Overview of non-Hodgkin lymphoma in children and adolescents

INTRODUCTION — 

Non-Hodgkin lymphoma (NHL) refers to a diverse group of lymphoid malignancies with varied clinical presentations. The malignant cells of NHL can be derived from B cell progenitors, T cell progenitors, mature B cells, or mature T cells.

Most cases of pediatric NHL exhibit high-grade pathology and aggressive clinical behavior, in contrast to NHL in adults, where low-grade, clinically indolent NHL subtypes are common. Management of pediatric NHL varies according to the lymphoma subtype, disease stage, and other clinical and prognostic features.

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 provides an overview of NHL in children and adolescents.

Related topics include:

●(See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

●(See "Overview of Hodgkin lymphoma in children and adolescents".)

●(See "Classification of hematopoietic neoplasms".)

EPIDEMIOLOGY — 

NHL is the fifth most common diagnosis of pediatric cancer in children <15 years.

NHL accounts for approximately 7 percent of childhood cancers in resource-abundant countries [1]. 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 [2-5]. The incidence appears to be increasing overall, reflecting a rise in NHL among adolescents.

The median age at diagnosis is 10 years, and the incidence increases with age [1]. Lymphomas are rare in infants (≤1 percent of cancers), accounting for approximately 4, 14, 22, and 25 percent of neoplasms in children 1 to 4 years, 5 to 9 years, 10 to 14 years, 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 differ by population and geographical region. Generally, the most common subtypes of pediatric NHL are derived from B cell progenitors. The most common subtypes in resource-abundant countries are Burkitt lymphoma, diffuse large B cell lymphoma, lymphoblastic T cell or B cell lymphoma, and anaplastic large cell lymphoma [5]. Other subtypes (eg, follicular lymphoma, marginal zone lymphoma) are less common, accounting for approximately 7 percent of pediatric NHL.

The risk for the development of NHL is increased in children with congenital and acquired immunodeficiency syndromes (AIDS), as discussed below. (See 'Lymphoproliferative disease in the immunocompromised patient' below.)

CLINICAL PRESENTATION

Oncologic emergencies — Emergency complications may be present at diagnosis and should be considered during the initial workup and evaluation of a child with suspected pediatric NHL. Oncologic emergencies may be life threatening or they can interfere with or delay treatment of the underlying NHL. Prompt recognition and management are critical for these situations.

As an example, large mediastinal masses at presentation increase the risk of respiratory or cardiac arrest during general anesthesia or heavy sedation and increase the risk of perioperative morbidity. Potential oncologic emergencies and their management are discussed separately:

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

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

●Cardiac tamponade (see "Cardiac tamponade")

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

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

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

●Hyperuricemia and tumor lysis syndrome (TLS) (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")

Clinical manifestations — The clinical presentation of pediatric NHL varies with the type of lymphoma and sites of involvement.

Symptoms generally develop over one to three weeks. Common presentations include enlarging, nontender lymphadenopathy, or symptoms due to compression of surrounding structures (eg, wheezing, facial swelling, respiratory distress, asymmetrical tonsils, acute abdominal pain).

Some patients have unexplained fever, weight loss, or night sweats (ie, "B symptoms"). Thromboemboli and metabolic complications (eg, TLS) can occur, and liver and/or spleen enlargement may be seen in patients with advanced NHL. CNS involvement occurs in 6 percent of pediatric NHL, with rates ranging from 8.8 percent in Burkitt lymphoma (BL) to <3 percent in diffuse large B cell lymphoma [6].

While certain clinical presentations may suggest specific types of NHL, diagnosis requires a biopsy of involved tissue, as described below. (See 'Diagnosis' below.)

Laboratory findings — Laboratory tests are often abnormal at presentation.

●Hematology – Blood counts may be normal. However, unexplained anemia, thrombocytopenia, or leukopenia can be caused by 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 – Elevated uric acid, potassium, and diminished kidney function are most often seen with rapidly proliferating tumors, such as BL or lymphoblastic lymphoma (LBL).

