The timely diagnosis of malignant cervical masses in children necessitates a high level of suspicion. The care of children with malignant cervical masses requires a multidisciplinary approach. Staging systems provide a basis for counseling, risk stratification, and treatment planning for children with cervical malignancies. Recent advances in molecular genetics, tumor biology, and treatment strategies are changing the management of head and neck malignancies in children.
Key points
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The timely diagnosis of malignant cervical masses in children necessitates a high level of suspicion.
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The care of children with malignant cervical masses requires a multidisciplinary approach.
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Staging systems provide a basis for counseling, risk stratification, and treatment planning for children with cervical malignancies.
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Recent advances in molecular genetics, tumor biology, and treatment strategies are changing the management of head and neck malignancies in children.
| BL | Burkitt lymphoma |
| CNS | Central nervous system |
| CT | Computed tomography |
| EBV | Epstein-Barr virus |
| EES | Extraskeletal Ewing sarcoma |
| FNA | Fine-needle aspiration |
| HL | Hodgkin lymphoma |
| INSS | International Neuroblastoma Staging System |
| IRS | Intergroup Rhabdomyosarcoma Studies |
| MRI | Magnetic resonance imaging |
| NCI | National Cancer Institute |
| NHL | Non-Hodgkin lymphoma |
| PET | Positron emission tomography |
| REAL | Revised European-American Lymphoma |
| RMS | Rhabdomyosarcoma |
| RS | Reed-Sternberg |
| SEER | Surveillance, Epidemiology and End Results |
| TNM | Tumor-node-metastasis |
| WHO | World Health Organization |
Introduction
Cervical masses commonly occur in the pediatric population. Although most are benign processes of inflammatory or congenital origin, a high level of suspicion is necessary given that more than 10% of all biopsied masses prove to be malignant. A working knowledge of the diagnostic possibilities is requisite, as is recognition of the potential short-term and long-term implications for children and their families.
Introduction
Cervical masses commonly occur in the pediatric population. Although most are benign processes of inflammatory or congenital origin, a high level of suspicion is necessary given that more than 10% of all biopsied masses prove to be malignant. A working knowledge of the diagnostic possibilities is requisite, as is recognition of the potential short-term and long-term implications for children and their families.
Epidemiology
Similar to the overall rate of pediatric cancer, the incidence of pediatric head and neck malignancies seems to be increasing based on the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) tumor registry. Estimates of the number of pediatric primary malignancies arising in the head and neck vary from 5% to 12% depending on whether or not retinoblastoma is included.
Reviews of childhood cervical malignancies have shown several histopathologic trends. Lymphomas are the predominant neoplasms of the head and neck region. Soft tissue sarcomas, specifically rhabdomyosarcoma (RMS), are the next most common, whereas skeletal sarcomas are comparatively rare. Thyroid carcinomas and salivary gland malignancies are less frequently reported. A summary of SEER pathologic diagnoses of pediatric cervicofacial neoplasms between 1973 and 2010 is provided in Table 1 . Pediatric head and neck cancer incidence rates vary significantly according to age, gender, race, ethnicity, and geography. In particular, age at presentation shows a variety of tendencies, as listed in Table 2 .
