Pediatric Otorhinolaryngology: Diagnosis and Treatment, 1st Ed.

20

Malignant Pediatric Neck Tumors

Kenneth R. Whittemore Jr. and Michael J. Cunningham

The majority of neck masses in the pediatric age group are of infectious, inflammatory, or congenital origin. Although comparatively less frequent, malignant cervical neoplasms occur and can be a significant cause of pediatric morbidity and mortality. This chapter focuses on the presentation, evaluation, and management of the more common pediatric neck malignancies.

Cervical malignancies arise primarily from structures in the neck, extend secondarily from adjacent regions such as the mediastinum or skull base, or represent from metastases from distant sites. As a result, the potential diagnoses of a firm neck mass in a child or adolescent can be quite broad. The patient's age, location of the mass, clinical history, associated physical examination findings, and evaluative work-up all help narrow this differential diagnosis.

Evaluation

A child presenting with a mass in the neck requires a thorough medical examination. The risk of malignancy is increased by positive family history, a history of radiation exposure, immunodeficiency or immunosuppression, or the presence of certain syndromes and genetic disorders. The age of the child is also predicative of the likelihood of particular malignancies.1

Given that cervical malignancies may be primary, secondary, or metastatic, both a thorough head and neck and systemic examination are necessary. The cervicofacial examination should include the skin seeking pigmented lesions, a complete cranial nerve review, and a detailed assessment of the upper aerodigestive tract including the nasopharynx, hypopharynx, and larynx. Depending on the age, cooperativeness, and health of the child, the latter examination may require a diagnostic laryngoscopy with or without a bronchoscopy and esophagoscopy.

Imaging is often necessary in the evaluation of pediatric neck masses and the type of imaging depends on the location and character of the mass, age of the patient, presence of hardware such as braces, and medical conditions such as renal insufficiency or potential airway obstruction with sedation. Ultrasonography has several advantages. It involves no radiation, can be performed even in children of all ages without sedation, and allows determination of mass location, consistency, and vascular flow characteristics. Ultrasound is also ideal for guiding fine-needle aspiration biopsies. Greater anatomical detail is often required for both diagnostic and therapeutic decision-making; such is provided by either computed tomography (CT) or magnetic resonance imaging (MRI). CT imaging is useful for masses adjacent to osseous or cartilaginous structures seeking evidence of erosion. CT imaging can be coordinated with a guided biopsy. In the case of a potential thyroid malignancy, contrast enhancement should be avoided as it precludes the subsequent use of radioactive iodine. MRI provides the greatest degree of soft tissue detail. Gadolinium enhancement determines vascularity, and magnetic resonance angiography may provide even greater detail. The anatomical detail and lack of radiation are major advantages of MRI. The presence of hardware can preclude its performance, and the need for anesthesia in younger children is a disadvantage. Additional imaging studies such as positron emission tomography (PET) and bone scans may be considered, particularly when metastatic disease is likely or the cervical lesion itself is a potential metastasis. Nonimaging evaluative studies of potential utility include a complete blood count with a manual differential, chemistry panel, lactate dehydrogenase level, liver function tests, renal function indices, and urinalysis. Metastatic assessment may require chest films, lumbar puncture, and bone marrow biopsy. Early consultation with an oncologist can be helpful in guiding the staging work-up, suggesting specific genetic marker screening, and speaking with the family both before and after a diagnosis is made. A tissue biopsy is nearly always required for diagnosis. On occasion in older children and adolescents, and with specific lesions such as suspected thyroid malignancies, ultrasound or CT-guided fine-needle aspiration biopsy may suffice. More frequently, operative incisional or excisional biopsy is necessary. The method of obtaining the tissue depends on several factors including the size, anatomical location and vascularity of the lesion, its potential resectability, and the probability that the primary treatment of the lesion will be surgical or nonsurgical.

Differential Diagnosis

The differential diagnosis of a firm neck mass in the pediatric population is broad given the variety of tissue types present within and adjacent to the neck, as well as the potential for regional and systemic metastases.2 This chapter will focus on the more common entities including Hodgkin lymphoma and non-Hodgkin lymphomas, rhabdomyosarcoma and neuroblastoma.