Hyperuricemia and/or TLS may be exacerbated by underlying kidney dysfunction 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 lactate dehydrogenase (LDH) – Serum LDH may be elevated in patients with a high tumor burden and/or extensive infiltration of the liver, especially with BL, LBL, or other rapidly proliferative tumors. Elevated LDH (especially if >2 to 3 times normal) is associated with an adverse prognosis [7].

Imaging — Imaging is important for evaluating findings at presentation and is required for disease staging.

●Initial evaluation – Ultrasonography, radiographs, and/or computed tomography (CT) are often used to evaluate presenting symptoms, such as enlarged lymph nodes, respiratory symptoms, or abdominal pain. These studies may demonstrate masses and/or lymphadenopathy in the neck, chest, or abdomen. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Imaging'.)

Evaluation of bone pain may involve imaging with bone radiography, CT, and/or magnetic resonance imaging (MRI). Bone lesions in NHL are mostly osteolytic on plain films, in contrast to predominantly osteoblastic bone lesions associated with Hodgkin lymphoma.

Imaging is important for investigating neurologic abnormalities. Brain MRI, with and without gadolinium, may identify CNS abnormalities in children with neurologic symptoms or signs. If spinal cord compression is suspected, urgent MRI of the entire spinal column should be performed, since there may be multiple sites of involvement. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis".)

●Staging – Integrated positron emission tomography/CT is more sensitive and specific than CT alone and is used to stage the most common NHL subtypes in children [8].

Contrast-enhanced CT of the neck, chest, abdomen, and pelvis is often used to define the initial disease stage and to provide a baseline for treatment response. (See 'Staging' below.)

DIAGNOSIS AND STAGING

Diagnosis — NHL should be suspected in a child or adolescent with unexplained lymphadenopathy, an abdominal or other mass, or constitutional symptoms. Pediatricians and other clinicians should promptly refer a patient with a suspected NHL to a pediatric oncologist for evaluation and diagnosis.

Diagnosis of NHL requires pathologic evaluation of involved tissue (eg, lymph node, abdominal mass, extranodal site) interpreted within the clinical context. NHL subtypes are defined by histology, immunophenotype, and genetic studies. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Analysis of biopsy material'.)

Diagnosis and classification should be based on either the International Consensus Classification (ICC) of Mature Lymphoid Neoplasms [9] or the World Health Organization 5^th edition (WHO5) [10]. Either system is acceptable, and they have superseded earlier diagnosis and classification schemes. (See "Classification of hematopoietic neoplasms", section on 'Lymphoid neoplasms'.)

The most common subtypes of NHL have distinctive clinical and pathologic features, as discussed in greater detail below. (See 'Management' below.)

Differential diagnosis — Various malignant, infectious, and inflammatory diseases can present with findings that resemble those of pediatric NHL. Disorders in the differential diagnosis of pediatric NHL must be distinguished by clinical evaluation, imaging, and/or biopsy.

Examples of disorders that must be distinguished from NHL include Hodgkin lymphoma, adenopathy from other primary tumors (eg, nasopharyngeal carcinoma, soft tissue sarcoma), appendicitis, intussusception, toxoplasmosis, mycobacterial infections, EBV infection, systemic lupus erythematosus, and reactive hyperplasia of lymph nodes. Note that a lymphoma-associated anterior mediastinal mass must be distinguished from normal thymus (which attains maximal size around age 10 years), and in contrast with Hodgkin lymphoma, NHL may manifest noncontiguous areas of involvement.

Specific conditions in the differential diagnosis are informed by the clinical presentation, as discussed in separate topics:

●(See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach".)

●(See "Causes of acute abdominal pain in children and adolescents".)

●(See "Evaluation of inguinal swelling in children".)

●(See "Acute respiratory distress in children: Emergency evaluation and initial stabilization".)

●(See "Approach to the adult patient with a mediastinal mass".)

Staging

Studies — Staging of NHL involves clinical evaluation, laboratory studies, and imaging. When possible, the staging evaluation should be undertaken at a comprehensive pediatric oncology center.

