Pediatric Head and Neck Malignancies Neil K

Pediatric head and neck malignancies Neil K. Chadha and Vito Forte

Department of Otolaryngology – Head and Neck Purpose of review Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada Although head and neck masses represent a common entity in children, malignancy is uncommon. The otolaryngologist may be the ﬁrst physician to see these children, and Correspondence to Dr Vito Forte, MD, FRCSC, Chief, Department of Otolaryngology – Head and Neck early recognition of malignancy is of obvious importance. This review aims to discuss the Surgery, The Hospital for Sick Children, 555 University cause, diagnosis, investigation, treatment options, and prognosis for the most common Avenue, Toronto, ON M5G 1X8, Canada Tel: +1 416 813 4938; fax: +1 416 813 5036; head and neck malignancies of childhood. e-mail: [email protected] Recent ﬁndings

Current Opinion in Otolaryngology & Head and Over recent years, signiﬁcant developments have been made in characterizing the Neck Surgery 2009, 17:471–476 epidemiologic, phenotypic, and genotypic variability of childhood head and neck cancers. Improved awareness of tumor biology is reﬂected by more sophisticated diagnostics, estimates of prognosis, and an increasing individualization of treatment regimens. Summary The latest evidence for the diagnosis and management of childhood head and neck malignancy is summarized. The rarity of these tumors inevitably results in a paucity of high-level evidence to guide treatment. A combination of translational research from tumor biology studies, multicenter clinical trials, and smaller case series and case reports will continue to guide new advances in diagnosis and treatment.

Keywords child, head and neck, lymphoma, malignancy, rhabdomyosarcoma

Curr Opin Otolaryngol Head Neck Surg 17:471–476 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1068-9508

of cases present in the head and neck region [2]. It affects Introduction about 250 children per year in the United States [3]. Although relatively uncommon, childhood cancer is sec- There are two peaks in incidence at an age of 2–6 years ond only to accidental trauma as a cause of death in and at 10–18 years [4]. Rhabdomyosarcoma is a malignant children over 5 years of age. Data from the United States tumor of mesenchymal origin and is within the category National Cancer Institute database suggest that the head of small blue cell tumors, which also includes neuroblas- and neck are involved in 12% of all childhood malig- toma and primitive neuroectodermal tumors. The embry- nancies [1]. onal form is most common at birth and incidence declines with age, and the alveolar form peaks in childhood and The most common pediatric head and neck malignancies adolescence [5]. Embryonal rhabdomyosarcoma comes in include non-Hodgkin lymphomas, Hodgkin lymphomas, spindle cell and botryoid variants and carries a better rhabdomyosarcomas, thyroid malignancies, nasopharyn- prognosis [6]. Many alveolar rhabdomyosarcomas carry geal carcinomas (NPCs), salivary gland malignancies, and chromosomal translocations, with the PAX3-FKHR gene neuroblastomas. We aim to discuss each of these diseases, translocation suggesting the poorest prognosis, particu- focusing on current management strategies and new larly with metastasis [7,8]. developments, as they relate to the role of the otolaryngologist–head and neck surgeon. Other rarer pediatric A multidisciplinary approach is required for treatment of head and neck malignancies, beyond the scope of this rhabdomyosarcoma. Presentation is often with an asymp- review, include nonrhabdomyosarcoma soft tissue sarco- tomatic mass, and an open or core needle biopsy is mas, malignant teratomas, primitive neuroectodermal required to provide adequate tissue for histopathologic tumors, and skin cancers. and molecular analysis. After radiological imaging, staging is based on location, size, extent, and the absence or presence of metastases (see Table 1) [9]. The outcomes Rhabdomyosarcoma of the Intergroup Rhabdomyosarcoma Studies (IRS I– Rhabdomyosarcoma is the most common soft tissue IV) allow patients to be prognosticated into low, inter- sarcoma in children and adolescents, and over one-third mediate, and high-risk groups based on a combination of

1068-9508 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MOO.0b013e3283323893

Table 1 Pretreatment Intergroup Rhabdomyosarcoma Study staging system IRS stage Site Size T stage N stage M stage

