Overview of non-Hodgkin lymphoma in children and adolescents

INTRODUCTION — Non-Hodgkin lymphoma (NHL) consists of a diverse group of malignant neoplasms of the lymphoid tissues variously derived from B cell progenitors, T cell progenitors, mature B cells, or mature T cells. Unlike in adults where low-grade, clinically indolent NHL subtypes predominate, most pediatric NHL cases are of high grade and have an aggressive clinical behavior [1]. Whenever possible, children with NHL should be treated in a comprehensive pediatric oncology center by a multidisciplinary team experienced in the diagnosis and care of children with cancer.

This topic will provide an overview of NHL in children and adolescents, focusing on issues that are of interest to primary care providers. The pathobiology of NHL and its diagnosis and management in adults are presented separately, as is an overview of Hodgkin lymphoma in children and adolescents. (See "Classification of hematopoietic neoplasms" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Overview of Hodgkin lymphoma in children and adolescents".)

EPIDEMIOLOGY — NHL is the fifth most common diagnosis of pediatric cancer in children under the age of 15 years, and it accounts for approximately 7 percent of childhood cancers in the developed world [2]. In the United States, approximately 800 new cases of pediatric NHL are diagnosed annually with an incidence of 10 to 20 cases per million people per year [3-6]. This incidence appears to be increasing overall, largely thought to reflect a rise in NHL among adolescents. The median age at diagnosis is approximately 10 years, and the incidence increases with age [2]. Lymphomas are rare in infants (≤1 percent) and account for approximately 4, 14, 22, and 25 percent of neoplasms in children age 1 to 4, 5 to 9, 10 to 14, and 15 to 19 years, respectively. There is a male predominance, and White children are more commonly affected than African American children.

The incidence and distribution of specific NHL subtypes differs by population (eg, age, race) and geographical region. In general, the most common subtypes of pediatric NHL are derived from B cell progenitors. In the United States and other developed countries, the most common subtypes are Burkitt lymphoma, diffuse large B cell lymphoma, lymphoblastic T cell or B cell lymphoma, and anaplastic large cell lymphoma [6]. Other subtypes (eg, follicular lymphoma, marginal zone lymphoma) are less common, accounting for approximately 7 percent of pediatric NHL.

Both congenital and acquired immunodeficiency syndromes are associated with an increased risk of NHL. Congenital immunodeficiencies associated with NHL include common variable immunodeficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia, and X-linked lymphoproliferative syndrome. Congenital immunodeficiencies may impact treatment decisions. As an example, the use of diagnostic tests and therapy involving X-rays and ionizing radiation should be limited in children with ataxia telangiectasia to minimize the risk of somatic mutations and subsequent malignancy. Acquired immunodeficiencies include human immunodeficiency virus (HIV) and the use of immunosuppressive medications. Post-transplant lymphoproliferative disorders can follow solid organ and hematopoietic cell transplantation. (See 'Lymphoproliferative disease in the immune compromised patient' below and "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders" and "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Epidemiology' and "Ataxia-telangiectasia".)

CLINICAL PRESENTATION

Oncologic emergencies — Potential emergency complications of NHL may be present at the time of diagnosis and need to be considered during the initial workup and evaluation of a patient with suspected pediatric NHL. Prompt recognition and therapy are critical for these situations, which may be life-threatening or may interfere with and delay treatment of the underlying NHL.

These can include:

●Superior or inferior vena cava obstruction (see "Malignancy-related superior vena cava syndrome")

●Acute airway obstruction (see "Emergency evaluation of acute upper airway obstruction in children")

●Intestinal obstruction, intussusception (see "Intussusception in children")

●Spinal cord compression (see "Clinical features and diagnosis of neoplastic epidural spinal cord compression")

●Pericardial tamponade (see "Cardiac tamponade")

●Lymphomatous meningitis and/or CNS mass lesions (see "Secondary central nervous system lymphoma: Clinical features and diagnosis")

●Hyperuricemia and tumor lysis syndrome (see "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors")

●Ureteral obstruction, unilateral or bilateral hydronephrosis (see "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis")

●Venous thromboembolic disease (see "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis")

Patients with large mediastinal masses are at increased risk of respiratory or cardiac arrest during general anesthesia or heavy sedation. Patients who present with cardiorespiratory symptoms or radiographic evidence of tracheal obstruction are at greatest risk of perioperative respiratory morbidity.

Tumor lysis syndrome is an oncologic emergency that is caused by massive tumor cell lysis and the release of large amounts of potassium, phosphate, and uric acid into the systemic circulation. Deposition of uric acid and/or calcium phosphate crystals in the renal tubules can result in acute renal failure, which is usually anuric. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Tumor lysis syndrome: Prevention and treatment".)

