NON-HODGKIN LYMPHOMA

Author: J Martin Johnston, MD, Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Pediatric Hematology/Oncology, Backus Children's Hospital; Consulting Oncologist/Hematologist Dec 5, 2008

Introduction
Background Lymphomas are malignant neoplasms of lymphoid lineage. Broadly classified as either Hodgkin disease (Hodgkin's disease) or as non-Hodgkin lymphoma (NHL), lymphomas are clinically, pathologically, and biologically distinct.1 According to the National Cancer Institute (NCI) formulation, most childhood non-Hodgkin lymphomas can be classified as one of the following types:

Lymphoblastic lymphomas Small noncleaved cell lymphomas (SNCCLs), or Burkitt lymphomas (Burkittlike lymphomas) (non-Burkitt lymphomas) Large cell lymphomas (LCLs)

In recent years, B-cell LCLs and anaplastic (usually T-cell) LCLs (ie, Ki-1+ lymphomas) have come to be viewed as distinct entities. In this article, these categories are considered separately. Other, less common forms of lymphoma are not discussed. Since the late 1960s, treatment outcomes for children with non-Hodgkin lymphoma have steadily improved. Even for patients with advanced disease, event-free survival rates are 6590%. The mainstay of conventional therapy is multiagent chemotherapy tailored to the histologic subtype and the clinical stage of disease. In certain individuals with non-Hodgkin lymphoma, surgical resection and radiation therapy are also key components of definitive treatment. Newer therapies that target immunologic and biologic aspects of the lymphoma are under development and are just beginning to appear in the clinical arena. Pathophysiology Most malignancies arise as disease localized in the organ or tissue of origin. They may then secondarily spread by means of local extension or distant metastases. In contrast, non-Hodgkin lymphoma is best regarded as a systemic disease because of the unique anatomy of the lymphoid

system and because of the physiology of lymphoid cells, which tend to migrate whether they are normal or malignant. Childhood non-Hodgkin lymphoma generally manifests as bulky extramedullary (usually extranodal) disease with or without demonstrable dissemination. The distinction between nonHodgkin lymphoma and acute leukemia is arbitrary. Therefore, these entities are best considered in terms of a spectrum ranging from clinically localized disease to overt leukemia. In most treatment protocols, acute leukemia is now defined on the basis of marrow involvement above than some threshold (typically a blast count of >25%) irrespective of the presence of bulky extramedullary disease. In contrast, a tumor accompanied by marrow involvement below than this threshold constitutes stage 4 lymphoma. Frequency International Over the last 3 decades, the incidence of non-Hodgkin lymphoma appears to have increased in Canada, as it has in the United States.3 The cause for this rise is unclear. Burkitt lymphoma is significantly most common in sub-Saharan Africa, where it accounts for approximately one half of childhood cancers. Its incidence also appears to be higher in Latin America, in North Africa, and in the Middle East than in the United States or Europe. Mortality/Morbidity Rapidly growing or bulky tumors can cause severe metabolic derangement, which may be life threatening. One indicator of the potential for tumor lysis syndrome is an elevated plasma lactate dehydrogenase level or hyperuricemia at the time of diagnosis. The start of effective chemotherapy acutely increases the risk of complications, including hyperkalemia, hyperphosphatemia, hypocalcemia, oliguria, and renal failure. Other immediate risks depend on the site and the extent of involvement. These risks vary according to the histologic subtype of disease. Individuals with lymphoblastic lymphoma often present with mediastinal involvement, which may be massive and life threatening. Airway compression is a particular concern and must be considered in any patient with neck or chest disease (see Media file 2). Even in the absence of symptomatic airway compromise, sudden obstruction may be a risk if the patient undergoes anesthesia for biopsy or placement of a central line. In these individuals, consider biopsy done under local anesthesia or immediate radiation therapy to the airway, provided that another site of disease is outside the radiation field (to allow for subsequent histologic confirmation of the diagnosis). Mediastinal tumors may cause compression of the great vessel (superior vena cava syndrome), with swelling of the neck, face, and upper extremities. Esophageal compression may lead to