Routine staging studies for pediatric NHL include:

●Integrated positron emission tomography (PET)/CT, with or without contrast-enhanced CT of the neck, chest, abdomen, and pelvis

●Bilateral iliac crest bone marrow aspiration and biopsy

●Lumbar puncture for examination of cerebrospinal fluid

●Brain MRI for patients with Burkitt lymphoma

Murphy staging system — Pediatric NHL is staged according to the Murphy staging system [11], as follows:

●Stage I – A single nodal area or a single extranodal tumor, excluding the abdomen and mediastinum.

Features of stage II to IV disease described below must be absent.

●Stage II – Any of the following:

•A 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 – Any 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 bone marrow, central nervous system, or both.

Some experts use the International Pediatric NHL Staging System (IPNHLSS) [12], a revision of the Murphy staging system that was developed by pediatric oncologists, pathologists, biologists, and radiologists. We await validation of the IPNHLSS before routinely implementing it for treatment outside of the context of a clinical trial.

OVERVIEW OF TREATMENT — 

For most children with NHL, we suggest systemic therapy alone, rather than systemic therapy combined with surgery or radiation therapy (RT).

Surgery is generally limited to diagnostic studies or the management of oncologic emergencies. RT is not commonly used because of short-term and long-term toxicity in growing children.

The components of the treatment regimen influence the early and late adverse effects (AEs) of treatment. The prognosis is generally good, with long-term survival >80 to >90 percent for most subtypes of pediatric NHL.

●Site of treatment – Whenever possible, we encourage treatment of pediatric NHL in a clinical trial, many of which are only offered at comprehensive pediatric oncology centers. (See 'Clinical trials' below.)

Optimal management 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 who are experienced in the diagnosis and care of children with cancer.

Assignment of disease stage and the treatment of NHL are best determined after the multidisciplinary team has examined the patient and reviewed the diagnostic images and staging study results. If it is not possible to enroll the child in a clinical trial or to treat the patient in a comprehensive pediatric oncology center, treatment should adhere closely to a contemporary published treatment protocol.

●Treatment approaches

•Chemotherapy – Combination chemotherapy is the primary modality used for treating pediatric NHL. Preferred regimens vary according to disease, as described in the sections that follow. (See 'Management' below.)

•Immunotherapy – Immunotherapeutic agents may be given along with chemotherapy (ie, immunochemotherapy) or used alone to treat NHL.

For B cell lymphomas that express CD20, such as diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma (BL), BL-like lymphoma, or primary mediastinal B cell lymphoma (PMBCL), rituximab is used in combination with chemotherapy.

Other immunotherapeutic agents that are used to treat pediatric NHL include blinatumomab (a CD19 x CD3 bispecific antibody) for the treatment of B cell lymphoblastic lymphoma and brentuximab vedotin (a CD30-directed immunoconjugate) that can treat certain T cell lymphomas.

•Radiation therapy (RT) – RT is not commonly used to treat pediatric NHL.

RT may cause substantial toxicity, but it does not appear to improve outcomes in early-stage NHL or when used for central nervous system (CNS) prophylaxis in children, as discussed in the disease-specific sections below. (See 'Management' below.)

•Surgery – Surgery is rarely needed for the treatment of pediatric NHL except to obtain a diagnostic biopsy specimen or to manage certain disease-related complications. (See 'Oncologic emergencies' above.)

●Acute toxicities – Adverse effects (AEs) vary with the treatment protocol.

•Myelosuppression – Myelosuppression is the most common dose-limiting acute AE of multiagent chemotherapy. Cytopenias can be treated with transfusions (red blood cells or platelets) or administration of colony-stimulating factors (eg, granulocyte colony-stimulating factor). Blood products should be irradiated to prevent the development of potentially 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 must be treated quickly and appropriately. (See "Fever in children with chemotherapy-induced neutropenia", section on 'Prompt initiation of antimicrobial therapy'.)