Signs and symptoms — The clinical presentation of pediatric NHL varies depending upon the type of lymphoma and the areas of involvement. Symptoms develop quickly, usually over one to three weeks. NHL commonly presents as enlarging, non-tender lymphadenopathy or as symptoms due to the compression of surrounding structures, such as new onset wheezing, facial swelling, respiratory distress, asymmetrical tonsils, or acute abdominal pain. Hepatic and/or splenic enlargement may be present in patients with advanced stage NHL.

Central nervous system (CNS) involvement occurs in 6 percent of pediatric NHL with rates ranging from 8.8 percent in Burkitt lymphoma to <3 percent in diffuse large B cell lymphoma [7]. A significant minority of patients will have systemic complaints of fever, weight loss, or night sweats (ie, B symptoms). While certain clinical presentations are suggestive of specific NHL histologies, a definitive diagnosis requires a biopsy of involved tissue, as described below. (See 'Diagnosis' below.)

Laboratory features — Laboratory tests that may be abnormal in patients with newly diagnosed pediatric NHL are listed below. It is important to remember that the complete blood count (CBC) may be normal.

●Unexplained anemia, thrombocytopenia, or leukopenia – These changes in peripheral blood counts can be due to extensive bone marrow infiltration, hypersplenism from splenic involvement, or blood loss from gastrointestinal tract involvement. (See "Causes of anemia in patients with cancer" and "Anemia of chronic disease/anemia of inflammation".)

●Hyperuricemia – Patients with rapidly proliferating tumors, particularly Burkitt lymphoma or lymphoblastic lymphoma, may demonstrate manifestations of tumor lysis syndrome with elevated uric acid, potassium, and diminished renal function. Hyperuricemia and tumor lysis syndrome are more commonly seen in patients presenting with underlying renal failure, due to either renal infiltration with lymphoma, pre-existing renal disease, or coincident obstruction of the ureters secondary to NHL. (See "Asymptomatic hyperuricemia" and "Uric acid kidney diseases" and "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

●Elevated level of serum lactate dehydrogenase (LDH) – LDH elevation associated with NHL may be due to high tumor burden, extensive infiltration of the liver, or association with particular rapidly proliferative NHL such as Burkitt or lymphoblastic lymphoma. An elevated LDH, especially if greater than two to three times normal, is associated with a poorer prognosis [8].

Imaging studies — Initial imaging studies (eg, ultrasound, radiographs, computed tomography) are often performed as part of the evaluation of presenting symptoms (eg, abdominal pain). These may demonstrate masses and/or lymphadenopathy in the neck, chest, or abdomen. Pediatric NHL, unlike Hodgkin lymphoma, may involve non-contiguous areas. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Imaging'.)

In addition, routine staging of pediatric NHL should include contrast enhanced computerized tomographic (CT) imaging of the neck, chest, abdomen, and pelvis. This CT both serves to help determine disease stage at diagnosis and to provide a baseline study for comparison to determine response to treatment. Integrated positron emissions tomography (PET)/CT scanning is more sensitive and specific than CT in certain histologic subtypes of NHL, including the most common subtypes seen in children [9]. (See 'Staging' below.)

Imaging of the bones with plain films, CT, and/or magnetic resonance imaging (MRI) is not routinely performed in NHL, but is indicated in the presence of bone pain and/or suspicion of a pathologic fracture. Bone lesions in NHL are mostly osteolytic on plain films, in contrast to those in patients with Hodgkin lymphoma, which are predominantly osteoblastic. If there is suspicion of spinal cord compression, urgent MRI of the entire spinal column is indicated, since multiple sites may be involved. MRI (with and without gadolinium) of the head is also indicated for patients with neurologic symptoms or signs. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis".)

DIAGNOSIS — The diagnosis of NHL is based upon the pathologic evaluation of involved tissue, usually an abdominal mass, extranodal site, or lymph node, interpreted within the clinical context [10]. Subtypes of NHL are identified using histology, immunophenotype, and genetic studies. Pediatricians should promptly refer children and teenagers with a suspected NHL to a pediatric oncologist for evaluation and diagnosis. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Analysis of biopsy material'.)

Specific subtypes of NHL have unique clinical and pathologic features. As examples:

●Burkitt lymphoma – Burkitt lymphoma frequently presents with abdominal pain that mimics acute appendicitis or intussusception [6]. Rapidly growing lymphadenopathy in the head and neck region is also common. Less common sites of involvement are the testes, bone, skin, bone marrow, and central nervous system. Spontaneous tumor lysis syndrome is common. There is a male predominance and the peak age at presentation is four to six years old. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma".)

