Lymphomas are the most common head and neck malignancies in children, followed by retinoblastoma, rhabdomyosarcoma, neuroblastoma, thyroid cancer, and melanoma.
Hodgkin lymphoma is the predominant malignant lymphoma in older children.
Even though surgery is not the primary treatment modality for pediatric lymphoma, the otolaryngologist often plays a key role in the diagnosis by obtaining tissue.
Although nasopharyngeal carcinoma accounts for less than 1% of all pediatric malignancies, it comprises 20% to 50% of tumors of the nasopharynx. The most common type seen in children is World Health Organization type III, undifferentiated carcinoma (lymphoepithelioma).
Rhabdomyosarcoma is the most common soft tissue sarcoma in the pediatric population, and about 25% to 35% present with a primary head and neck lesion.
Today, more rhabdomyosarcomas are considered surgically resectable because of the evolution in surgical approaches to the skull base.
Most teratomas in the head and neck region are diagnosed in the prenatal or neonatal period. Attention to the patency of the airway is essential in the initial evaluation.
Thyroid nodules are more likely to be malignant in children (25%) than in adults (<10%).
In children, most thyroid cancers are well differentiated, and papillary thyroid cancer comprises over 90%.
Neuroblastomas of the head and neck tend to present at an earlier stage than in other regions. A unique feature of these tumors is that they may demonstrate spontaneous regression.
In the United States each year, approximately 1.5 in every 10,000 individuals under the age of 20 years will be diagnosed with cancer. Pediatric cancers differ markedly in terms of types and prevalences from those of adults. Whereas epithelial tumors dominate among adults, mesenchymal and endothelial tumors are more common in the pediatric population. Pediatric cancers are tracked by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, which reports trends in anatomic sites, incidence, and survival. In addition, the International Classification of Childhood Cancer records the histology of all pediatric cancer cases.
For the pediatric population, the types of cancer seen in the head and neck region have remained stable. Lymphomas (Hodgkin and non-Hodgkin) remain the most common malignancies, followed by retinoblastoma, rhabdomyosarcoma, neuroblastoma, thyroid cancer, and melanoma. The neck is the site most commonly involved, related to lesions of the cervical lymphatics and thyroid, followed by the orbit, skin, nasopharynx, skeleton, and salivary glands. (Salivary gland malignancies are described in Chapter 22 .)
Data from the SEER program and the Children’s Oncology Group (COG)’s Childhood Cancer Research Network reveal that the most common types of pediatric cancer diagnoses vary between younger and older children ( Table 21-1 ). Thyroid cancers become more common in older teenagers and account for 8.0% of cancer diagnoses. Some lesions, such as neuroblastoma and retinoblastoma, occur predominantly in younger children and only very rarely occur in older children.
|0-1 Years||1-5 Years||6-10 Years||11-18 Years|
For children under 15 years of age, from 1975 to 1995, the incidence of pediatric cancers appears to have increased by about 1% each year, but these additional cases are distributed unevenly across different types of cancers and age groups. Notably, a more recent analysis of the period from 1992 to 2004 suggests a stabilization of cancer incidence overall. Differing incidences of cancer in particular demographic subgroups, such as an increase in thyroid cancer in females, may provide clues to better understanding the etiology of different cancers. It is believed that the increase in incidences for some tumors relates to improvements in diagnostic testing and reporting mechanisms. Mortality has decreased appreciably across all the major types of pediatric cancers, attributed largely to improved efficacy of treatment regimens for leukemias. However, cancer remains the most common cause of death by disease for children 1 to 19 years of age.
Consideration of the most relevant differential diagnoses impacts the approach to the child with a possible head and neck malignancy. A biopsy is essential to establishing a diagnosis and planning the most appropriate treatments to optimize the patient’s prognosis. The surgeon should perform the initial diagnostic biopsy in a way that does not compromise future resection and reconstruction. The amount of tissue required for pathologic analysis may vary depending on the suspected histology and the types of testing required. Obtaining and sending fresh tissue is essential to allow the pathologist to divide the tissue as needed for different diagnostic methods ( Table 21-2 ). Additional biopsies may be required for staging, to evaluate for metastatic disease, and to assess response to therapy.