Susceptibility to herpes zoster and varicella infections is increased because T cell and natural killer cell function may be impaired at baseline and further compromised by myelosuppression. Postexposure prophylaxis can be used to prevent the 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".)

•Other AEs – Nausea and vomiting are common in children who receive multiple chemotherapeutic agents. These effects can be modulated with serotonin receptor antagonist antiemetics and/or pretreatment with benzodiazepines. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)

Other acute AEs are associated with specific agents. For example, 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".)

●Late toxicities – The incidence, nature, and severity of late AEs are influenced by the disease, age, and type of treatment, as discussed below. (See 'Long-term toxicities' below.)

●Prognosis – Most children and adolescents with NHL have a good prognosis with current therapy. For many patients with pediatric NHL, treatment using a contemporary approach is associated with >80 or >90 percent five-year survival. Details of prognosis vary with the disease, stage, age, biomarkers, treatment, and other features, as described in the disease-specific sections below. (See 'Management' below.)

MANAGEMENT — 

Management is guided by the disease, stage, and age. We encourage enrollment in a clinical trial and management at a comprehensive pediatric oncology center.

Lymphoblastic lymphoma — Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) may be clinical manifestations of the same disease process (ALL/LBL). More than 80 percent of LBL cases are of T cell origin.

●Presentation – Presentation of LBL often differs according to the lineage of the malignant cells.

•T cell LBL commonly presents with respiratory distress, wheezing, or superior vena cava syndrome from mediastinal involvement, but the involvement of lymph nodes, spleen, bone marrow, and/or central nervous system (CNS) may be seen. T cell LBL is more common in males; the median age at diagnosis is 12 years, but the incidence is stable across all pediatric age groups. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

•B cell LBL commonly presents with lymphadenopathy.

●Management – The preferred treatment is combination chemotherapy according to a pediatric ALL/LBL regimen that includes treatment to prevent CNS relapse. Treatment is complex and prolonged, and it is stratified according to immunophenotype (T cell versus B cell) and cytogenetic/molecular features of the leukemic blasts, clinical features (eg, age, presenting leukocyte count), and response to initial therapy. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

Treatment of pediatric LBL should adhere closely to a contemporary published regimen. There is no need for surgical debulking of LBL because of its sensitivity to chemotherapy. Radiation therapy (RT) is not routinely used to treat mediastinal masses or testicular involvement. Intrathecal and/or systemic chemotherapy have replaced RT prophylaxis and its attendant toxicity for most patients with LBL; RT is generally reserved for patients with proven CNS involvement at diagnosis or relapse.

●Outcomes – Using contemporary approaches to management, children with early-stage (I or II) or advanced-stage (III or IV) LBL achieve long-term survival rates of >90 and >80 percent, respectively.

For example, adding bortezomib to the chemotherapy backbone achieved superior overall survival (OS) and event-free survival (EFS) in the AALL1231 trial of T cell LBL [13].

●Relapse – It is difficult to achieve a second remission in most children who relapse with T cell LBL, but allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice in children who respond to salvage therapy. We encourage enrollment in a clinical study that tests novel agents, when possible. Further discussion of the management of pediatric ALL/LBL is presented separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

Anaplastic large cell lymphoma — Anaplastic large cell lymphoma (ALCL) is the most common type of mature T cell NHL in children and adolescents. ALCL is characterized by the proliferation of CD30-positive neoplastic cells and frequent expression of anaplastic lymphoma kinase (ALK).

●Presentation – ALCL typically presents as painless lymphadenopathy, with or without skin or subcutaneous involvement. Fever and constitutional symptoms are common, but CNS involvement with ALCL is very rare. The median age at presentation is 12 years. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

●Management – The mainstay of treatment of ALCL is combination chemotherapy, but expression of CD30 and frequent expression of ALK enable the incorporation of targeted agents into treatment regimens for children and adolescents. The role of surgery is limited to diagnostic surgical biopsy, and RT is rarely used in this setting. (See "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)".)