●Diffuse large B cell lymphoma – Diffuse large B cell lymphoma has a variable presentation in children [6]. Patients may present with a rapidly enlarging symptomatic mass, most usually nodal enlargement in the neck or abdomen, or, in the case of primary mediastinal large B cell lymphoma, the mediastinum, but may present as a mass lesion anywhere in the body. Spontaneous tumor lysis syndrome is uncommon. Incidence increases with age. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

●T cell lymphoblastic lymphoma – The most common presentation of T cell lymphoblastic lymphoma is that of peripheral lymphadenopathy, respiratory distress, wheezing, and superior vena cava syndrome from mediastinal involvement [6]. T cell lymphoblastic lymphoma is more common in males. The incidence is stable across all pediatric age groups with a median age of diagnosis of 12 years. Children diagnosed with lymphoblastic lymphoma whose bone marrow is more than 25 percent replaced by lymphoblasts are classified and treated as acute lymphoblastic leukemia. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

●Anaplastic large cell lymphoma – Anaplastic large cell lymphoma is a peripheral T cell lymphoma that typically presents as painless lymphadenopathy with or without skin or subcutaneous involvement. Fever and constitutional symptoms are frequent. The median age of presentation is also 12 years [11]. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

DIFFERENTIAL DIAGNOSIS — The presenting symptoms and signs of NHL in children and adolescents may be caused by a variety of diseases and the differential diagnosis includes other malignant, infectious, and inflammatory diseases. They include Hodgkin lymphoma, metastatic adenopathy from other primary tumors (eg, nasopharyngeal carcinoma, soft tissue sarcoma), appendicitis, intussusception, toxoplasmosis, typical and atypical mycobacterium infections, EBV infection, systemic lupus erythematosus, and disorders causing reactive hyperplasia of lymph nodes [12]. (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach" and "Peripheral lymphadenopathy in children: Etiology" and "Cervical lymphadenitis in children: Diagnostic approach and initial management" and "Evaluation of inguinal swelling in children" and "Causes of acute abdominal pain in children and adolescents".)

The diagnostic considerations in patients with mediastinal masses depend upon the anatomic compartment in which the mass is located (figure 1). In children, anterior mediastinal mass must be distinguished from normal thymus, which attains maximal size when the child reaches approximately 10 years of age. Computed tomography and/or other imaging studies may be necessary to make this distinction [13]. (See "Approach to the adult patient with a mediastinal mass".)

STAGING — A complete evaluation of patients with suspected NHL is mandatory before beginning treatment. The goal is to evaluate the extent of disease, which in turn determines the clinical and pathologic stage, treatment, and, to a great extent, prognosis. This evaluation should be undertaken at a comprehensive pediatric oncology center. The superior results of children with malignancies treated in pediatric oncology centers as opposed to community hospitals is well documented [14]. (See 'Imaging studies' above.)

In general, routine staging studies for pediatric NHL include:

●Contrast enhanced computerized tomographic (CT) imaging of the neck, chest, abdomen, and pelvis with or without integrated positron emission tomography (PET)

●Bilateral iliac crest bone marrow aspiration and biopsy

●Lumbar puncture for examination of cerebrospinal fluid

Using information gathered from these studies, pediatric NHL is staged according to the Murphy stage [15]:

●Stage I – Stage I disease involves a single tumor (extranodal) or single anatomic area (nodal), excluding the abdomen and mediastinum. Features of stage II to IV disease described below must be absent.

●Stage II – Stage II disease is designated by any of the following:

•Single extranodal area plus regional lymph nodes

•Two single extranodal tumors on the same side of the diaphragm with or without regional lymph nodes

•Primary gastrointestinal tumor (completely resected) with or without mesenteric lymph nodes

●Stage III – Stage III disease is designated by any one of the following:

•Primary intrathoracic (mediastinal, thymic, pleural) disease

•Two extranodal sites on opposite sides of the diaphragm

•Extensive primary intra-abdominal disease

•Two or more nodal areas on opposite sides of the diaphragm

•Any paraspinal or epidural tumors

●Stage IV – Any of the above with involvement of the bone marrow, central nervous system, or both

An international group of pediatric oncologists, pathologists, biologists, and radiologists proposed a new staging system, the International Pediatric NHL Staging System (IPNHLSS), which is a revision of the Murphy staging system [16]. The major differences between the Murphy and the IPNHLSS are the following:

Stage III now includes two extranodal areas irrespective of side of the diaphragm and single bone lesions with extranodal and/or nonregional nodal involvement. The consensus group acknowledged that more sensitive methods play a role in determining if there is bone marrow or cerebral spinal fluid involvement, but stage IV will still depend on standard (Murphy) definitions. They do ask that the data regarding techniques of determining disease status in those sites be recorded. The proposed staging system modifications need to be validated, and currently the Murphy staging is considered standard of care.

TREATMENT AND PROGNOSIS

Overview — Children with NHL should be treated in a comprehensive pediatric oncology center [17]. Optimal therapy involves a multidisciplinary approach from the time of diagnosis, incorporating the skills of pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, and social workers experienced in the diagnosis and care of children with cancer. Assignment of stage and treatment are best determined after the multidisciplinary team has examined the patient and reviewed the diagnostic images and staging study results. Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Many of such trials are only offered at comprehensive pediatric oncology centers. (See 'Clinical trials' below.)