dysphagia. Pleural effusion is sometimes observed and may be large enough to cause symptoms. In affected individuals, thoracentesis may be both therapeutic and diagnostic, obviating biopsy. With current treatments, non-Hodgkin lymphomas in most children are apparently curable. The results depend on achieving a precise histologic diagnosis, thorough staging of the disease, and applying complex multiagent (and sometimes multimodal) treatment. The short-term morbidity of chemotherapy regimens is considerable, but the effects are usually manageable. Late effects of treatment are a growing concern, as survival rates are increasing (see Complications). Race In the United States, the incidence of non-Hodgkin lymphoma is twice as high among whites compared with blacks, with respective rates of 9.1 and 4.6 cases per million individuals per year. Sex In the United States, the incidence is 2-3 times higher in male individuals than in female individuals. Age In the United States, the age-specific incidence of non-Hodgkin lymphoma only slightly increases over the first 2 decades of life. By comparison, the incidence of Hodgkin disease increases more dramatically than this as children age (see Media file 1). In adulthood, the risk of non-Hodgkin lymphoma steadily climbs, whereas the age-specific incidence of Hodgkin disease is biphasic. Clinical History

The presentation of patients with non-Hodgkin lymphoma (NHL) is acute or subacute, in contrast to the indolent course that characterizes most lymphomas in adults. The duration of symptoms before diagnosis is generally one month or shorter. Specific complaints vary and depend on the predominant sites of involvement. Constitutional symptoms are uncommon, except in patients with anaplastic large cell lymphomas (LCLs). Many of these patients have low-grade fever, malaise, anorexia, and/or weight loss. LCLs are biologically disparate. As a result, these lesions have a varied presentation that may include chest or abdominal complications. In rare cases, an LCL appears as an isolated bone lesion in association with pain, swelling, and a risk of pathologic fracture. Bone marrow involvement may cause generalized or migratory bone pain. However, in individuals with non-Hodgkin lymphoma, clinically significant cytopenias are uncommon, and their presence suggests a diagnosis of acute leukemia.

Localized disease can manifest as lymphadenopathy (usually with firmness and no tenderness), tonsillar hypertrophy, or a mass in virtually any location. However, in children, non-Hodgkin lymphoma is primarily an extranodal disease. Patients with supradiaphragmatic disease (eg, lymphoblastic lymphoma) often report having a nonproductive cough, dyspnea, chest pain, and dysphagia. Abdominal tumors (usually small noncleaved cell lymphoma [SNCCLs] or B-cell LCLs) are associated with abdominal pain, constipation, masses, or ascites. An acute abdomen occasionally is observed and may be mistaken for appendicitis. Patients with anaplastic LCLs sometimes present with painful skin lesions, bone lesions, peripheral lymphadenopathy, and hepatosplenomegaly.4,5 The painful skin lesions may regress spontaneously. A finding less common than these is testicular, lung, or muscle involvement. Anaplastic LCLs may also result in an apparent cytokine storm, with fevers, vascular leakage, and altered blood counts that indicate anemia, thrombocytopenia, leukopenia, and leukocytosis. Patients occasionally develop symptomatic CNS involvement before diagnosis. Headache, meningismus, cranial nerve palsies, and altered sensorium may be observed. Although CNS involvement is uncommon at the time of diagnosis, patients with nonHodgkin lymphoma (particularly SNCCL) occasionally present with symptoms suggestive of meningoencephalitis.

Physical

In general, patients often appear mildly to moderately ill. They occasionally have a lowgrade fever. Patients may present with pallor, respiratory distress, pain, and discomfort. A jaw or orbital mass is present in as many as 10% of patients in developed countries. It is particularly common in African patients with endemic Burkitt lymphoma. Cervical or supraclavicular masses or adenopathy is firm, fixed, and nontender. Dyspnea or stridor may occur in patients with a mediastinal mass. In those with superior vena cava syndrome, distended neck veins and plethora may be observed. Decreased breath sounds are secondary to bronchial obstruction or pleural effusion. Thoracic dullness to percussion may be present with pleural effusion. Abdominal distention or a mass may be present with or without tenderness, rebound tenderness, and/or shifting dullness. Painful skin lesions suggest an anaplastic LCL. Obtundation, agitation, and meningismus may be observed in individuals with CNS involvement. Focal pain or swelling in the extremity may be present in patients with primary bone lymphoma. Relatively uncommon physical findings include the following: o Nasopharyngeal mass o Parotid enlargement o Nephromegaly o Testicular enlargement