1 Orbit; head and neck (excluding parameningeal); a or b T1 or T2 N0 or N1 or Nx M0 genitourinary (nonbladder, nonprostate); biliary tract 2 Bladder; prostate; extremity; cranial parameningeal; other a T1 or T2 N0 or Nx M0 3 Bladder; prostate; extremity; cranial parameningeal; other a T1 or T2 N1 or Nx M0 bT1orT2N0 M0 4 All a or b T1 or T2 N0 or N1 or Nx M1 Size: a, greatest dimension less than 5 cm; b, greatest dimension more than 5 cm. Tumor invasiveness (T stage): T1, conﬁned to anatomic site of origin; T2, extension and/or ﬁxation to surrounding tissue. Regional lymph nodes (N stage): N0, regional lymph nodes not clinically involved; N1, regional lymph nodes clinically involved; Nx, status of regional lymph nodes unknown. Metastasis (M stage): M0, no distant metastasis; M1, distant metastasis present. IRS, Intergroup Rhabdomyosarcoma Study. Adapted from [9].

disease stage, histology (embryonal versus alveolar), the Pure follicular carcinoma is less common, and anaplastic patient’s age, and postsurgery disease [10]. and undifferentiated forms are extremely rare. Medullary thyroid carcinoma (MTC) must be considered in children Rhabdomyosarcoma is rarely cured by one modality with multiple endocrine neoplasia (MEN) types IIA and alone, so multimodal treatment is indicated. This consists IIB. Radiation exposure has been identified as a risk of chemotherapy and either surgery or radiotherapy, the factor for childhood thyroid cancer, as recognized follow- decision being individualized to the tumor site and stage. ing the Chernobyl nuclear accident [15]. Risk is also The IRS-IV study protocol resulted in 5-year survival increased after treatment of lymphoma and leukemia, rates of 97% in embryonal nonorbital, nonparameningeal particularly for children treated before 10 years of age and head and neck cases, and 67% in the alveolar cases [11]. in those receiving radiation doses up to 30 Gy [16]. Surgical excision is recommended for localized disease Recent work has suggested that iodine deficiency could [12], as it improves survival and, if complete, avoids the increase incidence, reduce latency, and influence tumor need for radiotherapy, which is associated with a high risk aggressiveness of radiation-induced thyroid carcinogen- of morbidity in children (facial growth retardation, second esis [17]. neoplasm). In large or extensive rhabdomyosarcomas of the head and neck in which the morbidity of surgical Thyroid cancer should be suspected when a solitary resection is excessive and/or complete resection unob- thyroid nodule is identified in children and adolescents, tainable (e.g. nasaopharynx, paranasal sinuses, and with 20% estimated to represent malignancy compared temporal bone), treatment with combination chemo- with 5% in adults [18]. Initial investigation should radiotherapy is indicated. include measurement of serum thyroid-stimulating hor- mone (TSH), calcitonin (for diagnosis of MTC), and a Restaging at least 6 weeks after completion of therapy neck ultrasound scan. Ultrasound features suggestive of can include computed tomography (CT), MRI, and malignancy include indistinct margins, microcalcifica- fluoro-deoxyglucose PET [10]. For those cases with a tions, and variable echogenicity. As in adults, fine needle high probability of residual disease, postchemoradiother- aspiration (FNA) may be useful for distinguishing benign apy salvage surgery may be recommended by the multi- and malignant nodules, but data are limited in children. disciplinary team, but the potential for significant mor- When the aspirate demonstrates malignancy, surgery is bidity from extensive head and neck resection should be recommended. When the cytology is indeterminate or carefully considered. Tumor location may limit the abil- inadequate, options include repeating ultrasound-guided ity to achieve adequate resection margins, and extensive FNA within 3–6 months, or proceeding to surgery, after surgical reconstruction may be required. A significant discussion of the risk-to-benefit ratio. In young children proportion of patients undergoing salvage surgery will at higher risk of malignancy (under 10 years of age, die from the disease, so patients and families should be previous radiation exposure, family history of thyroid carefully counseled, and they may decline complex and cancer), prompt surgical treatment is advisable and morbid surgical resection in favor of palliation. FNA is not required.