Combination chemotherapy is the primary modality used for the treatment of pediatric NHL. Unlike in adults, radiation therapy is not commonly used. As described in more detail below, studies in children have demonstrated that radiation therapy does not appear to improve outcomes in early stage NHL or as prophylaxis of the CNS [18-21].

Most children and adolescents with NHL have a good prognosis with current therapy. Survival rates have improved dramatically over the past 40 years with modern treatment regimens resulting in estimated five-year survival rates of over 85 percent [2,22]. The preferred treatment regimen and expected outcome varies by histological subtype and stage. Outcomes are excellent (>90 percent survival) for stage I or II pediatric NHL, regardless of histology. Stage III or IV pediatric NHL has long-term survival rates of 80 to 90 percent.

The anti-CD20 monoclonal antibody, rituximab, is approved by the US Food and Drug Administration (FDA) for pediatric patients ≥6 months with previously untreated, advanced stage, CD20-positive diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma (BL), BL-like lymphoma, or mature B cell acute leukemia in combination with chemotherapy.

Acute toxicities — Acute effects of treatment for pediatric NHL depend upon the specific chemotherapeutic agents used.

Myelosuppression is the most common dose-limiting acute toxicity of multiagent chemotherapy and can be treated with transfusions (red cells and platelets) or the administration of colony-stimulating factors (eg, granulocyte colony-stimulating factor). Blood products, if given, need to be irradiated to prevent development of fatal transfusion-associated graft-versus-host disease in these immunocompromised subjects. (See "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Irradiated red blood cells' and "Transfusion-associated graft-versus-host disease".)

Chemotherapy-induced neutropenia and immunosuppression increase the risk of life-threatening infections with viruses, bacteria, and fungi, which need to be treated quickly and appropriately. (See "Fever in children with chemotherapy-induced neutropenia", section on 'Prompt initiation of antimicrobial therapy'.)

The cellular immune system, including decreased T cell and NK cell function, may be impaired at baseline and further compromised by myelosuppression, increasing the susceptibility to herpes zoster and varicella infections. Post-exposure prophylaxis can be used to prevent development of varicella infection in children who did not receive the varicella vaccine before undergoing chemotherapy. Antiviral therapy should be promptly initiated in patients who develop varicella infection or varicella zoster. (See "Post-exposure prophylaxis against varicella-zoster virus infection" and "Treatment of herpes zoster".)

Children who receive multiple chemotherapeutic agents for the treatment of NHL may develop nausea and vomiting. These effects can be modulated with serotonin receptor antagonist anti-emetics and/or pretreatment with benzodiazepines. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)

Other acute effects are related to particular agents. As examples, vincristine is associated with neurotoxicity, and doxorubicin with cardiac toxicity. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Vincristine' and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Lymphoblastic lymphoma — Children with lymphoblastic lymphoma should be enrolled in a clinical trial, whenever possible. Almost all patients with lymphoblastic lymphoma are eligible to enroll on trials for patients with acute lymphoblastic leukemia. The preferred treatment modality for pediatric lymphoblastic lymphoma is combination chemotherapy based on regimens used for acute lymphoblastic leukemia (ALL). With this approach, children with early stage (I or II) or advanced stage (III or IV) lymphoblastic lymphoma achieve survival rates of >90 and >80 percent, respectively. The role of surgery is limited to surgical biopsy of a peripheral lymph node, a bone marrow aspiration, or aspiration of pleural fluid to establish the diagnosis. There is no role for surgical debulking of disease due to the high sensitivity of the tumor to chemotherapy. Likewise, there is no routine need for radiation therapy [23]. Radiation is generally reserved for patients with pathologically proven involvement of the central nervous system (CNS) at the time of diagnosis. Testicular involvement at diagnosis does not require testicular radiation.

Initial support for the use of ALL protocols in patients with lymphoblastic lymphoma was based upon the significant biological and clinical overlap between these two entities. Indeed, the WHO classification system considers these entities to be the same disease with different clinical presentations [10]. Initial prospective trials demonstrated the efficacy of ALL protocols in patients with lymphoblastic lymphoma. Subsequent trials demonstrated that good outcomes can be maintained while decreasing the intensity of treatment. As examples:

●In the NHL-BFM-90 trial, 105 children with T cell lymphoblastic lymphoma received an eight-drug ALL induction regimen followed by consolidation therapy that included high dose methotrexate and maintenance therapy for a total treatment duration of two years [24]. Patients with stage III or IV disease also received prophylactic cranial irradiation, but no involved-field radiation. With a median follow-up of 4.5 years, estimated survival at five years was 90 percent.

●In the St. Jude NHL13 study, 41 children with advanced-stage lymphoblastic lymphoma were treated with a regimen used for T cell ALL that featured intensive intrathecal chemotherapy rather than prophylactic cranial irradiation [20]. With a median follow-up of 9.3 years, the estimated five-year survival rate was 90 percent.