|Light microscopy||Mandatory for all cases|
|Immunohistochemistry||First-choice ancillary diagnostic approach; widely used, inexpensive|
|Electron microscopy||Still widely used to augment light microscopy; particularly useful for pediatric soft tissue tumors|
|Molecular genetic: fluorescent in situ hybridization (FISH)||For tumors with known genetic abnormalities; replacing cytogenetics as a favored technique|
|Cytogenetics (karyotyping)||Necessary when no suitable FISH probes are available or to identify new translocations and known prognostic factors|
|Molecular genetic: reverse transcription polymerase chain reaction (RT-PCR)||Most common molecular diagnostic procedure; routinely available in most pediatric hospitals|
|Molecular genetic: in situ hybridization (ISH)||Specialized use to date, detects gene expression such as with Epstein-Barr virus genes|
|Molecular genetic: comparative genomic hybridization (CGH)||Able to screen thousands of single nucleotide polymorphisms for loss of heterozygosity|
|Molecular genetic: spectral karyotyping (SKY)||Useful to map chromosomal breakpoints, detect subtle translocations, and characterize complex rearrangements|
|Molecular genetic: DNA sequencing||Rare disorders as a result of known genetic mutations, such as Li-Fraumeni ( TP53 mutation) and other cancer syndromes|
Optimal imaging for diagnosis and staging of malignancies obviously depends on the type of lesion suspected. Conventional radiographs, computed tomography (CT), magnetic resonance imaging (MRI), and/or ultrasound (US) may be indicated. The selection of imaging modalities will often include a consideration of the need for sedation or general anesthesia. Consideration must be given to the general state of health of the patient in planning procedures. The various members of the team should coordinate efforts to minimize delays, discomfort, and inconvenience for the patient, particularly in scheduling procedures to be done under general anesthesia. Communication among the surgeon, radiologist, oncologist, and pathologist helps ensure that adequate tissue is obtained and processed appropriately and that a unified plan is presented to patients and families.
Unlike adult cancers, detection or amelioration of risk factors for pediatric cancers does not lower the incidence or improve survival rates. In adults, malignancies that result from the toxic and cumulative effects associated with tobacco exposure are manifested years later. In contrast, carcinogenic exposures that lead to pediatric cancers must by definition occur over a shorter time frame. Pediatric exposures may be incidental because of the child’s environment or, more likely, related to treatment of other diseases. For example, ionizing radiation is a risk factor for thyroid cancer, acute lymphoblastic leukemia, brain tumors, and osteosarcomas. Chemotherapeutic agents predispose patients to certain cancers, including acute myelocytic leukemia and osteosarcomas. Genetic syndromes identified in the pediatric population increase susceptibility for certain malignancies ( Table 21-3 ). The knowledge gained from epidemiologic studies and next-generation sequencing will likely identify additional specific predispositions to cancers as well as allow better differentiation of treatment responders by genotype.
|Neurofibromatosis type 1||Leukemia, gliomas, rhabdomyosarcoma, pheochromocytoma, astrocytoma|
|Neurofibromatosis type 2||Astrocytoma, melanoma, meningioma|
|Li-Fraumeni syndrome||Osteosarcoma, rhabdomyosarcoma, leukemia, lymphoma, breast|
|Gorlin syndrome||Basal cell carcinoma, medulloblastoma|
|Multiple endocrine neoplasia type 1||Parathyroid, pancreas, gastrinomas, insulinomas, carcinoid tumor|
|Multiple endocrine neoplasia type 2a||Medullary thyroid carcinoma, pheochromocytoma, parathyroid adenomas|
|Multiple endocrine neoplasia type 2b||Medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and ganglioneuromas|
|Peutz-Jeghers syndrome||Stomach, small intestine, colon, pancreas, uterine, breast|
|Beckwith-Wiedemann syndrome||Rhabdomyosarcoma, neuroblastoma, Wilms tumor, hepatoblastoma|
|Werner syndrome||Thyroid, leukemia, melanoma, osteosarcoma|
|Ataxia telangiectasia||Lymphoma, leukemia|
|Wiskott-Aldrich syndrome||Lymphoma (non-Hodgkin)|
Lymphoproliferative Disorders and Histiocytoses
Malignant lymphoma is the third most common malignancy diagnosed in children after leukemias and brain tumors, and it is the most common pediatric malignancy of the head and neck. In contrast to leukemias, which represent neoplasms of the bone marrow and peripheral blood, lymphomas involve similar kinds of clonal proliferations in discrete tissues outside of the bone marrow. Lymphocytic leukemias and lymphomas are both diseases of lymphoblasts and are now distinguished by characteristic tissue distribution and site of presentation. Pediatric lymphomas are divided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), a large and diverse collection of lymphomas that includes all malignant lymphomas not categorized as HL.