●Outcomes – The phase 3 ANHL12P1 trial randomly assigned 134 children with newly diagnosed, nonlocalized ALK-positive/CD30-positive ALCL to standard combination chemotherapy plus either brentuximab vedotin (CD30-directed immunoconjugate) or crizotinib (a small molecule inhibitor of ALK) [14,15]. The addition of either brentuximab vedotin or crizotinib achieved >95 percent two-year OS and >77 percent two-year EFS; although OS was similar, EFS was inferior to outcomes when vinblastine was added to chemotherapy in the earlier ALCL99 trial [16]. There were unexpected thromboembolic adverse effects (AEs) in one-fifth of the patients treated with crizotinib.

●Relapse – Management of relapsed or refractory (r/r) ALCL is informed by prior therapy, whether the malignant cells express ALK, and eligibility for HCT. As an example, brentuximab vedotin can achieve a meaningful response with acceptable toxicity in children/adolescents with r/r ALCL [17]. Management of r/r ALCL is discussed separately. (See "Treatment of relapsed/refractory systemic anaplastic large cell lymphoma (sALCL)".)

Burkitt lymphoma — Burkitt lymphoma (BL) is a highly aggressive type of B cell NHL. There are three distinct clinical forms of BL: endemic (African), sporadic (nonendemic), and immunodeficiency-associated. Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features.

●Presentation – BL frequently presents with abdominal pain that mimics acute appendicitis or intussusception. Rapidly growing lymphadenopathy in the head and neck region is also common. Less common sites of involvement are testes, bone, skin, bone marrow, and CNS. Spontaneous tumor lysis syndrome (TLS) is common with BL. 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".)

●Management – The mainstay of therapy for BL is chemoimmunotherapy. There is no role for the routine use of RT for the treatment of BL. 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. (See "Treatment of Burkitt leukemia/lymphoma in adults".)

The malignant cells of BL are exquisitely sensitive to chemoimmunotherapy. Although the preferred multiagent 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 the disease. With this approach, children with completely resected early-stage (I or II) BL have an estimated 98 percent four-year EFS and 99 percent four-year OS [18]. Children with unresected early-stage or advanced-stage (III) disease that does not involve the CNS or bone marrow have an estimated four-year EFS and OS >90 percent [19]. Patients presenting with stage IV disease, especially those with CNS involvement, have inferior outcomes [20].

●Outcomes – Chemoimmunotherapy achieves superior outcomes in patients with advanced-stage BL. A phase 3 trial that randomly assigned children (6 months to 18 years) with high-grade, high-risk mature B cell NHL (86 percent with BL) to multiagent chemotherapy, without or with rituximab, was stopped early after interim analysis indicated superior efficacy for the chemoimmunotherapy regimen; the inclusion of rituximab achieved superior three-year OS (95.1 versus 87.3 percent; hazard ratio [HR] for death, 0.36 [95% CI 0.16-0.82]) with acceptable incremental toxicity (primarily infusion or hypogammaglobulinemia) [21,22].

●Relapse – Relapses in children typically occur within the first two years and are clinically aggressive, and the prognosis for children with relapsed BL is poor. HCT and chimeric antigen receptor (CAR)-T cell therapy are useful approaches for the management of r/r BL [23,24].

Diffuse large B cell lymphoma — Diffuse large B cell lymphoma (DLBCL) is an aggressive subtype of B cell NHL that has a variable presentation in children.

●Presentation – Patients may present with a rapidly enlarging symptomatic mass, most often as lymph node enlargement in the neck or abdomen, but it may present as a mass lesion anywhere in the body. Spontaneous TLS is uncommon. The incidence of pediatric DLBCL increases with age. (See "Diffuse large B cell lymphoma and other large B cell lymphomas: Presentation, diagnosis, and classification".)

A B cell NHL that generally presents with a mediastinal mass shares some clinicopathologic features with DLBCL, but it is now considered a distinct subtype of B cell NHL, called primary mediastinal large B cell lymphoma. This subtype of NHL is most common in adolescents, particularly in females. (See "Primary mediastinal large B cell lymphoma".)

