Pediatric Head and Neck Neoplasms

Hodgkin Lymphoma

The introduction of chemotherapy regimens in the 1960s and further evolution of combination chemotherapy and radiation therapy (RT) regimens have dramatically improved the survival of pediatric patients with HL. Combined modality therapy has become the favored approach for treatment as a means to reduce the significant treatment effects associated with either standard-dose RT or alkylator-based chemotherapy alone. When radiation was used as the sole therapy, the risk of recurrence with doses of 35 to 44 Gy was 10% or less. However, extended high-dose RT has been associated with growth deficiencies, coronary heart disease, and secondary malignancies. Combination therapy allows for RT at reduced doses and limited volumes and less aggressive chemotherapy to minimize its side effects. Risk-based therapy regimens have been developed for pediatric HL that tailor the amount and volume of the therapies. The radiation field is designed to cover the side or sides of the abdomen involved with disease.

Currently, RT that uses doses of 15 to 25 Gy is combined with various chemotherapy regimens that include various permutations of drugs with different mechanisms of action and resistances to optimize tumoricidal activity and minimize side effects. For example, MOPP therapy consists of mechlorethamine (nitrogen mustard), vincristine (Oncovin), procarbazine, and prednisone, and it has achieved local control rates of 97%. ABVD therapy consists of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine. Another effective tactic is to alternate chemotherapy regimens. Even in advanced-stage disease, combination therapy has been shown to achieve 4-year event-free survival (EFS) of 87% and overall survival of 90%. Patients with earlier stages of disease who demonstrate early treatment response have achieved 8-year overall survival of 98% with combination therapy.

Non-Hodgkin Lymphoma

Treatment regimens for NHL are specific to the different subtypes and stages of disease and capitalize on knowledge of the cell cycle of lymphoma cells. In contrast to HL, NHL is less commonly treated with RT. RT is typically used in a cytoreductive capacity when pharmaceutic therapy with prednisone and cyclophosphamide has been insufficient, such as treating persistent mediastinal disease causing acute or nonacute airway compression. The pediatric otolaryngologist should be vigilant regarding possible airway complications in patients with NHL, particularly prior to induction of general anesthesia for any procedure, including imaging. When untreated bulky mediastinal disease is present, general anesthesia should be avoided if possible, as tracheotomy is not effective to bypass mediastinal obstruction in patients who cannot be intubated or ventilated. Thus airway management must be carefully planned by experienced providers to avoid respiratory failure and death.

Treatment duration is based on the patient’s tumor burden, typically in 4- to 7-day dose-intensive regimens to maximize tumor cell kill rates. Systemic therapy is a mainstay because occult micrometastases are always a concern in NHL. Chemotherapy protocols use a combination of corticosteroids, cyclophosphamide, ifosfamide, methotrexate, cytarabine, doxorubicin, vincristine, and etoposide. Success rates measured as event free survival (EFS) generally exceed 80% for all subtypes of NHL, which reflects a dramatic improvement over outcomes of several decades ago. Success rates for BL are reported as 90% to 98% for stages I through III. CNS involvement is a poor prognostic factor associated with worse outcomes, with 79% EFS at 4 years. Intrathecal chemotherapy has improved EFS for patients with CNS disease or for those at risk for CNS involvement.

Hodgkin Lymphoma

Two types of cells are classically described in HL, the Hodgkin cells and the pathognomonic Reed-Sternberg (RS) cells ( Fig. 26.1 ). The Hodgkin cells are mononuclear and tend to have clearly basophilic cytoplasm. The RS cells are large cells with abundant slightly basophilic cytoplasm that must be multinuclear, with at least two nuclei in two separate lobes, to be considered diagnostic. The nucleolus tends to be prominent and eosinophilic. RS cells represent the minority of cells; a reactive infiltrate of nonneoplastic cells constitutes the bulk of the lesion.

The use of microdissection and single-cell polymerase chain reaction (PCR) allowed for separation of the malignant cells from the background polyclonal reactive infiltrate. The RS and Hodgkin cells demonstrate monoclonal immunoglobulin gene rearrangements and expression of antigens consistent with B-cell lineage. Of note, with the identification of the B-cell origin of the malignant cells, the term Hodgkin lymphoma became preferred over the term Hodgkin disease.