Hodgkin Lymphoma

Hodgkin lymphoma (HL) is a malignant neoplasm of the lymphoreticular system with a bimodal distribution, one peak of which occurs in adolescence and the second in young adulthood. In contrast to NHL, HL is uncommon in preadolescent children and rarely occurs in children younger than 5 years of age.3 Although no definitive causal factors are known, there is an association between Epstein-Barr virus (EBV) infection and HL.

HL is distinguished pathologically by the diagnostic presence of Reed-Sternberg (RS) cells admixed within the appropriate pleomorphic cellular background. The historical HL classification system—the Rye classification system—recognizes four subtypes based upon this cellular background: lymphocyte predominant, lymphocyte depletion, nodular sclerosis, and mixed cellularity.4 The lymphocyte predominant category is characterized by an abundance of mature lymphocytes with only occasional RS cells. Such nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can also be distinguished from the other subtypes of HL by immunohistochemical staining techniques. The Revised European-American Lymphoma classification system accounts for this differentiation, dividing HL into two broad categories: classic HL and NLPHL.5 Further rationale for this classification system is documentation that NLPHL has different virologic features and is clinically less aggressive than classic HL.

HL arises within lymph nodes in more than 90% of childhood, adolescent, and young adult cases. The typical patient with HL has asymmetric firm, rubbery, and nontender lymphadenopathy. The cervical, supraclavicular, and mediastinal lymph nodes are the most frequently involved. Obstruction of the superior vena cava or tracheobronchial tree may occur as a complication of mediastinal lymphadenopathy. Extranodal involvement does occur with disease progression; the spleen, liver, lung, bone, and bone marrow are common organ systems affected. At presentation, 25 to 30% of HL patients manifest nonspecific systemic symptoms such as unexplained fever, night sweats, weight loss, weakness, anorexia, and pruritis.3

The diagnosis of HL is made by lymph node biopsy. Once the diagnosis is established, it is essential to define the full extent of disease before instituting specific treatment. The Ann Arbor staging system (Table 20.1) is used to stratify risk for HL patients. This staging system is based on the premise that HL arises in a unifocal lymph node site, spreads via lymphatics to contiguous lymph node groups, and involves extralymphatic sites, including the spleen, principally by hematogenous dissemination. The system recognizes that patients with localized extralymphatic spread—denoted by the letter E—do as well as comparable patients of the same stage without such disease extension. Systemic symptoms are considered significant in HL staging and are designated A when absent and B when present.6

The treatment of HL varies according to stage and is typically multimodal. Stage IA and IIA disease is usually treated with a combination of low-dose multiagent chemotherapy and radiation therapy to the involved field. Intermediate risk patients include those with Stage IIIA disease or Stages I or II disease with B symptoms, bulky disease, or spleen involvement. These patients require an increased number of chemotherapy cycles and either increased dose or volume of radiation therapy. For patients with high-risk advanced Stage IIIB and IV diseases, multiagent chemotherapy alone or in combination with radiation therapy is used. The recent management of HL distinguishes between children who have obtained full growth and those who are still growing in an attempt to limit the high doses and extended fields of radiation therapy that cause considerable long-term morbidity for children and young adolescents. Similarly, chemo-therapeutic regimens have been changed to reduce the risks of sterility, pulmonary toxicity, and secondary malignancies. HL patients who relapse may be candidates for autologous stem cell transplantation.

Table 20.1 Ann Arbor Staging Classification of Hodgkin Lymphoma

Stage

Definition

I

Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE).

II

Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (IIE). An optional recommendation is that the numbers of node regions involved be indicated by a subscript numerals (e.g., II3).

III

Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIS), or both (IIISE).

IV

Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement. The reason for classifying the patient as Stage IV should be identified further by defining site by symbols.

aEach stage is subdivided into A and B categories indicating the absence or presence, respectively, of documented unexplained fever, night sweats, or weight loss (>10% of body weight in the past 6 months).

Adapted from: Cunningham MJ, Myers EN, Bluestone CD. Malignant tumors of the head and neck in children: a twenty-year review. Int J Pediatr Otorhinolaryngol 1987;13(3):279–292

With current treatments, more than 90% of all HL patients, regardless of stage, initially achieve a complete remission. Prolonged remission and cure is achieved in approximately 90% of patients with early Stage I and II disease and in 35 to 60% of patients with advanced Stage III and IV disease. Patients with lymphocyte predominant lesions have the most favorable survival statistics.3,7

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) designates a heterogeneous group of solid primary neoplasms of the lymphoreticular system. In children, NHL most commonly occurs between the ages of 2 and 12 years and, as in HL, demonstrates a male predilection. Both congenital and acquired immunodeficiency disorders predispose to the development of NHL.8

Immunologic staining techniques allow separation of NHL into categories of B-cell, T-cell, and histiocytic origin. The B- and T-cell lymphomas are further subdivided based on their morphologic appearance, degree of lymphocytic transformation, and responsiveness to therapy.9 The classification schema of NHL is dynamic due to constant advances in immunophenotyping.