The surgical approach for children remains controversial Thyroid cancer due to the balance between improved disease eradication Children and adolescents account for 2% of all thyroid and possibly increased risk from total thyroidectomy cancer, with an annual incidence of 2.4 per 100 000 [13]. versus increased chance of residual or recurrent disease Sporadic differentiated thyroid cancers (papillary and with hemithyroidectomy. Newer techniques for thyroid- mixed papillary–follicular) are the most common endo- ectomy such as microbipolar dissection minimize poten- crine malignancies in children, and a female preponder- tial risks of nerve injury and hypocalcemia. Additionally, ance is most pronounced in postpubertal children [14]. at least 40% of differentiated thyroid cancer in children is

multifocal, and total thyroidectomy allows for postopera- aggressive malignancy in view of the high risk of radi- tive administration of radioactive iodine and the use of ation-related complications in children. serial thyroglobulin measurement for surveillance. Hence, a reasonable approach would be hemithyroidectomy in the suspicion of malignancy, with total thryoi- Neuroblastoma dectomy (initial or completion) in the presence of defini- Neuroblastoma is the most common extracranial solid tive cancer diagnosis. Central compartment lymph node tumor of childhood, but primary head and neck incidence dissection for palpable or ultrasound-detected nodes is accounts for less than 5% of cases [25]. These tumors recommended at the time of total or completion thyroid- arise in the neural crest progenitor cells of the sympath- ectomy. etic nervous system. Those originating from the sym- pathetic cervical ganglia will arise as a lateral neck mass or In children with MEN types IIA and IIB and RET proto- retropharyngeal mass. They present with an impinge- oncogene mutation, MTC is the most common cause of ment of head and neck structures such as the jugular death, as it spreads early and is relatively resistant to foramen cranial nerves, upper aerodigestive structures chemoradiotherapy. The most effective management is (causing stridor, dysphagia, or aspiration), or with Hor- prophylactic thyroidectomy before MTC presentation, ner’s syndrome. Metastatic spread from an abdominal or but timing of surgery is controversial. MTC occurs at thoracic primary to the orbital soft tissues can also occur different ages as influenced by the genotype and has been and presents with periorbital swelling, ecchymosis, or reported as early as 17 months in a germline mutation ophthalmoplegia. Overall survival, with a median fol- carrier [19]. A pragmatic approach may be individualized low-up of 4 years, has been estimated as 91%, with no ‘codon-directed’ timing, in which prophylactic thyroid- significant difference between cervical and cervicothor- ectomy timing is dictated by the specific genotype and acic neuroblastoma [25]. performed before the earliest reported age of MTC diagnosis for the specific RET mutation codon [20,21]. Diagnostic tests include plain radiography, ultrasound, Alternatively, universal early total thyroidectomy can be CT, and MRI. Metastatic evaluation may include advocated to reduce anxiety and the risk of early pres- bone marrow studies, bone scans, and scintigraphy with entation. 131I-metaiodobenzylmandelic [metaiodobenzylguani- dine (MIBG)] to assess bone disease and response to therapy [26]. Treatment involves surgery in most cases, Salivary gland malignancy with adjuvant chemotherapy, and occasionally radio- Salivary gland neoplasms are rare in childhood, but after therapy, depending on the stage of the disease. If exclusion of vascular lesions, approximately half are localized, primary or secondary head and neck neuro- malignant [22]. Malignant lesions are more common in blastoma may be amenable to complete surgical exci- older children, and overall usually have a good prognosis. sion, providing a more favorable prognosis. In extensive Five-year survival is similar to adults (over 90%) [23]. or metastatic disease, multimodal treatment is indivi- The majority of salivary malignancies occur in the parotid dualized to the patient. MIBG has recently shown gland, in which the most common lesion is mucoepider- efficacy in high-risk cases as an induction therapy moid carcinoma, and, in contrast to adults, most subman- before surgery [27]. dibular gland and minor salivary gland tumors are benign [22]. Mucoepidermoid carcinoma is also the commonest radiation-induced salivary gland tumor in children [24]. Nasopharyngeal carcinoma Other malignant lesions described include acinic cell NPC is rare in North America but more common in carcinoma, adenoid cystic carcinoma, and adenocarci- southern China, Southeast Asia, the Mediterranean basin, noma. Newer techniques such as microbipolar dissection and Alaska [28]. In children, the median age of NPC and extracapsular dissection with nerve monitoring allow development is 13 years and incidence is higher in males partial parotidectomy for the resection of malignant [29]. Factors implicated in the cause and development of lesions, preserving full nerve function. NPC include genotype (specific human leukocyte antigen subtypes), environment (such as salted fish high in Surveillance is dependent on tumor resection margins, volatile nitrosamines [28]), and infection [with Epstein– tumor subtype, and ease of clinical assessment by palpa- Barr virus (EBV) implicated in the pathogenesis of child- tion. A baseline MRI scan may be indicated once surgical hood NPC and elevated EBV titers potentially correlat- healing is complete, with follow-up MRI scanning as in ing with more extensive disease]. The WHO classifi- adults. Regular chest radiographs may be required for cation of NPC includes type I (keratinizing squamous cases of acinic cell carcinoma. Re-excision is recom- cell carcinoma), type II (nonkeratinizing carcinoma), and mended for salivary gland disease recurrence, and radio- type III (undifferentiated carcinoma). The most common therapy should be used only in carefully selected cases of histopathological type in children is type III [29].