Children with cervical lymphadenopathy commonly present to the pediatric otolaryngologist, and expertise in the differential diagnosis of the pediatric neck mass is essential to a complete evaluation and workup (see Chapter 19 ). Although most localized lymphadenopathy in children is due to infectious or inflammatory causes, persistent or refractory lymphadenopathy and constitutional symptoms should prompt further investigation. Even though surgery is not the primary treatment modality for pediatric lymphoma, the otolaryngologist often plays a key role in the diagnosis by obtaining tissue.
According to the current World Health Organization (WHO) classification ( Box 21-1 ), two clinical subtypes of HL are recognized: classic Hodgkin lymphoma (CHL) and nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL). The distribution of HL varies markedly in different countries and among different ethnicities. In the United States, CHL represents about 95% of HL pediatric cases, and NLPHL is far less common. The age at presentation for CHL overall has a bimodal distribution, between 15 and 40 years old and after 60 years old. However, epidemiologic studies identify three distinct forms of CHL: a childhood form (±14 years), a young adult form (15 to 34 years), and an older adult form (most commonly presenting between 55 and 74 years). In the childhood form, a slightly increased incidence in boys has been observed. Whereas the incidence of HL peaks in later childhood, NHL’s incidence is higher in younger children, although it is rare in infants ( Table 21-4 ).
Nodular lymphocyte–predominant Hodgkin lymphoma
Classic Hodgkin lymphoma
Nodular sclerosis subtype
Mixed cellularity subtype
|Hodgkin Lymphoma||Non-Hodgkin Lymphoma|
NHL encompasses a wide variety of histologic patterns with different clinical presentations. It may derive from immature or mature lymphoid cells and from cells of B-cell, T-cell, or natural killer cell origin. Three therapeutic groups of NHL are recognized: 1) lymphoblastic lymphomas; 2) peripheral B-cell lymphomas, which includes Burkitt lymphoma; and 3) anaplastic large cell lymphomas. Burkitt lymphoma (BL), which is derived from mature B cells, is by far the predominant variety of NHL in children.
Presentation and Evaluation of Malignant Lymphoma
Commonly, the pediatric otolaryngologist will encounter lymphoma in patients with a painless supraclavicular or cervical mass. The lymphadenopathy associated with lymphoma feels firmer than reactive, inflammatory lymphadenopathy and is often described as “rubbery.” Some tenderness may be noted in those patients who have had rapid enlargement of lymph nodes. The presence of B symptoms or constitutional symptoms—fever above 38.0° C for three consecutive days, unexplained weight loss of 10% or more of body weight in the 6 months preceding presentation, and drenching night sweats—are incorporated into the staging system for HL ( Box 21-2 ). Disease in the Waldeyer ring is more characteristic of NHL than it is of HL and occurs in 25% to 30% of pediatric cases. Physical examination should explore other lymph node basins.
Stage I: Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (I E )
Stage II: Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (II E )
Stage III: Involvement of lymph node regions on both sides of the diaphragm (III), which may be accompanied by involvement of the spleen (III S ) or by localized involvement of an extralymphatic organ or site (III E ) or both (III SE )
Stage IV: Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement
NHL in children typically presents as a diffuse, extranodal lymphoma. With advanced stage disease of all types of NHL, metastatic involvement or direct extension to the central nervous system (CNS) can lead to neurologic impairment. The varieties of BL tend to have distinct presentations: sporadic BL commonly involves the abdomen, bone marrow, and the Waldeyer ring, whereas endemic BL involves the mandible, abdomen, orbit, and CNS. Ulcerative skin lesions may be identified at presentation in patients with BL. The most common extranodal sites at the time of presentation of pediatric NHL are the mediastinum and the abdomen, involved in 35% to 45% and 25% to 30% of patients, respectively. Mediastinal involvement may occur in as many as two thirds of cases of HL. Signs of airway compression that include nonproductive cough, stridor, and respiratory compromise should prompt heightened concern for mediastinal disease. Axillary, inguinal, and subdiaphragmatic lymphadenopathy are less common.