●Management – Children with DLBCL are generally treated with regimens like those used for BL. Older adolescents can be treated with pediatric regimens or with adult regimens for DLBCL, but standard adult DLBCL regimens (eg, R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]) expose the patient to higher doses of anthracycline than those used for pediatric BL. (See 'Burkitt lymphoma' above and "Initial treatment of advanced-stage diffuse large B cell lymphoma" and "Diffuse large B cell lymphoma: Treatment of limited-stage disease".)

●Relapse – Management of relapsed DLBCL is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

Rare pediatric NHL variants — Less common subtypes of NHL in children and adolescents include follicular lymphoma, marginal zone lymphomas, and peripheral T cell lymphomas. These subtypes account for approximately 7 percent of pediatric NHL.

Treatment of these uncommon lymphomas is often based on experience in adults. However, 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 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 immunocompromised patient — There is an increased incidence of lymphoproliferative disorders in immunocompromised children and adolescents.

The incidence of lymphoproliferative disease or lymphoma in immunocompromised children is 100-fold higher than in the general population. The underlying immune deficiencies may be inherited genetic variants, associated with human immunodeficiency virus (HIV) infection, or they can be iatrogenic in patients who have undergone transplantation.

Examples include:

●Congenital immunodeficiencies – Common variable immunodeficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia, and X-linked lymphoproliferative syndrome are associated with an increased risk for NHL. (See "Common variable immunodeficiency in children" and "Ataxia-telangiectasia" and "Wiskott-Aldrich syndrome" and "X-linked severe combined immunodeficiency (X-SCID)".)

NHL associated with a primary immunodeficiency usually shows a mature B cell phenotype and large cell histology. These children often have higher-stage disease and present with symptoms related to extranodal disease, particularly those involving the gastrointestinal tract or central nervous system (CNS).

Treatment decisions for the management of a child with lymphoma are influenced by the underlying congenital immunodeficiency. 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. Children with congenital immunodeficiencies may require allogeneic hematopoietic cell transplantation (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".)

●Acquired immunodeficiencies – Immunosuppression associated with HIV infection and iatrogenic immunosuppression (eg, from medications used for solid organ transplantation and HCT) is associated with increased lymphoproliferative disorders.

•HIV – People living with HIV are at increased risk for various cancers, including lymphomas. Systemic high-grade B cell NHL, primary CNS lymphoma, and primary effusion lymphoma are considered AIDS-defining cancers. (See "HIV infection and malignancy: Epidemiology and pathogenesis".)

Improved immune function and reduced HIV viral load from antiretroviral therapy (ART) are associated with better tolerance of chemotherapy, fewer opportunistic infections, and improved outcomes. Children with HIV and NHL should be treated with standard chemotherapy regimens for NHL, with careful attention to the early detection of infections and appropriate prophylaxis.

Treatment of AIDS-related B cell NHL is discussed separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma".)

●Iatrogenic immunosuppression – Immunosuppressive agents used in solid organ transplantation and allogeneic HCT are associated with post-transplant lymphoproliferative disorders (PTLDs). (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology" and "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)

PTLDs describe a spectrum of clinically and morphologically heterogeneous lymphoid proliferations, ranging from processes that resemble a normal reactive process to diseases that look like NHL. Nearly all PTLDs following HCT are associated with Epstein-Barr virus (EBV), but EBV-negative PTLDs can be seen following solid organ transplant. Reduction of immunosuppression is generally the first line of therapy for PTLDs, but low-dose chemotherapy or rituximab may be given when the reduction of immunosuppression has failed to control the disease. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Adolescent and young adult NHL — NHL in adolescents and young adults includes a higher percentage of subtypes typically seen in adulthood.

The most common NHL in adolescent and young adult patients is diffuse large B cell lymphoma, followed by follicular lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, and mycosis fungoides [25,26]. There is a paucity of data regarding the preferred treatment regimens for adolescents and young adults with NHL. Older adolescents may be treated with pediatric regimens or adult regimens.