●In the COG-A5971 trial, 60 children with stage I or II lymphoblastic lymphoma (75 percent B cell) were treated with a similar two-year ALL regimen without prophylactic cranial radiation [25]. At a median follow-up of 5.9 years, the estimated survival at five years was 96 percent. For children and adolescents with stage III/IV disease without CNS involvement, the A5971 protocol produced a five-year event-free survival rate of 81 percent with intensification and backbone therapy not significantly impacting the outcome. Effective CNS prophylaxis occurred with either intensive intrathecal chemotherapy or with high dose methotrexate during interim maintenance and no intrathecal therapy during the maintenance phase. The study demonstrated a CNS relapse incidence of 1.2 percent at five years. In contrast, this same trial reported that the 12 children with disseminated CNS disease at the time of diagnosis had estimated event-free survival, overall survival, and relapse rates of 63, 81, and 25 percent at five years, respectively [26].

Together, these and other trials demonstrate that treatment based upon protocols for ALL produce excellent survival rates among children with lymphoblastic lymphoma. Prophylactic cranial irradiation adds toxicity and can be eliminated for the vast majority of patients. For patients with disseminated T cell disease without CNS involvement at diagnosis, there appears to be no benefit to extra intensification of therapy during the induction or delayed intensification phases, and no benefit to using high dose methotrexate during interim maintenance [26].

Patients who relapse do poorly due to difficulty obtaining a second remission. For patients who do obtain a second remission, allogeneic hematopoietic cell transplantation is the treatment of choice [27].

Anaplastic large cell lymphoma — Children with anaplastic large cell lymphoma should be enrolled in a clinical trial, whenever possible. The preferred treatment modality is combination chemotherapy. The role of surgery is limited to surgical biopsy to establish the diagnosis. Radiation is rarely used. Central nervous system involvement is very rare.

Oncologists in the United States historically used prolonged intermittent therapy with vincristine, an anthracycline, and steroids [28]. In Europe, a more intense infusional therapy has been administered over six months [29,30]. Both approaches produced a 65 to 75 percent five-year event-free survival [28-30].

Patients with recurrent disease may obtain prolonged remission following the administration of single agent vinblastine [31,32]. In contrast, vinblastine does not appear to improve outcomes when used instead of vincristine as initial therapy or as maintenance therapy and is associated with increased hematologic toxicity [29,33]. Autologous and allogeneic hematopoietic cell transplantation (HCT) can also produce prolonged remissions in relapsed patients [27,34-36]. When compared with allogeneic HCT, autologous HCT is associated with a higher risk of recurrence [27]. However, it is unclear whether the lower rate of relapse with allogeneic HCT translates into a survival benefit.

Two targeted therapies have demonstrated significant initial activity in relapsed anaplastic large cell lymphoma:

●Brentuximab vedotin is an immunotoxin with a CD30-directed antibody linked to the antitubulin agent monomethyl auristatin E [37]. Brentuximab vedotin is approved by the US Food and Drug Administration for the treatment of adults with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen [38]. (See "Treatment of relapsed or refractory peripheral T cell lymphoma", section on 'Brentuximab'.)

●Crizotinib is a small molecule inhibitor of the ALK tyrosine kinase that has demonstrated activity in a subset of patients with non-small cell lung cancer. Case reports and a phase I study have described responses in patients with multiply relapsed ALK positive anaplastic large cell lymphoma [39-41]. Further studies of this agent in ALK positive anaplastic large cell lymphoma are underway.

The use of these targeted therapies in children with newly diagnosed stage II-IV anaplastic large cell lymphoma is being evaluated in a Children's Oncology Group randomized phase II trial (NCT01979536) using six months infusional chemotherapy combined with either brentuximab vedotin or crizotinib. Outcomes for each arm will be compared with historical outcomes from the ALCL99 trial [29].

Burkitt lymphoma — The mainstay of therapy for Burkitt lymphoma (BL) is chemoimmunotherapy. There is no role for routine inclusion of radiation therapy (RT) or surgical debulking in the treatment of BL. We encourage enrollment in a clinical trial, whenever possible.

The malignant cells of BL are exquisitely sensitive to chemoimmunotherapy. Although the preferred multi-agent chemotherapy regimen varies by institution, rituximab (anti-CD20 monoclonal antibody) should be incorporated into the regimen. The duration of treatment may range from six weeks to eight months, depending on the stage of disease. With this approach, children with completely resected early stage (I or II) Burkitt lymphoma have an estimated 98 percent four-year event-free survival (EFS) and 99 percent four-year overall survival (OS) [42]. Children with unresected early stage or advanced stage (III) disease that does not involve the CNS or bone marrow have estimated four-year EFS and OS >90 percent [43]. Patients presenting with stage IV disease, especially those with CNS involvement, have inferior outcomes [44].