After the history and physical examination, laboratory values and imaging should be obtained. Laboratory testing should include a complete blood count (CBC), erythrocyte sedimentation rate, serum copper, serum ferritin, alkaline phosphatase, and a C-reactive protein level. Necessary imaging includes chest radiographs, CT of the neck and chest, and CT or MRI of the abdomen and pelvis. Abdominal MRI is more useful than CT in the pediatric population because of the low volume of retroperitoneal fat and better definition of pelvic structures as well as the advantages of minimizing radiation exposure. Ultrasound may be an option for imaging of the abdomen and pelvis, although this modality is highly dependent on the technician. For all imaging modalities, the location and dimension of enlarged lymph nodes should be documented for future reference. Cranial imaging, preferably MRI, can diagnose CNS involvement that has not yet become clinically evident or has not been diagnosed by cerebrospinal fluid (CSF) analysis. However, some advocate that clinical assessment and lumbar puncture with CSF analysis are sufficient. Any site of suspected bony involvement should be evaluated with CT.
Positron emission tomography (PET), often in combination with CT, is increasingly used for initial staging and follow-up. PET is able to identify abnormalities not seen on CT that impact staging in 10% to 20% of cases, but these lesions may be extranodal sites. However, some are concerned that PET may lead to upstaging of disease and to more aggressive treatments with increased side effects and morbidity without improving outcomes; therefore further study will be necessary to define the role of PET in pediatric lymphoma.
Surgical resection is rarely indicated, unless it can be accomplished at the time of initial biopsy without causing a functional deficit. The goal of biopsy is to obtain sufficient tissue while minimizing trauma to nearby tissues. The tissue should be sent for permanent fixation and frozen section for evaluation of morphology, touch prep should be done for rapid identification of malignancy and cell type, and fresh tissue (not on formalin) should be submitted for flow cytometry. The pediatric oncologist and pathologist should be available at the time of biopsy to ensure that adequate and appropriate tissue is obtained. Further studies such as immunohistochemistry (IHC) can often be performed on the fixed tissue and the touch prep to identify subtypes. Bone marrow biopsy is indicated in patients with B symptoms or clinical stage III or IV disease and may be coordinated with CSF sampling under the same general anesthetic. Staging no longer involves exploratory laparotomy for lymph node sampling or splenectomy; imaging has become sufficient for detection of disease in these locations, and splenectomy is associated with an increased risk of complications.
Most children and adults with HL present with stage I or II disease. Features associated with unfavorable clinical outcomes include the presence of B symptoms, bulky mediastinal disease, extranodal extension of disease, and advanced stage at presentation. Patients may have concurrent pleural and cardiac effusions, or they may present acutely or emergently with superior vena cava syndrome, small bowel obstruction, ileus, cranial nerve palsies, or disseminated intravascular coagulation. After initial diagnostic steps are completed, the patient’s disease stage is determined by the extent of disease ( Table 21-5 ).
|Clinical presentation||5 to 10 years old |
Males > females
|6 to 12 years old |
Males > females
|Most common distribution of disease||Equatorial Africa, New Guinea, Amazonian Brazil, Turkey||North America, Europe|
|Annual incidence||10 in 100,000||0.2 in 100,000|
|Common tumor sites||Jaw, abdomen, central nervous system, cerebrospinal fluid||Abdomen, marrow, lymph nodes, ovaries|
|Histopathologic features||CD20+, usually IgM, κ or λ CD10+, BCL2-||CD10 + , usually IgM, κ or λ CD10 + , BCL2 –|
|Presence of Epstein-Barr virus DNA in tumor cells||95%||15%|
|Presence of t(8;14), t(2;8), or t(8;22) translocations||Yes||Yes|
|Chromosome 8 breakpoints||Upstream of cMYC||Within cMYC|
Management of Malignant Lymphoma
The introduction of chemotherapy regimens in the 1960s and further evolution in combination chemotherapy and radiation therapy (RT) 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 as well as 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 utilizes 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 in order 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 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.
Treatment regimens for NHL are specific to the different subtypes and stages of disease and capitalize on knowledge of the cell-cycle duration of lymphoma cells. RT is less commonly used in the treatment of NHL than in HL. It is used in a cytoreductive capacity, usually when pharmaceutical therapy with prednisone and cyclophosphamide have been insufficient. An example of such usage is to reduce the burden of mediastinal disease that causes acute or nonacute airway compression. The pediatric otolaryngologist should be vigilant regarding possible airway complications in NHL patients, particularly prior to induction of anesthesia for any procedure. Careful intubation to secure the airway should be the primary step in management, followed by chest CT, if that has not already been obtained.