| Pathologic Diagnosis | Number of Malignancies | ||
|---|---|---|---|
| Total | Male | Female | |
| Acinar cell carcinoma | 133 | 45 | 88 |
| Adenocarcinoma | 39 | 21 | 18 |
| Adenoid cystic | 37 | 12 | 25 |
| Germ cell | 58 | 25 | 33 |
| Lymphoma | 2239 | 1395 | 844 |
| Hodgkin lymphoma | 1399 | 800 | 599 |
| Non-Hodgkin lymphoma | 840 | 595 | 245 |
| Melanoma | 581 | 316 | 265 |
| Mucoepidermoid | 276 | 120 | 156 |
| Neural malignancies | 3277 | 1739 | 1538 |
| Neuroblastoma | 1447 | 810 | 637 |
| Retinoblastoma | 1533 | 794 | 739 |
| Other neural malignancies | 297 | 135 | 162 |
| Skeletal sarcoma | 256 | 150 | 106 |
| Osteosarcoma | 98 | 58 | 40 |
| Chondrosarcoma | 50 | 32 | 18 |
| Ewing sarcoma | 77 | 41 | 36 |
| Other skeletal sarcomas | 31 | 19 | 12 |
| Soft tissue sarcoma | 1030 | 536 | 494 |
| RMS | 755 | 395 | 360 |
| Non-RMS soft tissue sarcomas | 275 | 141 | 134 |
| Squamous cell carcinoma | 149 | 95 | 54 |
| Thyroid carcinoma | 2763 | 541 | 2222 |
| Follicular | 250 | 43 | 207 |
| Medullary | 132 | 55 | 77 |
| Papillary | 2381 | 443 | 1938 |
| Total | 10,838 | 4995 | 5843 |
| Average Age (y) | Age Range (y) | |
|---|---|---|
| Malignant teratoma | — | NB |
| Neuroblastoma | 1.9 | NB–5 |
| RMS | 6.4 | NB–17 |
| Non-Hodgkin lymphoma | 8.0 | 2–18 |
| Other sarcomas | 8.1 | NB–18 |
| Hodgkin lymphoma | 11.8 | 4–19 |
| Thyroid carcinoma | 12.4 | 6–18 |
| Nasopharyngeal carcinoma | 14.4 | 9–18 |
| Salivary gland malignancies | 15.2 | 7–8 |
Evaluation
The evaluation of a child with a suspected cervical malignancy requires a thorough diagnostic approach, often requiring multiple modalities. A comprehensive history establishes the presentation, progression, and associated symptoms of the lesion as well as systemic manifestations. The most common presentation of a cervical malignancy is simply an asymptomatic mass. Attention to the child’s past history of risk factors such as prior radiation therapy, exposure to carcinogenic or immunosuppressive drugs, a previous primary malignancy, and a family history of childhood cancer or systemic cancer predisposition is useful. All children with a suspected malignancy require a complete otolaryngologic and systemic examination, frequently including an endoscopic assessment of the upper aerodigestive tract.
Imaging
Imaging is an important adjunct in the evaluation of suspected malignancies to precisely define the principal lesion and detect additional primary or metastatic sites of disease for accurate clinical staging. Ultrasonography provides an initial modality that is readily available and not associated with the risks of radiation, contrast administration, or sedation. Ultrasonography allows determination of mass location and consistency as well as vascular flow characteristics. However, the improved anatomic detail provided by computed tomography (CT) or MRI is often required for both diagnostic and therapeutic decision making. CT has traditionally been the imaging modality of choice for many otolaryngologists given the ease of acquisition combined with an excellent ability to assess the degree of tumor extension within and across anatomic planes, provide differentiation between solid and cystic masses, and evaluate osseous erosion. Concerns about diagnostic radiation exposure in children have significantly increased the use of MRI. MRI offers additional advantages, including better contrast of tissues of similar densities, better delineation of neoplasms from surrounding soft tissue structures, and the avoidance of intravenous iodinated contrast material. The need for sedation and the lack of osseous detail present significant drawbacks in some patients. Functional imaging with PET with 18-F-fluoro-2-deoxy- d -glucose can additionally be used to evaluate both primary and metastatic tumor response to treatment, as well as to screen for neoplastic disease recurrence.
Fine-needle Aspiration
Fine-needle aspiration (FNA) biopsy is common in the evaluation of adult head and neck malignancies, particularly thyroid and salivary gland lesions. The reliability of an FNA biopsy diagnosis is highly dependent on the expertise of the cytopathologist and often proves challenging to obtain, particularly in young children, without the need for sedation. When necessary, the open biopsy of a cervical mass is performed in either excisional or incisional fashion depending on the size, location, and differential diagnosis of the lesion. The planning of an excisional or incisional biopsy must take into account potential implications with respect to future definitive resection from both a therapeutic and cosmetic standpoint.
Multidisciplinary Approach
Childhood head and neck malignancies require a multidisciplinary team approach to provide treatment. In addition to otolaryngologists, the team often includes pediatricians, medical oncologists, radiation oncologists, diagnostic and interventional radiologists, pediatric surgeons, and additional pediatric surgical specialists. Supportive services include speech language pathologists, nutritionists, child psychologists, social workers, and child life specialists. Most institutions treating children with head and neck cancer do so in the setting of a multidisciplinary tumor board to coordinate comprehensive therapy.
Lymphatic malignancy
Cervical lymphadenopathy in children is typically of benign infectious or inflammatory cause. However, neoplasms of the lymphatic system must be kept in mind as part of the differential diagnosis.
Hodgkin Lymphoma
Hodgkin lymphoma (HL) is a malignant neoplasm of the lymphatic system with a bimodal age distribution, one peak occurring during adolescence and young adulthood, and another peak after the age of 50 years. HL is uncommon in preadolescent children and rarely occurs in children younger than 5 years old.