All histologic subtypes of HL are now considered equally responsive to current chemotherapy regimens; different characteristics of the various immunophenotypes may present opportunities for directed therapies in the future. CHL is further subdivided into four subtypes based on histologic characteristics: (1) nodular sclerosis, (2) mixed cellularity, (3) lymphocyte-depleted, and (4) lymphocyte-rich. Nodular sclerosis CHL is the most common variant and accounts for 40% of younger pediatric cases and 70% of adolescent cases; it has a tendency to involve the lower cervical, supraclavicular, and mediastinal lymph nodes. The characteristic sclerosis is composed of neoplastic cells and inflammatory cells, which may develop into nodules that can be seen on gross specimens. The fibrosis of the lesions may be so pronounced such that the mass effect persists even in patients with a clinical treatment response. Mixed cellularity CHL includes about 30% of cases and is more common among patients younger than 10 years; it tends to have minimal fibrosis. Lymphocyte-depleted CHL tends to have many more RS cells amid few lymphocytes; it is common in patients with human immunodeficiency virus (HIV) infection but is otherwise rare in children. Lymphocyte-rich CHL has a background of many small B lymphocytes with an overall nodular or diffuse pattern.

NLPHL affects 10% to 15% of patients, more commonly male patients and more commonly younger children. This subtype is characterized by lymphocytic and/or histiocytic RS cell variants, which are mononuclear malignant cells (also called “popcorn cells” because of the lobulated appearance of their nuclei). NLPHL has few RS cells and must be immunophenotypically distinguished from lymphocyte-rich CHL.

A large proportion of patients with HL have high circulating Epstein-Barr virus (EBV) titers, and EBV-associated antigens within Hodgkin tissues, suggestive of latent infection. The expression of EBV in patients with HL and strains of EBV associated with HL vary throughout the world. However, whereas an association between EBV and HL appears strong, a causative role of the virus in the pathology of HL has not been defined.

Non-Hodgkin Lymphoma

The clinical and biologic diversity of NHL has made it difficult to create comprehensive classification schemes. Systems for classifying NHL include the Rappaport Classification (1956), the Lukes-Collins system (1975), and the Kiel system, which was predominantly used in Europe. Current classifications emphasize the clinical picture, the associated cell of origin, and the degree of differentiation to produce prognostic categories; one example is the WHO classification system created by the International Lymphoma Study Group ( Box 26.4 ). The high prevalence among African children led to the identification of endemic and sporadic varieties with characteristic immunohistologic and genetic profiles ( Table 26.5 ).

Most pediatric NHL subtypes present with a diffuse, rather than follicular or nodular, pattern of growth. In BL, the lymphoma cells are usually monomorphic, medium-sized cells with basophilic cytoplasm, round to ovoid nuclei, and multiple nucleoli. A “starry sky” appearance, which represents the ingested apoptotic cells, has been described. Burkitt-like lymphoma and plasmacytoid differentiation are also recognized morphologic variants.

BL is believed to derive from a B-cell lineage, confirmed by the B-cell antigens common to the lymphoma cells: CD19, CD20, CD22, and CD79a. BL cells tend to be negative for CD5, CD23, and terminal deoxyribonucleotide transferase (TdT). The most important genetic feature of BL is a translocation that places the c-myc locus on chromosome 8 adjacent to enhancers that increase gene expression. EBV status also correlates to specific break points; EBV positivity is associated with break points outside of c-myc, whereas EBV negativity is associated with break points within the gene. Ultimately, these genetic translocations lead to a characteristic gene expression profile that distinguishes BL from other NHL subtypes. The abnormally high expression of these MYC target genes leads to disruption of the normal cell cycle.

The exact role of EBV in the etiology of BL has not been completely elucidated. ^, The EBV genome can be found in 90% of endemic cases, 20% of sporadic cases, and about 40% of HIV-associated cases. EBV viral gene products have been associated with induction of B-cell lymphomas and have been found to be essential to B-cell transformation.