Compared to multi-agent chemotherapy alone, addition of rituximab to the same chemotherapy regimen (ie, chemoimmunotherapy) achieves superior outcomes in patients with advanced stage disease (ie, stage III with elevated lactate dehydrogenase or stage IV). An international trial randomly assigned 328 children (6 months to 18 years old) with high-grade, high-risk mature B cell NHL (86 percent with Burkitt lymphoma) to multi-agent chemotherapy, without or with rituximab (375 mg/m² on day -2 and day 1 of each induction course and on day 1 of two consolidation courses) [45]. Randomization was stopped early after interim analysis of the first 310 patients (11.5 month median follow-up) indicated superior efficacy for the chemoimmunotherapy regimen. The primary end-point of the trial was EFS (ie, primary refractory disease, relapse, progressive disease, second cancer, or death from any cause). After median follow-up of 40 months, three-year EFS with chemoimmunotherapy (93.9 percent; 95% CI 89.1-96.7) was superior to chemotherapy alone (82.3 percent, 95% CI 75.7-87.5); the hazard ratio (HR) for an event was 0.32 (95% CI 0.15-0.66). Chemoimmunotherapy also achieved superior three-year OS (95.1 versus 87.3 percent; HR for death, 0.36; 95% CI 0.16-0.82). Rituximab infusion-related reactions occurred with the first infusion in 33 percent (4 percent grade 3) but subsequently in <10 percent (2 percent grade 3). More children treated with rituximab had hypogammaglobulinemia (70 versus 47 percent) and required immunoglobulin infusion, and there were more episodes of grade ≥4 febrile neutropenia and infections in patients treated with rituximab, but the differences were not statistically different.

BL is often encountered during surgery for acute abdominal symptoms or during a tonsillectomy. If the surgeon can remove the tumor entirely, it is appropriate to do so, but otherwise, there is no role for surgical debulking of BL.

Among children with BL, relapses typically occur within the first two years and are clinically aggressive. The outcome of children with relapsed BL is poor, usually due to failure to achieve a second remission. Rituximab plus ICE (ifosfamide, carboplatin, and etoposide) was effective in a small study of children with relapsed mature B cell lymphoma [46]. Both autologous and allogeneic hematopoietic cell transplantation play a role in salvage therapy for the patient who has chemotherapy sensitive disease following relapse [27].

Diffuse large B cell lymphoma — Children with diffuse large B cell lymphoma (DLBCL) should be enrolled in a clinical trial whenever possible. Children with DLBCL are treated with regimens used for Burkitt lymphoma. This differs from the management of DLBCL in adults where patients with DLBCL and patients with Burkitt lymphoma are treated with different regimens.

Older adolescents with DLBCL may be treated with pediatric regimens or with adult regimens. However, the standard adult regimen R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) would expose the patient to higher doses of anthracycline than used in pediatric Burkitt lymphoma protocols. In one study, gene expression profiles were able to distinguish pediatric DLBCL from pediatric Burkitt lymphoma, but also identified minor differences between pediatric DLBCL and adult DLBCL [47]. These results suggest the pediatric and adult cases have distinct pathogenetic mechanisms. (See 'Burkitt lymphoma' above and "Initial treatment of advanced stage diffuse large B cell lymphoma" and "Initial treatment of limited stage diffuse large B cell lymphoma".)

Rare pediatric NHL variants — As described above, the most common subtypes of pediatric NHL are Burkitt lymphoma, diffuse large B cell lymphoma, lymphoblastic T cell or B cell lymphoma, and anaplastic large cell lymphoma [6]. Other subtypes (eg, follicular lymphoma, marginal zone lymphoma) are less common, accounting for approximately 7 percent of pediatric NHL.

Primary mediastinal B cell lymphoma is a mature B cell neoplasm presenting in the mediastinum that is morphologically, genetically, and biologically different from other mature B cell neoplasms seen in pediatric patients [10,48-50]. It is most common in adolescent patients, particularly women. In adults, R-EPOCH (rituximab plus dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) resulted in estimated five-year event-free survival of 93 percent and five-year overall survival of 97 percent [51]. A phase 2 study of dose-adjusted R-EPOCH was embedded in an international B cell clinical trial for adolescents with primary mediastinal B cell lymphoma (NCT01516567); results are not yet available [52]. The use of radiation therapy in this disease remains controversial. (See "Primary mediastinal large B cell lymphoma", section on 'Chemoimmunotherapy'.)

A retrospective multi-institution analysis of pediatric and adult patients receiving dose-adjusted R-EPOCH for primary mediastinal B cell lymphoma reported a three-year event-free survival of 86 percent and overall survival of 95 percent [53]. A negative PET scan (Deauville score 1 through 3) at the end of therapy was associated with improved event-free survival (95 versus 55 percent for Deauville 4/5).