NPC most commonly presents late with a painless upper cervical lymphadenopathy. Other regions that may be neck mass. The tumor may mimic the common cold or involved include the salivary glands, larynx, sinuses, and rhinitis by presenting with nasal obstruction, and other orbit. NHL may also manifest in the extranodal lymphoid symptoms include epistaxis, otalgia, and conductive hear- tissue of Waldeyer’s ring, presenting as an asymmetric ing loss. NPC may directly invade the skull base and tonsillar enlargement or mimicking adenoidal hypertro- involve cranial nerve VI, causing weakness of lateral gaze phy. Up to one-fifth of children undergoing routine and diplopia. Other cranial nerves that can become tonsillectomy may have some degree of coincidental involved include III, IV, and V, and eventually cranial innocent tonsillar asymmetry [34]. Therefore, tonsillect- nerves IX–XII. Investigation includes diagnostic biopsy, omy may not be indicated by asymmetry alone, without CT and/or MRI of the primary site, and potentially may consideration of other factors such as constitutional symp- include chest CT, abdominal ultrasound or CT, and bone toms (fever, weight loss, and night sweats), a history of marrow biopsy for metastasis screening. EBV caspid rapid unilateral enlargement, or associated cervical lymph- antigen immunoglobulin A (IgA) may be useful for adenopathy or hepatosplenomegaly. disease monitoring. Histological subclassification may be challenging, and an Treatment of NPC has generally followed guidelines open excisional biopsy of lymph nodes is considered the established for adults, with high-dose radiotherapy to gold standard for diagnostic evaluation. Recently, publi- the nasopharynx and involved neck lymph nodes. How- cations have advocated diagnosing and classifying lym- ever, childhood NPC is distinguished from adult NPC phomas using less invasive techniques, benefiting from by its close association with EBV, predominance of image-guided cutting needle biopsies and advances in type III histology, and high incidence of advanced- the use of cytopathological and immunohistochemical stage disease, in addition to the significant morbidity of techniques with small specimens [35]. These techniques high-dose radiotherapy in childhood [28]. This has led have been very successfully applied to cervical lympha- to an increase in trials of adjuvant, neoadjuvant, and denopathy in some units [36] but remain controversial concomitant chemotherapy. A recent study [30] [37] and may not be applicable to the pediatric popu- employing first-line chemotherapy with or without lation. Biopsy tissue should be sent fresh to the pathol- radiotherapy showed 5-year survival rates of 73%. ogist to facilitate flow cytometry, immunohistochemical Extensive surgical resection, such as the maxillary staining, electron microscopy, and molecular genetic swing procedure, is not applicable to children due to testing. skeletal immaturity, surgical morbidity, and concern about incomplete resection. The foundation of treatment for pediatric NHL is based on aggressive multiagent chemotherapy directed by the histology and disease stage. The most commonly used Non-Hodgkin’s lymphoma agents include CHOP-based regimens (cyclophospha- Pediatric non-Hodgkin’s lymphoma (NHL) occurs in mide, hydroxydaunomycin, vincristine, and prednisone), about 600 new cases annually in the United States, with and some protocols include other agents in more nearly 25% in children aged less than 10 years [31]. The advanced stages of recurrence. Radiotherapy is not rou- overall incidence in children and adolescents is approxi- tinely used for local NHL treatment but has been used in mately 30 per million, with increasing incidence with central nervous system (CNS) prophylaxis, although this age and a male predominance [31]. Histological may not be helpful in CNS-negative children with an varieties of NHL are divided into low, intermediate, adequate response to induction chemotherapy [38]. The and high grade, and the vast majority presenting in disease-free survival period for pediatric NHL has been childhood are high grade [32]. About 90% of childhood improving with the continuously evolving treatment NHLs are mature B-cell lymphomas [Burkitt (40%) or regimes, resulting in long-term survival being achieved diffuse large B-cell (10%)], lymphoblastic lymphomas in over 80% [33]. (30%), or anaplastic large cell lymphomas (10%). The remaining 10% consist of the diseases commonly seen in adults such as follicular lymphoma, mucosa-associ- Hodgkin’s lymphoma ated lymphoid tissue lymphoma, and mature T-cell Pediatric Hodgkin’s lymphoma occurs in about 1000 lymphoma [33]. Immunodeficient individuals (congeni- cases annually in the United States, the majority occur- tal or acquired) are at an increased risk of NHL, pre- ring in teenage children [31]. Overall incidence in chil- dominantly of the mature B-cell type, and these are dren and adolescents is about 50 per million, with only associated with EBV. 5% of these occurring in children under 10 years old, in whom incidence is significantly lower than NHL [31]. In Childhood NHL presents in the head and neck region in young children, there is a male predominance, but there 5–10% of cases, most commonly with asymptomatic are no sex differences after puberty. As in NHL, there is