FOLLOW-UP — 

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

Follow-up evaluations are guided by the protocol described in the clinical trial that informed the choice of treatment.

Treatment response — Patients are evaluated during and after completing therapy to assess treatment response.

Assessment — Response to therapy for NHL is based on clinical evaluation, imaging, and pathologic evaluation of cerebrospinal fluid (CSF) and bone marrow.

●Imaging – The preferred imaging modality varies with the sites of involvement.

CT and 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.

●Pathology – Residual masses should be biopsied to distinguish between a residual disease and other masses (eg, fibrosis, thymus). Bone marrow examination and evaluation of CSF should be performed as part of the response assessment.

Response criteria — There are no standardized response criteria for pediatric NHL. An international consensus panel developed the International Pediatric NHL response criteria to assess treatment response [27]. These criteria can be summarized as follows:

●Complete response (CR) – Disappearance of all disease (one of the following):

•No disease is detected by physical examination, CT, and/or MRI; PET is negative (ie, five-point Deauville score (table 1) is 1 to 3); examination of bone marrow and CSF is morphologically negative; and there is no new and/or progressive disease elsewhere.

•A residual or new mass is present, but it was completely resected and is morphologically negative for disease (disease may be detectable by immunohistochemistry, flow cytometry, cytogenetics or fluorescence in situ hybridization [FISH], or molecular techniques); bone marrow and CSF are morphologically negative; and there is no new and/or progressive disease elsewhere.

●CR biopsy negative – Residual mass on CT or MRI is biopsied (limited biopsy or core biopsy but not resected) and there is no morphologic evidence of residual disease (disease may be detected using one of the more sensitive techniques described above); there are no new lesions by imaging.

●CR unconfirmed – Residual mass on CT or MRI is negative by PET; bone marrow and CSF are morphologically free of disease; and there are no new lesions by imaging.

●Partial response – There is ≥50 percent decrease in size of mass by CT or MRI; PET may be positive (Deauville score of 4 or 5, with reduced lesional uptake compared with baseline); there may be morphologic detection of disease in a biopsy sample of the mass or in bone marrow or CSF (but there should be ≥50 percent reduction in the percentage of lymphoma cells); and there is no new and/or progressive disease elsewhere.

●Progressive disease – There is ≥25 percent increase by CT or MRI; PET shows Deauville score 4 or 5 with an increase in lesional uptake from baseline; and/or development of new morphologic evidence of disease in bone marrow or CSF.

Response definitions need to be validated in clinical trials.

In a prospective study, 34 children with nonlymphoblastic NHL underwent imaging with PET/CT and conventional contrast-enhanced CT at baseline, after two cycles of chemotherapy, and after completion of chemotherapy [28]. 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 survival (PFS) or overall survival (OS). Both post-treatment PET/CT and CT could predict PFS, but only post-treatment contrast-enhanced CT could predict OS.

Surveillance — Patients who have no evidence of residual disease are monitored for disease relapse and long-term treatment-related toxicity.

Relapsed disease can be suggested by changes on imaging but must be confirmed by biopsy to document relapsed disease before proceeding to salvage therapy.

Survivors should have comprehensive follow-up care, with attention to nutritional assessments, education, growth monitoring, mental health and social functioning, and education, to prevent high-risk behaviors.

When possible, care should transition to a clinic dedicated to childhood cancer long-term survivors or to a clinician (eg, pediatrician, family practice, internal medicine, nurse practitioner) who has contact with a long-term survivor clinic.

Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group.

Long-term toxicities — Survivors of childhood cancer are at increased risk for long-term sequelae of treatment.

Late adverse effects (AEs) in survivors of pediatric NHL may include neurocognitive dysfunction, other CNS complications, endocrinopathies, heart failure and other cardiotoxicity, infertility, infections, second cancers, decreased linear growth, depression, fatigue, and anxiety.