Follicular lymphoma, marginal zone lymphoma, and peripheral T cell lymphomas also occur in pediatric patients. Therapy is often based on treatment literature in adults. Of note, follicular lymphoma and marginal zone lymphomas in pediatrics often demonstrate better outcomes than their adult counterparts. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Pediatric-type FL' and "Initial treatment of stage I follicular lymphoma" and "Initial treatment of stage II to IV follicular lymphoma" and "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)" and "Initial treatment of peripheral T cell lymphoma".)

SPECIAL POPULATIONS

Lymphoproliferative disease in the immune compromised patient — The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The cause of such immune deficiencies may be a genetically inherited defect [54], secondary to human immunodeficiency virus (HIV) infection [55], or iatrogenic following transplantation (solid organ transplantation or allogeneic hematopoietic cell transplantation [HCT]) [56]. Epstein-Barr virus (EBV) is associated with most of these tumors, but some tumors are not associated with any infectious agent. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)

NHL observed in primary immunodeficiency usually shows a mature B cell phenotype and large cell histology [54]. Children with primary immunodeficiency and NHL are more likely to have high-stage disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and central nervous system. Patients with primary immunodeficiency often require allogeneic HCT to restore sufficient immunity to prevent recurrences. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

NHL is an AIDS-defining malignancy. A key component of the treatment of all HIV-infected patients with an AIDS-related NHL is the administration of antiretroviral therapy (ART). The reduction in HIV viral load and improvement in immune function associated with ART is expected to result in better tolerance of chemotherapy, fewer opportunistic infections, and improvement in overall treatment outcome. As such, children with HIV and NHL should be treated with standard chemotherapy regimens for NHL, but careful attention to prophylaxis against and early detection of infection is warranted. The treatment of AIDS-related lymphomas in adults is presented separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma".)

Post-transplant lymphoproliferative disease (PTLD) represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations, ranging from disease that looks like a normal reactive process to disease that looks like NHL. Essentially all PTLD following HCT is associated with EBV, but EBV-negative PTLD can be seen following solid organ transplant. In PTLD, first-line therapy is the reduction of immunosuppression. Low-dose chemotherapy or rituximab, an anti-CD20 antibody, have been used with some success where reduction of immunosuppression has failed to cure the disease. EBV-specific T cell therapies for PTLD are under investigation [57]. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Adolescent and young adult NHL — NHL diagnosed in adolescent and young adults (AYA) includes a higher percentage of subtypes typically seen in adulthood. The most common NHL in AYA is diffuse large B cell lymphoma, followed by follicular lymphoma, Burkitt lymphoma, lymphoblastic lymphoma and then mycosis fungoides [58,59]. There is a paucity of data regarding the preferred treatment regimens for AYA with NHL. Older adolescents may be treated with pediatric regimens or with adult regimens.

FOLLOW-UP — After completion of the initially planned therapy, patients should be evaluated to determine the disease response to treatment and should be followed longitudinally for relapse.

Assessing treatment response — Patients are evaluated after the completion of therapy to determine disease response. The choice of imaging modality depends at least partially upon the sites originally involved. Computed tomography (CT) and magnetic resonance imaging (MRI) can provide an assessment of mass size alone, while positron emission tomography (PET) can provide information regarding the metabolic activity of residual masses. MRI is preferred for the evaluation of central nervous system (CNS) disease and bone marrow, while CT is preferred for assessing the lungs. All patients should have pathologic evaluation of their cerebrospinal fluid (CSF) and bone marrow as part of the disease response assessment.

The goal of therapy is achievement of a complete response (CR) as defined by the disappearance of all disease. The proposed international pediatric NHL response criteria subclassify CR into one of three types, depending upon the degree of investigation [60]:

●CR – This designation may be used for patients in whom CT or MRI reveals no residual disease or new lesions and for patients in whom residual masses have been completely excised and found to be pathologically negative for disease. In each of these cases, bone marrow and CSF must be morphologically free of disease.

●CR, biopsy negative – This designation may be used for patients with no new disease in whom limited or core biopsy of a residual mass reveals no morphologic evidence of disease and in whom the bone marrow and CSF are morphologically free of disease. In such cases, it is possible that a sampling error missed residual disease.

●CR, unconfirmed – This designation may be used for patients with no new disease in whom a residual mass has not been biopsied but is negative on PET/CT scan. Bone marrow and CSF must be morphologically free of disease. This designation acknowledges the paucity of data regarding the negative predictive value of PET/CT scan in pediatric NHL.

The International Pediatric NHL Staging System (IPNHLSS) proposed definitions will need to be validated in clinical trials. Until then, patients who have no evidence of residual disease upon restaging are seen at periodic intervals to monitor for relapse. Residual masses should be biopsied to distinguish between residual disease and other masses (eg, fibrosis, thymus). Relapsed disease can be suggested by changes on imaging studies but can only be confirmed by biopsy. As such, a biopsy should always be obtained to document relapsed disease before proceeding to salvage therapy.