The clinical features of NHL reflect the site of origin of the primary tumor and the extent of local and systemic disease. Asymptomatic cervical lymphadenopathy is the most common initial presentation; inguinal, axillary, and generalized nodal presentations are comparatively less frequent. Although nodal growth may be rapid, insidious presentations are more typical.

Extranodal NHL occurs frequently in children.10 Extranodal head and neck sites include the oropharynx and nasopharynx, the nose and paranasal sinuses, the orbit, and the maxilla and mandible. The signs and symptoms attributable to extranodal cervicofacial NHL are quite variable and site specific; these may include nasal blockage and other manifestations of upper airway obstruction, dysphagia, orbital or facial swelling, and cranial nerve deficits. Oronaso-pharyngeal NHL may mimic benign adenotonsillar hypertrophy; biopsy via adenoidectomy or tonsillectomy may be warranted if there is asymmetry, discoloration, or evidence of systemic symptoms.

The St. Jude's classification system (Table 20.2) is the staging system most commonly used for NHL. This system attempts to account for both the characteristic extranodal presentations and the tendency toward hematogenous dissemination, bone marrow infiltration, and central nervous system (CNS) involvement in childhood NHL.11 The clinical staging of NHL of the head and neck requires a comprehensive history and physical examination, serologic testing such as a complete blood count and lactate dehydrogenase level, chest radiograph, skeletal survey or bone scan, bone marrow biopsy, and cerebrospinal fluid analysis in addition to appropriate head and neck imaging by means of CT and MRI. Abdominal CT with contrast or ultrasound may be used to assess for mesenteric lymph node involvement. More recently, gallium-67 scanning and PET with 18F-fluoro-2-deoxy-D-glucose have been used for disease staging and for following treatment response.

The diagnosis of NHL requires biopsy; typically excisional biopsy for nodal disease or incisional biopsy for extranodal disease. Surgery plays little additional role in NHL treatment with the exception of surgical debulking in selected cases of aerodigestive tract compression or when reduction of tumor load may lower the risk of development of tumor lysis syndrome. The latter is particularly true for Burkitt lymphoma.

Stage I NHL is infrequently diagnosed in the pediatric age group; the exception to this rule is follicular lymphoma. The vast majority of children with NHL have advanced Stage II, III, or IV disease at presentation. The principal treatment for nearly all stages of pediatric head and neck NHL is systemic chemotherapy; the rapid doubling time of high-grade NHL makes it very chemoresponsive.12

Table 20.2 St. Jude's Classification System of Non-Hodgkin Lymphoma

Stage

Criteria for Extent of Disease

I

A single tumor (extranodal) or single anatomic area (nodal), with the exclusion of mediastinum or abdomen.

II

• A single tumor (extranodal) with regional node involvement.

• Two or more nodal areas on the same side of the diaphragm.

• Two single (extranodal) tumors with or without regional node involvement on the same side of the diaphragm.

• A primary gastrointestinal tract tumor, usually in the ileocecal area, with or without involvement of associated mesenteric nodes only.

III

• Two single tumors (extranodal) on opposite sides of the diaphragm.

• Two or more nodal areas above and below the diaphragm.

• All the primary intrathoracic tumors (mediastinal, pleural, thymic).

• All extensive primary intra-abdominal disease.

• All paraspinal or epidural tumors, regardless of other tumor site(s).

IV

Any of the above with initial central nervous system and/or bone marrow involvement.

Adapted from: Murphy SB. Childhood non-Hodgkin lymphoma . N Engl L Med 1978;299:1446–1448.

Both early and late therapeutic complications are common. Early complications generally result from the rapid lysis of tumor cells and bone marrow suppression. The most significant long-term complications relate to the development of secondary malignancies.