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 patients. Chemotherapy protocols utilize a combination of corticosteroids, cyclophosphamide, ifosfamide, methotrexate, cytarabine, doxorubicin, vincristine, and etoposide. Successful treatment for these patients generally exceeds 80% for all subtypes, measured as event-free survival (EVS), which reflects a dramatic improvement over outcomes of several decades ago. Success rates for BL have been 90% to 98% for stages I through III. CNS involvement is a poor prognostic factor associated with worse outcomes, with 79% EVS at 4 years. Intrathecal chemotherapy has improved EVS for patients with CNS disease or for those at risk for CNS involvement.
Two types of cells are classically described in HL, the Hodgkin cells and the pathognomonic Reed-Sternberg (RS) cells ( Fig. 21-1 ). 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 comprised 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 comprises 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 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 males and more commonly younger children. This subtype is characterized by lymphocytic and/or histiocytic Reed-Sternberg 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, as well as EBV-associated antigens within Hodgkin tissues, that are suggestive of latent infection. The expression of EBV in HL patients 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.
The clinical and biologic diversity of NHL has made the creation of comprehensive classification schemes difficult. 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 21-3 ). The high prevalence among African children led to the identification of endemic and sporadic varieties with characteristic immunohistologic and genetic profiles ( Table 21-6 ).
Stage I: A single tumor (extranodal) or single anatomic area (nodal) with the exclusion of mediastinum or abdomen
Stage 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 tumor usually in the ileocecal area with or without involvement of associated mesenteric nodes only, grossly completely resected
Stage III: Two single tumors (extranodal) on opposite sides of the diaphragm
Two or more nodal areas above and below the diaphragm
All primary intrathoracic tumors (mediastinal, pleural, thymic)
All extensive primary intraabdominal disease
All paraspinal or epidural tumors regardless of other tumor site(s)
Stage IV: Any of the above with initial central nervous system and/or bone marrow involvement
|Subtype of Lymphoma||Frequency|
|Precursor Lymphoid Neoplasms|
|Mature B-Cell Neoplasms|
|Diffuse large B-cell lymphoma||15%-20%|
|Primary mediastinal B-cell lymphoma||1%-2%|
|Pediatric follicular lymphoma||Rare|
|Pediatric nodal marginal zone lymphoma||Rare|
|Mature T-Cell Neoplasms|
|Anaplastic large cell lymphoma, ALK positive||15%-20%|
|Peripheral T-cell lymphoma (NOS)||Rare|
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 breakpoints—EBV positivity is associated with breakpoints outside of c-myc , whereas EBV negativity is associated with breakpoints 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.
Posttransplant Lymphoproliferative Disease
People who have undergone previous solid organ or bone marrow transplants have an increased lifetime risk for malignancies estimated to be fivefold to tenfold higher than that of the population at large. Posttransplant lymphoproliferative disease (PTLD) is the most common malignancy that occurs in transplant recipients. Risk factors include young age at time of transplant, exposure to potential carcinogenic agents (chemotherapy, RT, immunosuppressive antimetabolites), and EBV-negative status. The rate of PTLD in children after bone marrow transplant is 45%, and the rate after solid organ transplant has been reported to be as high as 80%. The type of organ transplant also plays a role in the prevalence of PTLD ; patients with kidney transplants have the lowest risk, and those who receive multivisceral transplants, such as lung and heart, are at the highest risk.
The clinical manifestations of PTLD include localized or diffuse lymphomatous lesions ( Fig. 21-2 ), isolated hepatitis, meningoencephalitis, and an infectious-mononucleosis-type syndrome. The most extreme presentation of PTLD is a rapidly progressive disseminated illness that presents like septic shock and is usually fatal, at times diagnosed postmortem.
Patients with increased T-cell specific immunosuppression are more likely to develop PTLD. A new EBV infection places the posttransplant patient at risk for developing PTLD through activation of EBV-specific T cells that leads to an imbalance of the host immune response and to clonal proliferation of B cells. For immunocompetent patients, EBV infection may be subclinical, or it may present as a febrile upper respiratory tract infection in young children or as a classic infectious mononucleosis in older children. In immunocompromised patients, however, the presentation can range from a subclinical disease to a life-threatening infection. The infection in transplant patients may be either primary, acquired through new exposure to EBV in the environment or from the transplant, or secondary, as a reactivation of latent virus as a result of immunocompromise. PTLD associated with EBV typically presents earlier after transplant in children, whereas PTLD that arises through other mechanisms generally presents in older patients much later after transplant.