In a prospective study, 34 children with nonlymphoblastic NHL underwent imaging with PET/CT and conventional contrast material-enhanced CT at baseline, after two cycles of chemotherapy, and after completion of chemotherapy [61]. Baseline PET/CT and conventional CT were concordant in 112 disease sites, while PET/CT depicted 18 more disease sites and two fewer disease sites resulting in disease upstaging in five patients, but no change in treatment. There was 100 percent concordance regarding bone marrow involvement between PET/CT and bone marrow biopsy. Interim imaging did not predict progression-free or overall survival. Both post-treatment PET/CT and CT could predict progression-free survival, but only post-treatment contrast-enhanced CT could predict overall survival.

A discussion of the accuracy of PET/CT in the follow-up of adults with lymphoma is presented separately. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)

Long-term toxicities — Survivors of childhood cancer are at increased risk for long-term sequelae. Late adverse effects are primarily dependent upon the type and intensity of therapy. Patients who received more intense chemotherapy are more likely to have late complications. The late effects consist primarily of those related to anthracycline and alkylating toxicity. Radiation therapy plays a limited role in treatment, thus most patients do not face the long-term effects of radiation.

The late effects of treatment for pediatric NHL are primarily related to anthracycline and alkylating agent exposure, and include an increased incidence of infertility, second cancers, and congestive heart failure. Patients with lymphoblastic lymphoma receive treatment similar to children with acute lymphoblastic leukemia. Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group, and are available at www.survivorshipguidelines.org.

A subset of patients is treated with hematopoietic cell transplantation. These therapies place NHL survivors at risk for the development of a diverse array of long-term sequelae, with the potential to negatively impact both their quality of life and ultimately their survival. (See "Long-term care of the adult hematopoietic cell transplantation survivor".)

CLINICAL TRIALS — All children with NHL should be considered for entry into a clinical trial. Trials are designed to compare potentially better therapy with that which is currently accepted as standard. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

SUMMARY AND RECOMMENDATIONS

●Non-Hodgkin lymphoma (NHL) consists of a diverse group of malignant neoplasms of the lymphoid tissues variously derived from B cell progenitors, T cell progenitors, mature B cells, or mature T cells. Unlike in adults where low-grade, clinically indolent NHL subtypes predominate, most pediatric NHL cases are of high-grade and have an aggressive clinical behavior. (See 'Epidemiology' above.)

●The clinical presentation of pediatric NHL varies depending upon the type of lymphoma and the areas of involvement. Signs and symptoms develop quickly, usually over a few weeks to months. NHL commonly presents as enlarging, non-tender lymphadenopathy or as symptoms due to the compression of surrounding structures, such as new onset wheezing, facial swelling, respiratory distress, asymmetrical tonsils, or acute abdominal pain. (See 'Signs and symptoms' above.)

●Potential emergency complications of NHL may be present at the time of diagnosis and need to be considered during the initial workup and evaluation of a patient with suspected pediatric NHL. These may be life-threatening and include but are not limited to superior vena cava obstruction, acute airway obstruction, and tumor lysis syndrome. Prompt recognition and therapy are critical. (See 'Oncologic emergencies' above.)

●Pediatricians should promptly refer children and teenagers with a suspected NHL to a pediatric oncologist for evaluation and diagnosis. The diagnosis of NHL is based upon the pathologic evaluation of involved tissue, usually an abdominal mass, extranodal site, or lymph node, interpreted within the clinical context. Subtypes of NHL are identified using histology, immunophenotype, and genetic studies. (See 'Diagnosis' above.)

●Combination chemotherapy is the primary modality used for the treatment of pediatric NHL. The role of surgery is limited to surgical biopsy of a peripheral lymph node, a bone marrow aspiration, or aspiration of pleural fluid to establish the diagnosis. Unlike in adults, radiation therapy is not commonly used. (See 'Overview' above.)

●For children and adolescents with stage III disease and an elevated lactate dehydrogenase level or stage IV Burkitt lymphoma, we recommend chemoimmunotherapy (multi-agent chemotherapy plus rituximab) rather than chemotherapy alone (Grade 1B), based on superior event-free survival and overall survival with modest incremental toxicity that did not outweigh the benefits. (See 'Burkitt lymphoma' above.)

●Most children and adolescents with NHL have a good prognosis with current therapy. Long-term overall survival is achieved in >80 percent of pediatric NHL cases overall, and in >90 percent of stage I or II pediatric NHL. (See 'Overview' above.)

●Survivors of childhood cancer are at increased risk for long-term sequelae. Late adverse effects are primarily dependent upon the type and intensity of therapy. The late effects of treatment for pediatric NHL consist primarily of those related to anthracycline and alkylating agent exposure. Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group, and are available at www.survivorshipguidelines.org. (See 'Long-term toxicities' above.)