell carcinoma parotid malignancies in children? | Janz TA et al |
| 35 | 30664630 | 2019 | Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands. | Haller F et al |
| 36 | 3291035 | 1988 | [A case of left atrial myxoma complicated with acute myocardial infarction]. | Doi Y et al |
| 37 | 34486543 | 2022 | Secretory Carcinoma of the Salivary Gland: A Rarity in Children. | Kelly GA et al |
| 38 | 33459993 | 2021 | Clinicopathologic and Molecular Characterization of Four Cases of Pediatric Salivary Secretory Carcinoma (SSC), One with ETV6-RET Fusion. | Salgado CM et al |
| 39 | 31257547 | 2019 | Sialoblastoma of the submandibular gland: a distinct entity? | Di Micco R et al |
| 40 | 39807824 | 2025 | Sialoblastomas With Solid Pattern Have FGFR2 Mutations and an Unfavorable Prognosis. | Jia X et al |
| 41 | 35860547 | 2022 | The Cellular and Molecular Landscape of Synchronous Pediatric Sialoblastoma and Hepatoblastoma. | Yang R et al |
| 42 | 19167616 | 2009 | Clonal chromosome aberrations in a sialoblastoma. | Mertens F et al |
| 43 | 31322911 | 2019 | Update in pediatric nasopharyngeal undifferentiated carcinoma. | Claude L et al |
| 44 | 31521748 | 2020 | Translational genomics of nasopharyngeal cancer. | Tsang CM et al |
| 45 | 35372003 | 2022 | NUT Carcinoma: Clinicopathologic Features, Molecular Genetics and Epigenetics. | Moreno V et al |
| 46 | 32077054 | 2021 | Salivary Gland NUT Carcinoma with Prolonged Survival in Children: Case Illustration and Systematic Review of Literature. | Wang H et al |
| 47 | 23157742 | 2012 | [Utility of NUT gene expression and rearrangement in diagnosis of NUT midline carcinoma in upper respiratory tract]. | Fang W et al |
| 48 | 36853558 | 2023 | Melanotic Neuroectodermal Tumour of Infancy. | Janardhanan M et al |
| 49 | 34094962 | 2021 | Melanotic Neuroectodermal Tumor of Infancy: A Clinicopathological and BRAF V600E Mutation Study of 11 Cases. | Xia RH et al |
| 50 | 27519597 | 2016 | A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case report. | Barnes DJ et al |
Citation
Paola Dal Cin, PhD
Pediatric head and neck tumors
Atlas Genet Cytogenet Oncol Haematol. 2025-06-23
Online version: http://atlasgeneticsoncology.org/solid-tumor/209323/pediatric-head-and-neck-tumors