The WHO has divided PTLD into subtypes that include early, CHL-type, monomorphic, and polymorphic lesions. However, clonal proliferations of different subtypes can arise simultaneously within the same patient and even within the same lesion. The early lesions represent the benign end of the spectrum and resemble an infectious mononucleosis syndrome or a plasmacytic proliferation. Monomorphic PTLD is further identified by the cell involved in the clonal proliferation—B cell, T cell, or natural killer cell. When monomorphic PTLD manifests as NHL, diffuse large B-cell lymphoma is more common than BL—an inversion of the usual pattern seen in children. Overall, the NHL-type presentation in PTLD has a similar histologic profile in adults and children.
In the head and neck region, cervical lymphadenopathy or enlargement of the adenotonsillar tissue in a transplant patient should prompt a concern for a lymphomatous process, although a malignant lymphoma is less likely than a benign proliferation of lymphoid tissue. The role of the otolaryngologist is to manage airway obstruction related to mass effect and to obtain tissue for histologic analysis. Whereas many centers no longer send tonsillar tissue for histopathologic analysis after routine tonsillectomy, it is mandatory to send the tonsils fresh to pathology in transplant patients. Communication with the patient’s transplant physician and the pathologist is essential to ensure that the appropriate tissue is obtained and processed correctly.
Imaging and endoscopy may be indicated for evaluation, and review of serial imaging may be helpful to evaluate progression. CT is useful for evaluating lymphadenopathy and compression of the surrounding structures, and PET-CT is a useful modality for diagnosis and recurrence because PTLD lesions will manifest increased metabolic activity.
Management of Posttransplant Lymphoproliferative Disorder
Because PTLD results from reduced cellular immunity, the first approach to management is reduction in immunosuppression (RIS). A common approach is to discontinue antimetabolite agents, to reduce by half the dose of calcineurin inhibitors, and to add corticosteroids. The average time to response after initiation of RIS is reported as 1 to 4 weeks; early lesions and polymorphic PTLD have better responses to RIS. Complete cessation of immunosuppressive therapy is not routinely used. Other treatment options for PTLD include chemotherapy and RT, and evidence suggests that RIS followed by chemotherapy (cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone [CHOP]) results in worse function of the transplanted organ. It is not clear whether immunosuppressive therapy can be reduced or stopped during chemotherapy or RT. Ultimately, the balance between overall patient health and preserving function of the transplanted organ must be weighed. RIS treatment is not utilized in patients with PTLD who are very ill at the time of presentation; because the response to RIS is too gradual, more aggressive treatments must be initiated in those cases.
Langerhans Cell Histiocytosis
The histiocytoses are a group of diseases defined by the pathologic behavior of cells regularly involved in phagocytosis and antigen presentation. Formerly, the disorder that encompassed eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease was referred to as histiocytosis X ; the preferred term is now Langerhans cell histiocytosis (LCH; Fig. 21-3, A and B ). The Langerhans cell is an antigen-presenting cell found in normal skin, characterized by Birbeck granules; identification of cells that stain positively for the Birbeck granule-associated antigen CD207 is diagnostic of LCH, and other defining markers of LCH include CD1a and S100 ( Fig. 21-3, C ).
The presentation of LCH is quite varied, but it most commonly includes a skin rash or painful bone lesion followed by fever, weight loss, diarrhea, edema, dyspnea, polydipsia, and polyuria. The severity of the presentation corresponds to the time to diagnosis because single-organ involvement may be unrecognized. Although LCH is usually monoclonal, isolated pulmonary disease appears to be nonclonal and more typical of a pattern of immune dysregulation. Considering the entire spectrum of LCH, from unifocal to disseminated disease, the head and neck are involved in about 60% to 75% of all patients.
Whereas the three classic forms of LCH are well described, the broad spectrum of manifestations of LCH has led to categorizing each particular case by its involved organs and presentation. Eosinophilic granuloma is the most common pediatric type, and the skull is the most common site involved. Other sites of involvement are the long bones of extremities, facial bones, vertebral bodies, ribs, and pelvis. The lesion may be painless or painful, and the local mass effect of the lytic lesion may be compounded by an associated soft tissue component; nonskull sites are more likely to be painful. CT imaging usually demonstrates a lytic bone lesion, and the course tends to be benign with an excellent prognosis.