Prognosis is principally associated with disease stage and response to initial therapy. The current overall 5-year disease-free survival rate for NHL of the head and neck approximates 70 to 76%. The event-free survival rate for NHL, irrespective of site of origin, is 85 to 95% for stage I and II disease, and 50 to 85% for stage III and IV disease, depending on immunohistopathologic subtype.10,13

Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in children with an incidence of about 6 in 1,000,000 in the pediatric population. Anderson et al reported that 50% of cases occur in children younger than 6 years of age, and a cervicofacial presentation is common, accounting for 40% cases.14

RMS is of primitive muscle cell origin and is considered one of the small blue-cell tumors. Positive staining for muscle-specific proteins such as vimentin, muscle actin, desmin, myoglobin, and myo-D1 is diagnostic.15 RMS is classified into four histopathologic subtypes—embryonal, alveolar, undifferentiated, and botryoid (meaning grape-like)—with relative percentages at presentation of 55, 20, 20, and 5%, respectively.16

RMS generally presents as a rapidly growing, painless, cervicofacial mass. Symptomatic manifestations reflect the site of origin; these may include dysphonia, dysphagia, dyspnea, trismus, cranial nerve deficits, brachial plexus neuropathy, and Horner syndrome. RMS may also manifest at systemic sites with presenting symptoms dependent upon the organ system involved. Metastatic spread may occur through direct extension, via the lymphatic system, and hematogenously to distal organs. The risk of CNS involvement is particularly high if the primary tumor is in a parameningeal location.

The treatment of RMS is guided by the primary site of involvement and stage of disease. The Intergroup Rhabdomyosarcoma Study Group (IRSG) established a staging system (Table 20.3) based on extent of disease (localized, regional, or systemic) and if excision of local or regional disease can be accomplished.17,18 Extent of disease is determined by the bounds of the primary tumor, regional lymphatic spread, and the presence of metastatic disease. Various studies may be ordered to aid in assessing the stage of disease. A complete blood count may show anemia if there is bone marrow invasion; liver enzyme elevation can indicate hepatic metastases. Contrast-enhanced CT or MRI will aid in determining the extent of the primary tumor, specifically if there is extension beyond the muscle group of origin. Imaging of the chest, abdomen, and brain may also be required to complete the metastatic work-up. Both CNS imaging and lumbar puncture are necessary if the primary tumor is in a parameningeal location.

Complete excision of the primary tumor is indicated when removal imposes no major functional disability and permits either the elimination of postoperative radiation therapy or a reduction in radiation dose. When only partial tumor resection is possible, initial surgery is often limited to biopsy. A study comparing the role of surgical biopsy versus debulking in patients with IRSG III disease showed no difference in outcome.19

The role of a “second-look” surgical procedure following primary therapy is controversial. In the IRSG III study, patients with group III disease, confirmed to be partial responders to multimodality therapy based on a “second-look” surgical procedure, benefited from additional chemotherapy.20 Postoperative radiation therapy in patients with group III nonalveolar RMS may benefit from the use of follow-up radiotherapy even when a “second-look” procedure shows a complete response.21 Another study looking at the prognostic significance of RMS at the end of primary therapy suggests that there is no improvement in disease recurrence or mortality whether the patients were complete responders or partial or nonresponders, suggesting that in this group of patients aggressive follow-up therapy may not be necessary.22 These study results suggest that a second-look procedure may be helpful to determine if further radiotherapy or chemotherapy may be beneficial depending on the stage and histology of the disease.

Chemotherapy is typically administered postoperatively to patients with small resectable lesions and preoperatively to patients with larger lesions to decrease tumor volume before local treatment. Such local treatment may require a combination of surgical resection and radiation. Radiation therapy is also indicated for patients with group II, III, or IV tumors. Children with a clinically positive neck benefit from neck dissection and postoperative radiotherapy.

Prognosis is dependent on histopathologic subtype, genetic predisposition, and stage of disease. Alveolar and undifferentiated RMS have a poorer survival rate compared with embryonal and botryoid RMS.23Chromosomal abnormalities such as the PAX3-FKHR fusion associated with the translocation t(2;13) (q35;q14) have a negative prognostic implication.24 Spontaneous occurrence of RMS has been associated with a mutation of the PTCH gene (abnormality in 9q22.3 locus), implying that environmental exposure may play a role.25,26

The IRSG was formed in 1972 to systematically study patients with RMS regarding treatment, prognosis, and staging.27 The IRSG summary studies are designated as RMS-I, -II, -III, -IV. These designations need to be distinguished from the group staging of patients with RMS.