an association between Hodgkin’s lymphoma and EBV References and recommended reading infection, with many children having evidence of prior Papers of particular interest, published within the annual period of review, have exposure, and in-situ hybridization demonstrating been highlighted as: of special interest Epstein–Barr genomes in the pathognomonic Reed– of outstanding interest Sternberg cell [39]. Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 496).

Hodgkin’s lymphoma is histologically separated into two 1 Albright JT, Topham AK, Reilly JS. Pediatric head and neck malignancies: US incidence and trends over 2 decades. Arch Otolaryngol Head Neck Surg broad categories: ‘classical’ Hodgkin’s lymphoma (90%), 2002; 128:655–659. comprising lymphocyte-depleted (rare in children), nod- 2 Cofer BR, Wiener ES. Rhabdomyosarcoma. In: Andrassy RJ, editor. ular sclerosing, and mixed cellularity subtypes, and Pediatric surgical oncology. Philadelphia: W.B. Saunders; 1998. pp. 221– ‘lymphocyte-predominant’ Hodgkin’s lymphoma (10%). 237. 3 Simon JH, Paulino AC, Smith RB, et al. Prognostic factors in head and neck Classical Hodgkin’s lymphoma is characterized by the rhabdomyosarcoma. Head Neck 2002; 24:468–473. presence of CD15 and CD30-positive Reed–Sternberg 4 Miller RW, Young JL Jr, Novakovic B. Childhood cancer. Cancer 1995; cells. Lymphocyte-predominant Hodgkin’s lymphoma is 75:395–405. CD20 positive and has a distinctive phenotype, presenting 5 Toro JR, Travis LB, Wu HJ, et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results at an early stage without systemic symptoms, involving program, 1978-2001: an analysis of 26 758 cases. Int J Cancer 2006; localized peripheral lymph nodes, and having a disease- 119:2922–2930. free survival of over 95% [40]. 6 Leaphart C, Rodeberg D. Pediatric surgical oncology: management of rhabdomyosarcoma. Surg Oncol 2007; 16:173–185. 7 Oda Y, Tsuneyoshi M. Recent advances in the molecular pathology of Hodgkin’s lymphoma most commonly presents in children soft tissue sarcoma: implications for diagnosis, patient prognosis, and with asymptomatic cervical and supraclavicular lympha- molecular target therapy in the future. Cancer Sci 2008; 100:200– 208. denopathy, with or without systemic constitutional symp- This study provides a useful summary of recent advances in the molecular toms (fever, weight loss, and night sweats), which unfa- pathology of soft tissue sarcomas, including prognostic markers and potential vorably affect prognosis [41]. The lymphadenopathy is targets for molecular therapy. 8 Sorensen PH, Lynch JC, Qualman SJ, et al. PAX3-FKHR and PAX7-FKHR described as firm, rubbery, and nontender. As in NHL, gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a lymph node biopsy is considered the gold standard report from the children’s oncology group. J Clin Oncol 2002; 20:2672– for diagnosis of Hodgkin’s lymphoma. Treatment for 2679. 