Late AEs are primarily dependent upon the type and intensity of therapy. More intense chemotherapy is more likely to cause late treatment-related complications. Late AEs are primarily related to anthracyclines and alkylating agents. Radiation therapy (RT) plays only a limited role in treatment, and most patients do not face long-term RT-associated AEs. Additional late AEs may affect patients who undergo hematopoietic cell transplantation. (See "Long-term care of the adult hematopoietic cell transplantation survivor".)

Additional details of late AEs associated with the treatment of pediatric NHL are discussed separately. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents".)

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

●Description – Non-Hodgkin lymphoma (NHL) refers to lymphoid malignancies derived from B or T cell progenitors or mature B or T cells. Most cases of pediatric NHL are high-grade tumors with aggressive clinical behavior. (See 'Epidemiology' above.)

●Clinical presentation – Common presentations include enlarging, nontender lymphadenopathy or symptoms related to compression of surrounding structures. Clinical findings usually develop over weeks to months. (See 'Clinical manifestations' above.)

●Emergencies – Oncologic emergencies at diagnosis may include superior vena cava obstruction, acute airway obstruction, tumor lysis syndrome, and others. Prompt recognition and therapy of oncologic emergencies are critical. (See 'Oncologic emergencies' above.)

●Diagnosis – NHL should be suspected in a child with unexplained lymphadenopathy, abdominal or other mass, or constitutional symptoms. Children should be promptly referred to a pediatric oncologist for evaluation and diagnosis. (See 'Diagnosis' above.)

Diagnosis is based on the pathologic evaluation of involved tissue (eg, lymph node, abdominal mass, extranodal site) interpreted within the clinical context. NHL subtypes are defined by histology, immunophenotype, and genetic studies, as discussed separately. (See "Classification of hematopoietic neoplasms", section on 'Lymphoid neoplasms'.)

●Differential diagnosis – The differential diagnosis depends on clinical findings and sites(s) of involvement. This generally includes other malignancies (eg, Hodgkin lymphoma; metastases from nasopharyngeal carcinoma, soft tissue sarcoma, or other primary tumors), appendicitis, intussusception, infections (eg, toxoplasmosis, mycobacteria, Epstein-Barr virus), systemic lupus erythematosus, and reactive hyperplasia of lymph nodes. (See 'Differential diagnosis' above.)

●Staging

•Studies – Staging involves clinical evaluation, laboratory studies, contrast-enhanced CT of the neck, chest, abdomen, and pelvis, with or without integrated positron emission tomography (PET); bilateral iliac crest bone marrow aspiration/biopsy; and lumbar puncture. (See 'Studies' above.)

•Murphy staging system – The Murphy staging system is used for staging pediatric NHL, as described above. (See 'Staging' above.)

●Overview of treatment – For most children with NHL, we suggest systemic therapy alone, rather than combined with surgery or radiation (Grade 2C). (See 'Overview of treatment' above.)

Surgery is generally limited to diagnostic studies or oncologic emergencies, and RT is not commonly used because of toxicity in growing children.

We encourage treatment in a clinical trial at a comprehensive pediatric oncology center.

●Management – Details of management vary with disease, stage, and patient age. The most common types of pediatric NHL and their management and outcomes are:

•(See 'Lymphoblastic lymphoma' above.)

•(See 'Anaplastic large cell lymphoma' above.)

•(See 'Burkitt lymphoma' above.)

•(See 'Diffuse large B cell lymphoma' above.)

●Follow-up

•Treatment response

-Assessment – Response is based on clinical evaluation, imaging, and pathologic evaluation of cerebrospinal fluid and bone marrow. (See 'Treatment response' above.)

-Response criteria – Detailed criteria are presented above. (See 'Response criteria' above.)

•Surveillance – Patients are monitored for relapse and late AEs, ideally in a setting with expertise in childhood cancers. Specific guidelines are available. (See 'Surveillance' above.)

•Late toxicity – Late AEs vary with the disease, age at treatment, and regimen, but they may include neurocognitive dysfunction, endocrinopathies, heart failure, infertility, infections, second cancers, decreased linear growth, depression, fatigue, and anxiety. (See 'Long-term toxicities' above.)