Table 20.3 Staging of rhabdomyosarcoma according to the Intergroup Rhabdomyosarcoma Study

Group I

Localized disease with tumor completely resected and regional nodes not affected.

Confined to muscle or organ of origin.

No contiguous involvement or infiltration outside the muscle or organ of origin.

Group II

Localized disease with microscopic residual disease, or regional disease with neither microscopic nor residual disease.

Grossly resected tumor with microscopic residual disease (nodes negative).

Regional tumor completely resected (nodes positive or negative).

Regional disease with involved nodes grossly resected but with evidence of microscopic residual disease.

Group III

Incomplete resection or biopsy with gross residual disease.

Group IV

Metastatic disease present at onset.

The 5-year survival rate in IRSG-III for select groups is as follows: group I favorable histology (93%); group I unfavorable histology and group II (54 to 81%); group III (74%); and group IV (27 to 31%).20Individuals who are free of recurrence 2 years after treatment are probably cured.28 The time to relapse appears to have prognostic significance that is independent of histology or tumor site: children in whom recurrence was at less than 6 months, between 6 and 12 months, and after 12 months had 4-year survival rates of 12, 21, and 41%, respectively.29

The overall 5-year survival rate for patients with nonmetastatic RMS approximates 80%; this rate decreases to 30% in patients with metastatic disease.30 The IRSG-IV protocol addresses distant metastases with trials of various chemotherapeutic agents before the introduction of standard chemotherapy and radiation therapy.31 IRSG-V is in progress and groups patients based on their risk of recurrence and is looking at the best combination of therapies based on these groupings.27

Neuroblastoma

Neuroblastoma is a malignancy that most commonly arises in patients under the age of 5 years. It is slightly more common in boys, with an overall incidence of about 1 in 100,000. Cervicofacial neuroblastoma may represent either primary or metastatic disease. Approximately 2 to 4% of primary neuroblastoma arises in the cervical region.

Mutations in the ALK and PHOX2B genes have been identified in patients with neuroblastoma. The PHOX2B mutation is also associated with congenital central hypoventilation syndrome and Hirschsprung disease; a family history of either of these diseases or neuroblastoma warrants genetic screening.32,33 Only 1 to 2% of children with neuroblastoma have this familial form which is autosomal dominant with incomplete penetrance.

Neuroblastoma arises from neural crest cells of the sympathetic nervous system. It falls into the category of small, round, blue-cell tumors that also include desmoplastic small cell tumor, Ewing sarcoma, acute leukemia, primitive neuroectodermal tumor, RMS, and Wilms tumor. The cells are round with a high nuclear to cytoplasmic ratio, may form rosettes, and have necrotic areas. Positive immunohistochemical staining for neuron-specific enolase distinguishes neuroblastoma from the other small, round, blue-cell tumors.

Primary cervical neuroblastoma usually arises in children in the first few years of life. The lesion typically occurs in the lateral neck and is often firm. Both the specific location of the mass and any present neurological deficits may predict what structures are affected by the lesion. Numbness or weakness of the upper limbs indicates involvement of the brachial plexus. Horner syndrome and/or heterochromia are reflective of sympathetic chain involvement.34 Dysphagia, dysphonia, or dyspnea may be found secondary to compression of the aerodigestive tract or by involvement of cranial nerves IX through XII.

Cervical neuroblastoma most commonly represents metastatic disease from a distant systemic site. As the adrenal medulla is a frequent primary site, palpation of the abdomen is needed to evaluate for a mass. Spinal tenderness may be indicative of disease in a vertebral body. Dissemination of disease through the vascular system occurs in 25% of children below 1 year of age and in 68% of children older than 1 year of age; common hematogenous metastatic sites include bone marrow, skin, and liver.35,36

The diagnosis of neuroblastoma requires adequate tissue for histopathologic examination; an open biopsy is often necessary. The evaluation of a child with suspected or confirmed neuroblastoma should additionally include the following: 24-hour urinalysis for the catecholamine by-products homovanillic acid and vanillylmandelic acid; imaging of the neck, abdomen, and chest with contrast-enhanced CT or MRI; bone scanning to detect osseous metastases; and meta-iodobenzylguanidine (MIBG) scintiscan to identify tumors particularly in nonosseous sites, as MIBG is taken up by sympathetic tissue.

Table 20.4 International Neuroblastoma Staging System Classification

Stage 1

Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive).