9 Walterhouse DO, Pappo AS, Baker KS, et al. Rhabdomyosarcoma of the Hodgkin’s lymphoma is based on stratification of risk parotid region occurring in childhood and adolescence. A report from the groups determined by histology, stage at presentation, Intergroup Rhabdomyosarcoma Study Group. Cancer 2001; 92:3135– number of involved sites, disease bulk, and the presence 3146. or absence of constitutional symptoms. Early lymphocyte- 10 Gillespie MB, Marshall DT, Day TA, et al. Pediatric rhabdomyosarcoma of the head and neck. Curr Treat Options Oncol 2006; 7:13–22. predominant Hodgkin’s lymphoma can be considered 11 Pappo AS, Meza JL, Donaldson SS, et al. Treatment of localized nonorbital, separately and may be treated by radiation alone or some- nonparameningeal head and neck rhabdomyosarcoma: lessons learned from times by surgical excision and observation. Low-risk intergroup rhabdomyosarcoma studies III and IV. J Clin Oncol 2003; 21:638– 645. (localized and nonbulky), classical Hodgkin’s lymphoma 12 Daya H, Chan HS, Sirkin W, et al. Pediatric rhabdomyosarcoma of the head can be treated by limited cycles of chemotherapy with and neck: is there a place for surgical management? Arch Otolaryngol Head minimal radiotherapy to achieve cure. In contrast, high- Neck Surg 2000; 126:468–472. risk, classical Hodgkin’s lymphoma treatment relies on 13 Horner MJ, Ries LAG, Krapcho M, et al., editors. SEER Cancer Statistics intense chemotherapy regimes with diverse agents, in Review, 1975–2006. Bethesda, Maryland: National Cancer Institute; 2009. 14 Howe HL, Wu X, Ries LA, et al. Annual report to the nation on the status of combination with radiotherapy [40]. Disease-free survival cancer, 1975-2003, featuring cancer among U.S. Hispanic/Latino popula- ratesofover 90%have been achievedwith recentprotocols. tions. Cancer 2006; 107:1711–1742. 15 Williams ED, Abrosimov A, Bogdanova T, et al. Thyroid carcinoma after Chernobyl latent period, morphology and aggressiveness. Br J Cancer 2004; 90:2219–2224. Conclusion 16 Maule M, Scelo G, Pastore G, et al. Risk of second malignant neoplasms after The care of children affected by head and neck malig- childhood leukemia and lymphoma: an international study. J Natl Cancer Inst nancy must continue to be collaborative and multidisci- 2007; 99:790–800. plinary. Improved survival rates should lead to greater 17 Williams ED, Abrosimov A, Bogdanova T, et al. Morphologic characteristics of Chernobyl-related childhood papillary thyroid carcinomas are indepen- recognition and monitoring of the late psychosocial, dent of radiation exposure but vary with iodine intake. Thyroid 2008; physical, and economic impacts of a cancer diagnosis 18:847–852. An observational study suggesting that iodine deficiency may have wide implica- in childhood, including treatment-induced second tions in thyroid carcinoma, influencing tumor morphology and aggressiveness. primary tumors. The rarity of these tumors inevitably 18 Dinauer CA, Breuer C, Rivkees SA. Differentiated thyroid cancer in children: diagnosis and management. Curr Opin Oncol 2008; 20:59–65. results in a paucity of high-level evidence to guide A succinct review of the diagnosis, staging, and management options for pediatric treatment. A combination of translational research from differentiated thyroid cancer. tumor biology studies, multicenter clinical trials, and 19 Sanso GE, Domene HM, Garcia R, et al. Very early detection of RET proto- smaller case series and case reports will continue to guide oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in new advances in diagnosis and treatment. asymptomatic carriers. Cancer 2002; 94:323–330.