Epidemiology
Although no definitive causal factors are known, there is an association between Epstein-Barr virus (EBV) infection and HL. Increased titers of EBV-induced antibodies have been documented in patients with HL, and there is an increased risk of developing HL following a confirmed bout of infectious mononucleosis. HL is distinguished histopathologically by the presence of Reed-Sternberg (RS) cells, which are multinucleated cells with large nucleoli and a halo or clear zone around the nucleolus. The RS cell seems to be most commonly of germinal center B-cell origin, but cases of T-cell origin have been described.
Classification of Hodgkin lymphoma
The Rye classification was historically the most common method to designate the various types of HL based on the cellular background: lymphocyte predominant, lymphocyte depletion, nodular sclerosis, and mixed cellularity. Recognition that nodular lymphocyte-predominant HL differs both morphologically and immunophenotypically from the other classic subtypes of HL led to an alternative pathologic classification, called the Revised European-American Lymphoma (REAL) classification system. This schema divides HL into 2 broad categories: classic HL and nodular lymphocyte-predominant HL. The REAL classification was eventually adopted into the World Health Organization (WHO) classification, the latter currently serving as the most widely accepted means to describe hematopoietic and lymphoid neoplasms.
Clinical features of Hodgkin lymphoma
Although extranodal primary sites of origin such as the lymphoid tissue of the Waldeyer ring have been described, HL arises within lymph nodes in more than 90% of childhood, adolescent, and young adult cases. The typical patient with HL has asymmetric lymphadenopathy that is firm, rubbery, and nontender. The cervical, supraclavicular, and mediastinal lymph nodes are the most frequent sites of presentation. Extranodal involvement occurs with disease progression, the spleen, liver, lung, bone, and bone marrow being the common organ systems affected. At presentation, 25% to 30% of children with HL have nonspecific systemic symptoms, termed B-symptoms, including unexplained fever, night sweats, weight loss, weakness, anorexia, and pruritus.
Staging of Hodgkin lymphoma
The Ann Arbor staging system ( Table 3 ) is used to stratify risk for patients with HL. This staging system is based on the premise that HL progresses from a unifocal lymph node site, spreads via lymphatics to contiguous lymph node groups, and then involves extralymphatic sites principally by hematogenous dissemination. Pretreatment staging of HL consists of a combination of history, physical examination findings, and both anatomic and functional imaging. Bone marrow aspirate with biopsy is necessary for patients with clinical stage III or IV disease and for patients of any stage with B-symptoms.
| Stage a | Definition |
|---|---|
| I | Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (I E ) |
| II | Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of extralymphatic organ or site and of 1 or more lymph node regions on the same side of the diaphragm (II E ). An optional recommendation is that the numbers of node regions involved be indicated by a subscript (eg, II 3 ) |
| 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 (III E ) or by involvement of the spleen (III S ), or both (III SE ) |
| IV | Diffuse or disseminated involvement of 1 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 |
a Each 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 prior 6 months).
Management of Hodgkin lymphoma
The treatment of HL varies according to stage. Surgery often plays little role beyond initial diagnostic biopsy; multimodal chemotherapy and radiation constitute the primary therapies. Patients with HL who relapse may be candidates for autologous stem cell transplantation. With current therapeutic regimens, more than 90% of all patients with HL, 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. Histopathologic findings also have prognostic implications. Patients with lymphocyte-predominant lesions have the most favorable survival, followed in prognostic order by the nodular sclerosis, mixed cellularity, and lymphocyte depletion subtypes.
Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) designates a heterogeneous group of solid primary neoplasms of the lymphatic system. In children, NHL most commonly occurs between the ages of 2 to 12 years and shows a male predilection. Both congenital and acquired immunodeficiency disorders predispose to the development of NHL.
Classification of non-Hodgkin lymphoma
The classification of NHL continues to evolve. In the 1950s, Hicks and colleagues unified older classification systems by recognizing the resemblance of malignant lymphoma cells to their benign lymphocytic or histiocytic counterparts that became known as the Rappaport classification. Subsequent advances in immunophenotyping allowed separation of NHL into categories of B-cell, T-cell, and true histiocytic origins. In 2001 and 2008 the WHO developed and subsequently updated an evidence-based classification system using a combination of tumor morphology; immunophenotyping; and genetic, molecular, and clinical features for all neoplasms of lymphatic origin. This system is currently the most robust and widely used classification scheme for all lymphomas.