Stage 2A

Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.

Stage 2B

Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically.

Stage 3

Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement.

Stage 4

Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for Stage 4S).

Stage 4S

Localized primary tumor (as defined for Stages 1, 2A, or 2B), with dissemination limited to skin, liver, and/or bone marrow (limited to infants <1 year of age).

A risk-stratification protocol categorizes neuroblastoma patients into 4 broad groups based on 13 parameters. Several of the more important parameters include age, tumor histology, stage of disease (Table 20.4), tumor ploidy, and the presence or absence of the molecular genetic marker N-myc.37 Tumors that are determined to be triploidy tend to not metastasize and have a better prognosis than those tumors that are diploid. The presence of N-myc amplification is less common in localized disease compared with more disseminated disease, and the higher the amplification of N-myc in a tumor, the poorer the patient's prognosis.

Primary cervical neuroblastoma may be treated with surgical removal alone if completely resectable. Partly resectable primary or metastatic cervical neuroblastoma requires chemotherapy and/or radiation therapy in accordance with the following parameters. Surgery alone with minimal morbidity is recommended for low-risk, isolated disease. Intermediate risk disease involves surgery and moderately intensive chemotherapy. High-risk disease requires intensive chemotherapy, surgery, and external beam radiotherapy to primary tumor and resistant metastatic sites, myeloablative chemotherapy with autologous hematopoietic stem cell rescue, and possible immunotherapy.38 Five-year event-free survival rates based on these risk groups are as follows: very low risk (>85%), low risk (>75 to ≤85%), intermediate risk (≥50 to ≤75%), and high risk (<50%).37

Conclusion

Children diagnosed with a head and neck malignancy require multiple services for optimal care. In addition to the management provided by various surgical and medical pediatric specialists, there is a need for social and psychological support of the child, parents, and other family members. Child psychiatry, social work, child-life specialists, chaplin services, and parental support groups will complement the medical and surgical care of both the child and the family through this difficult time. In addition, one must also keep in mind that this is a lifelong commitment, as the survivors of childhood malignancies require long-term follow-up due to potential therapeutic complications and the risk of secondary malignancies.

References

1. Cunningham MJ, Myers EN, Bluestone CD. Malignant tumors of the head and neck in children: a twenty-year review. Int J Pediatr Otorhinolaryngol 1987;13(3):279–292

2. Albright JT, Topham AK, Reilly JS. Pediatric head and neck malignancies: US incidence and trends over 2 decades. Arch Otolaryngol Head Neck Surg 2002;128(6):655–659

3. Hudson MM, Donaldson SS. Hodgkin's disease. Pediatr Clin North Am 1997;44(4):891–906

4. Lukes RJ, Craver LF, Hall TC, Rappaport H, Ruben P. Report of the Nomenclature Committee. Cancer Res 1966;26:1311–1383

5. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84(5):1361–1392

6. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 1971;31(11):1860–1861

7. Pötter R. Paediatric Hodgkin's disease. Eur J Cancer 1999;35(10): 1466–1474, discussion 1474–1476

8. Sandlund JT, Downing JR, Crist WM. Non-Hodgkin's lymphoma in childhood. N Engl J Med 1996;334(19):1238–1248

9. National Cancer Institute sponsored study of classifications of non-Hodgkin lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin Lymphoma Pathologic Classification Project. Cancer 1982;49:2112–2135

10. La Quaglia MP. Non-Hodgkin's lymphoma of the head and neck in childhood. Semin Pediatr Surg 1994;3(3):207–215

11. Murphy SB. Classification, staging and end results of treatment of childhood non-Hodgkin's lymphomas: dissimilarities from lymphomas in adults. Semin Oncol 1980;7(3):332–339

12. Whalen TV, La Quaglia MP. The lymphomas: an update for surgeons. Semin Pediatr Surg 1997;6(1):50–55

13. Murphy SB. Childhood non-Hodgkin's lymphoma. N Engl J Med 1978;299(26):1446–1448

14. Anderson GJ, Tom LW, Womer RB, Handler SD, Wetmore RF, Potsic WP. Rhabdomyosarcoma of the head and neck in children. Arch Otolaryngol Head Neck Surg 1990;116(4):428–431