Hand-Schüller-Christian disease is characterized by the triad of lytic skull lesions, exophthalmos secondary to orbital bone involvement, and diabetes insipidus secondary to involvement of the pituitary gland or hypothalamus. This classic triad is present in about 25% of patients with the syndrome. The course tends to be prolonged, and prognosis depends on the severity of the endocrine involvement. Letterer-Siwe is a rapidly progressive and usually fatal form and is typically seen in newborns. Patients present with disseminated disease manifested as fever, rash, lymphadenopathy, hepatosplenomegaly, increasing respiratory effort, and blood dyscrasias.
In patients with single-system disease, limited treatment is often successful. For those with only skin involvement, observation is an option; for treatment, topical steroids or emollients may suffice, and oral steroids have not been as successful. Oral therapy options of methotrexate, thalidomide, cyclosporine, and tacrolimus have reportedly been effective. When eosinophilic granuloma is suspected, conservative biopsy, rather than an attempt at complete resection, is recommended; single-site bony involvement often responds to minimal treatment with only curettage or repeat curettage with or without local steroid injection. Because LCH is rarely fatal, treatment decisions must consider the possible short- and long-term side effects. Currently, the Histiocyte Society recommends enrolling patients with LCH in their clinical trials.
Nasopharyngeal carcinoma (NPC) is a rare malignancy and one of the few pediatric malignancies of epithelial origin. Overall, the age distribution of this cancer tends to be bimodal, with one peak in adolescence and the other between 40 and 60 years of age. Whereas NPC accounts for less than 1% of pediatric malignancies, it accounts for 20% to 50% of pediatric tumors of the nasopharynx. Internationally, the incidence of NPC is highest in southern China, Southeast Asia, and the Mediterranean basin. In the United States, pediatric NPC is more commonly seen in the southern states and in black children. The regional and ethnic profiles of the disease suggest environmental and genetic risk factors. In all regions, pediatric disease does appear to be associated with EBV infection.
Presentation and Evaluation
The most common symptom of NPC at presentation is a painless neck mass, which occurs in 70% to 90% of patients. These tumors can also cause symptoms at their site of origin that include nasal obstruction, epistaxis, and secondary eustachian tube dysfunction, which may lead to conductive hearing loss and serous otitis media. The initial evaluation of the patient should involve a thorough physical examination with careful attention to the cranial nerve examination because local invasion of the skull base places cranial nerves at risk. Manifestations may include ocular symptoms (pain, vision changes), orbital displacement, difficulty swallowing, voice changes, shoulder weakness, taste disturbances, and spasms of masticatory muscles. Associated otalgia, headaches, facial pain, and neck pain are also common. Advanced or systemic disease may be manifested by metastases to the lungs, bone, bone marrow, liver, and mediastinum.
The duration of symptoms at the time of presentation ranges from 1 month to 2 years, with a median time of 5 months. Patients with distant metastases may have related pain or organ dysfunction. Those with systemic disease may present with paraneoplastic syndromes such as hypertrophic osteoarthropathy, dermatomyositis, or syndrome of inappropriate antidiuretic hormone. Imaging with CT with contrast and MRI should be obtained to visualize the primary tumor and to evaluate skull base involvement and cervical lymphadenopathy. For the evaluation of distant disease, CT of the chest and abdomen, bone scans, and liver ultrasound are useful.
Biopsy is required to obtain a tissue diagnosis, considering the differential diagnoses of rhabdomyosarcoma, NHL, angiofibroma, and esthesioneuroblastoma. Patients with advanced disease should undergo a bone marrow biopsy coordinated with the biopsy of the primary lesion if feasible. In those cases with suspected or known skull base involvement, CSF should be sent for cytologic analysis. Recommended laboratory work includes a CBC, liver function tests, serum chemistry, and lactic acid dehydrogenase (LDH) levels; LDH levels greater than 500 IU/mL correspond with a poor prognosis. Staging follows the tumor-node-metastasis (TNM) classification structure, with special definitions for tumor stage based on anatomic location ( Table 21-7 ). More than 80% of children present with locoregionally advanced disease (stage IV), occasionally with detectable distant metastases.