Clinical features of non-Hodgkin lymphoma
The clinical features of NHL reflect the site of origin of the primary tumor and the extent of local and systemic disease. Asymptomatic lymphadenopathy is the most common initial presentation, with approximately 45% of patients having head and neck involvement at diagnosis. Nodal growth may be rapid, but insidious presentations more often occur.
Childhood NHL additionally differs from adult NHL in that it has a greater likelihood of being composed of unfavorable cell types, a tendency toward both leukemic transformation and hematogenous dissemination, and a higher risk of central nervous system (CNS) involvement. Constitutional signs and symptoms that correlate with advanced disease include fever, weight loss, malaise, pancytopenia resulting from bone marrow infiltration, and neurologic manifestations.
Staging for non-Hodgkin lymphoma
The Ann Arbor staging classification for HL (see Table 3 ) is often still applied to patients with NHL. Alternatively the St Jude classification system ( Table 4 ), first described in 1980, is commonly used. The St Jude classification system attempts to account for the characteristic extranodal presentations and tendency toward hematogenous dissemination, bone metastases, and CNS involvement in childhood NHL. The staging of NHL of the head and neck requires a comprehensive history and physical examination, serologic testing including complete blood count and lactate dehydrogenase level, chest radiograph, bone marrow biopsy, and cerebrospinal fluid analysis in addition to appropriate head and neck imaging typically by means of CT and often MRI. More recently, PET has shown utility for disease staging and for following disease progression during treatment.
| 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 sites |
| IV | Any of the earlier criteria with initial CNS and/or bone marrow involvement |
Stage I NHL is infrequently diagnosed in the pediatric age group. Approximately 80% of children with NHL have advanced stage II, III, or IV disease. As in HL, surgery plays little role in NHL management beyond diagnostic biopsy and occasional surgical debulking in the setting of aerodigestive tract compression. The principal treatment of nearly all stages of cervical NHL is systemic chemotherapy; the rapid doubling time of high-grade NHL makes it highly chemosensitive. Radiation therapy has a limited role in the treatment of NHL. Treatment of relapse consists of high-dose chemotherapy; bone marrow transplantation may be considered.
Prognosis
Prognosis is principally associated with disease stage and response to initial therapy. The 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 the histologic type. Given the observation that most childhood NHL is characterized by T-cell or B-cell differentiation, immunotherapy may have a future therapeutic role.
Burkitt Lymphoma
Burkitt lymphoma (BL) is an NHL deserving special attention because of its predilection for children and distinct epidemiologic and clinical features. Epidemiologic differences separate BL into endemic and a sporadic types. Endemic BL is generally limited to equatorial Africa and is characterized by serologic evidence supporting a causal role for EBV. Almost all patients with endemic BL show high antibody titers to EBV determinant antigens, and 80% to 90% of their tumor cells contain copies of the EBV DNA genome; in contrast, only 15% to 20% of patients with the sporadic form of BL show this EBV association.
Clinical features
BL almost exclusively affects children, with a predilection for boys. However, the clinical characteristics of endemic BL differ greatly from those of the sporadic form. Endemic BL is diagnosed at an average age of 9 years and characteristically occurs as a facial mass originating from the jaw. In contrast, sporadic BL is associated with slightly older children (average age 12 years) and usually presents in the abdomen. Approximately one-quarter of sporadic BL cases involve the head and neck. Asymptomatic cervical lymph node enlargement is the most common presentation; jaw involvement as seen in endemic BL is comparatively rare.
Staging for Burkitt lymphoma
Staging work-up for BL is similar to that used in other NHLs. The primary treatment modality for both endemic and sporadic BL is chemotherapy. Surgery is typically limited to diagnostic biopsy purposes. The exception to this rule is surgical reduction of tumor bulk, which has been shown to improve survival in abdominal BL; a similar role for tumor debulking or resection of head and neck BL has not been defined. Event-free survival rates at 3 and 5 years for both endemic and sporadic BL are 85% to 95% for limited disease and 75% to 85% for advanced disease; relapse rates are lower and survival rates significantly higher in patients with a smaller tumor burden at presentation. For localized disease limited to the head and neck, a 90% long-term survival is reported. Children younger than 12 years of age do significantly better than older patients, and high anti-EBV antigen titers in patients with sporadic BL seem to be associated with more favorable prognoses.
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