15. Pilch BZ. Head and Neck Surgical Pathology. Philadelphia, PA: Lippincott Williams and Wilkins; 2001:422–424

16. Pappo AS, Shapiro DN, Crist WM, Maurer HM. Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 1995;13(8):2123–2139

17. Barnes L. Tumors and tumor-like lesions of the soft tissues. In: Barnes L, ed. Surgical Pathology of the Head and Neck. New York, NY: Marcel Dekker; 1985:725–880

18. Maurer HM, Moon T, Donaldson M, et al. The intergroup rhabdomyosarcoma study: a preliminary report. Cancer 1977; 40(5):2015–2026

19. Cecchetto G, Bisogno G, De Corti F, et al; Italian Cooperative Group. Biopsy or debulking surgery as initial surgery for locally advanced rhabdomyosarcomas in children?: the experience of the Italian Cooperative Group studies. Cancer 2007;110(11):2561–2567

20. Crist W, Gehan EA, Ragab AH, et al. The third intergroup rhabdomyosarcoma study. J Clin Oncol 1995;13(3):610–630

21. Cecchetto G, Carretto E, Bisogno G, et al. Complete second look operation and radiotherapy in locally advanced non-alveolar rhabdo-myosarcoma in children: A report from the AIEOP soft tissue sarcoma committee. Pediatr Blood Cancer 2008;51(5):593–597

22. Rodeberg DA, Stoner JA, Hayes-Jordan A, et al. Prognostic significance of tumor response at the end of therapy in group III rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 2009;27(22):3705–3711

23. Hays DM, Newton W Jr., Soule EH, et al. Mortality among children with rhabdomyosarcomas of the alveolar histologic subtype. J Pediatr Surg 1983;18(4):412–417

24. Anderson J, Gordon T, McManus A, et al; UK Children's Cancer Study Group (UKCCSG) and the UK Cancer Cytogenetics Group. Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome? Br J Cancer 2001;85(6):831–835

25. Calzada-Wack J, Schnitzbauer U, Walch A, et al. Analysis of the PTCH coding region in human rhabdomyosarcoma. Hum Mutat 2002;20(3):233–234

26. Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgård R, Undén AB. Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol 2006; 208(1):17–25

27. Raney RB, Maurer HM, Anderson JR, et al. The Intergroup Rhabdomyosarcoma Study Group (IRSG): major lessons from the IRS-I through IRS-IV studies as background for the current IRS-V treatment protocols. Sarcoma 2001;5(1):9–15

28. Raney RB Jr., Crist WM, Maurer HM, Foulkes MA. Prognosis of children with soft tissue sarcoma who relapse after achieving a complete response. A report from the Intergroup Rhabdomyosarcoma Study I. Cancer 1983;52(1):44–50

29. Mattke AC, Bailey EJ, Schuck A, et al. Does the time-point of relapse influence outcome in pediatric rhabdomyosarcomas? Pediatr Blood Cancer 2009;52(7):772–776

30. Punyko JA, Mertens AC, Baker KS, Ness KK, Robison LL, Gurney JG. Long-term survival probabilities for childhood rhabdomyosarcoma. A population-based evaluation. Cancer 2005;103(7):1475–1483

31. Raney RB Jr., Tefft M, Maurer HM, et al. Disease patterns and survival rate in children with metastatic soft-tissue sarcoma. A report from the Intergroup Rhabdomyosarcoma Study (IRS)-I. Cancer 1988;62(7):1257–1266

32. Mosse YP, Laudenslager M, Khazi D, et al. Germline PHOX2B mutation in hereditary neuroblastoma. Am J Hum Genet 2004;75(4): 727–730

33. Trochet D, Bourdeaut F, Janoueix-Lerosey I, et al. Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Am J Hum Genet 2004;74(4):761–764

34. Jaffe N, Cassady R, Petersen R, Traggis D. Heterochromia and Horner syndrome associated with cervical and mediastinal neuroblastoma. J Pediatr 1975;87(1):75–77

35. Brodeur GM, Castleberry RP, Pizzo PA. Principles and Practice of Pediatric Oncology: Neuroblastoma. Philadelphia, PA:JB Lippincott;1997:771

36. Castleberry RP. Predicting outcome in neuroblastoma. N Engl J Med 1999;340(25):1992–1993

37. Cohn SL, Pearson AD, London WB, et al; INRG Task Force. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 2009;27(2): 289–297

38. Maris JM. Recent advances in neuroblastoma. N Engl J Med 2010;362(23):2202–2211