20 Machens A, Ukkat J, Brauckhoff M, et al. Advances in the management 31 O’Leary M, Sheaffer B, Keller F, et al. Lymphomas and reticuloendothelial of hereditary medullary thyroid cancer. J Intern Med 2005; 257:50– neoplasms. In: Bleyer A, O’Leary M, Barr R, Ries LAG, editors. Cancer 59. epidemiology in older adolescents and young adults 15 to 29 years of age, including SEER incidence and survival: 1975-2000. Bethesda, Maryland: 21 Moore SW, Appfelstaedt J, Zaahl MG. Familial medullary carcinoma preven- National Cancer Institute; 2006. pp. 25–38. tion, risk evaluation, and RET in children of families with MEN2. J Pediatr Surg 2007; 42:326–332. 32 Sandlund JT, Downing JR, Crist WM. Non-Hodgkin’s lymphoma in childhood. N Engl J Med 1996; 334:1238–1248. 22 Bradley P, McClelland L, Mehta D. Paediatric salivary gland epi- thelial neoplasms. ORL J Otorhinolaryngol Relat Spec 2007; 69:137– 33 Gross TG, Termuhlen AM. Pediatric non-Hodgkin’s lymphoma. Curr Oncol 145. Rep 2007; 9:459–465. 23 Guzzo M, Ferrari A, Marcon I, et al. Salivary gland neoplasms in children: the 34 Harley EH. Asymmetric tonsil size in children. Arch Otolaryngol Head Neck experience of the Istituto Nazionale Tumori of Milan. Pediatr Blood Cancer Surg 2002; 128:767–769. 2006; 47:806–810. 35 de Kerviler E, de Bazelaire C, Mounier N, et al. Image-guided core-needle 24 Kessler A, Handler SD. Salivary gland neoplasms in children: a 10-year survey biopsy of peripheral lymph nodes allows the diagnosis of lymphomas. Eur at the Children’s Hospital of Philadelphia. Int J Pediatr Otorhinolaryngol 1994; Radiol 2007; 17:843–849. 29:195–202. 36 Pfeiffer J, Kayser G, Ridder GJ. Sonography-assisted cutting needle biopsy in 25 Haddad M, Triglia JM, Helardot P, et al. Localized cervical neuroblastoma: the head and neck for the diagnosis of lymphoma: can it replace lymph node prevention of surgical complications. Int J Pediatr Otorhinolaryngol 2003; extirpation? Laryngoscope 2009; 119:689–695. 67:1361–1367. The authors of this study of ultrasound-guided core needle biopsy for lymphoma diagnosis in adults suggest the sensitivity and speciﬁcity (89.7 and 100%, 26 Mehta K, Haller JO, Legasto AC. Imaging neuroblastoma in children. Crit Rev respectively) merit consideration ahead of lymph node biopsy. Comput Tomogr 2003; 44:47–61. 37 Morris-Stiff G, Cheang P, Key S, et al. Does the surgeon still have a role to play 27 de Kraker J, Hoefnagel KA, Verschuur AC, et al. Iodine-131-metaiodobenzyl- in the diagnosis and management of lymphomas? World J Surg Oncol 2008; guanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 6:13. year of age. Eur J Cancer 2008; 44:551–556. 38 Burkhardt B, Woessmann W, Zimmermann M, et al. Impact of cranial A case series demonstrating the potential usefulness of targeted induction therapy radiotherapy on central nervous system prophylaxis in children and adoles- with iodine-131-MIBG before surgery or neoadjuvant chemotherapy and surgery in cents with central nervous system-negative stage III or IV lymphoblastic pediatric neuroblastoma. lymphoma. J Clin Oncol 2006; 24:491–499. 28 Ayan I, Kaytan E, Ayan N. Childhood nasopharyngeal carcinoma: from biology 39 Weiner MA, Leventhal BG, Marcus R, et al. Intensive chemotherapy and low- to treatment. Lancet Oncol 2003; 4:13–21. dose radiotherapy for the treatment of advanced-stage Hodgkin’s disease in 29 Ayan I, Altun M. Nasopharyngeal carcinoma in children: retrospective pediatric patients: a Pediatric Oncology Group study. J Clin Oncol 1991; review of 50 patients. Int J Radiat Oncol Biol Phys 1996; 35:485– 9:1591–1598. 492. 40 Olson MR, Donaldson SS. Treatment of pediatric Hodgkin lymphoma. Curr Treat Options Oncol 2008; 9:81–94. 30 Orbach D, Brisse H, Helfre S, et al. Radiation and chemotherapy combination for nasopharyngeal carcinoma in children: radiotherapy dose adaptation after 41 Smith RS, Chen Q, Hudson MM, et al. Prognostic factors for children with chemotherapy response to minimize late effects. Pediatr Blood Cancer 2008; Hodgkin’s disease treated with combined-modality therapy. J Clin Oncol 50:849–853. 2003; 21:2026–2033.