Causes In developed countries, most individuals with non-Hodgkin lymphoma have no known etiology or association. Epidemiologic data suggest that certain human leukocyte antigen (HLA) types, and even certain blood types, may increase or decrease the likelihood of developing non-Hodgkin lymphoma.6,7 Findings from several epidemiologic studies suggest that pesticide exposure may play a role in the development of adult non-Hodgkin lymphoma; the case for its involvement in childhood non-Hodgkin lymphoma is less compelling than the case for adults, but this is still under investigation.8,9 The epidemiologic association between non-Hodgkin lymphoma and certain paternal occupations (eg, those that increase contact with other individuals) suggest a possible infective etiology for childhood non-Hodgkin lymphoma.10 Regarding protective factors, results of one case-control study suggested that exposure to sunlight may protect individuals against non-Hodgkin lymphoma, presumably because of enhanced vitamin D synthesis.11 Immunosuppression and viral infection Immunosuppressed individuals, such as those with HIV infection or those who have undergone bone marrow transplantation, are at increased risk for developing non-Hodgkin lymphoma, particularly SNCCL and LCL of B-cell origin. The Epstein-Barr virus, which causes B-cell proliferation and in vitro immortalization, has been implicated in most of these lymphomas. Primary CNS lymphoma is more common in these patients than in others. Previous Hodgkin disease Patients successfully treated for Hodgkin disease are at increased risk for developing nonHodgkin lymphoma. This effect appears to reflect the combined effects of chemotherapy and radiotherapy, as well as the immunosuppressive effects of Hodgkin disease. Adults older than 40 years who received combined-modality therapy are at particular risk; their 15-year incidence of non-Hodgkin lymphoma is as high as 39%.12 Splenectomy, now rarely performed in patients with Hodgkin disease, is another reported risk factor for second malignancies, including non-Hodgkin lymphoma.13 Secondary non-Hodgkin lymphoma is less common among pediatric patients who survive cancer than among adults. A cohort of 5484 children was treated for various malignancies at St Jude Children's Research Hospital. Over 30,710 person-years of follow-up care, only 3 had secondary non-Hodgkin lymphoma. The 15-year actuarial risk of non-Hodgkin lymphoma was 0.16% in this group.

However, even among children, patients treated for Hodgkin disease are particularly at risk. In 1991, a literature review revealed 24 incidents of secondary non-Hodgkin lymphoma among patients whose primary malignancy had been diagnosed when they were younger than 20 years. Eighteen (75%) of the patients previously had Hodgkin disease.14 Geographic location In sub-Saharan Africa, the development of endemic Burkitt lymphoma is strongly associated with previous exposures to both malaria (with resultant T-cell suppression) and the Epstein-Barr virus. Recent speculation suggests that mosquito-borne arboviruses may also play a role in the development of Burkitt lymphoma in this part of the world. In addition, exposure to 4-deoxyphorbol ester from the plant Euphorbia tirucalli (by means of goat's milk) is tentatively implicated in the pathogenesis of endemic Burkitt lymphoma.15,16 Genetic causes The genetic basis of pediatric non-Hodgkin lymphoma has been studied extensively.17 Each subtype of non-Hodgkin lymphoma is characterized by 1 or more molecular alterations that contribute to the malignant phenotype. Many of these alterations are chromosomal translocations involving genes for immunoglobulin or T-cell receptor (TCR) molecules. During normal lymphocyte development, these loci undergo recombination that enhances immunologic diversification. However, mistargeted recombination leads to translocations with other genes, typically those that regulate cell growth. The resulting dysregulation of these other genes contributes to the transformed phenotype. For example, the hallmark of Burkitt lymphoma is a t(8;14)(q24;q32) translocation, which is observed in approximately 80% of patients. This translocation juxtaposes c-myc, which encodes a transcription factor important in initiation of the cell cycle, with the locus for the immunoglobulin heavy chain. In a relatively uncommon alteration, c-myc is adjoined to the gene encoding the immunoglobulin kappa light chain [t(2;8)(p11;q24)] or the lambda light chain [t(8;22)(q24;q11)]. In all 3 instances, the result is aberrant expression of the c-MYC protein under the influence of regulatory sequences of immunoglobulin genes. This aberration contributes to the pathogenesis of Burkitt lymphoma.18 Aside from the t(8;14) translocation, Burkitt lymphoma frequently involves a gain of chromosomal material that can affect any of a number of chromosomes. Abnormalities of chromosomal arms 1q, 7q, or 13q may portend a poor prognosis.19,18 A small portion of T-lymphoblastic lymphomas are also associated with translocations involving 1 of the TCR loci: TCR alpha delta (14q11) or TCR beta (7q34). The most common example (observed in 7% of children with T-lymphoblastic lymphomas) is the t(11;14)(p13;q11) translocation, which enhances expression of the LMO2 gene on chromosome 11. This gene encodes LIM protein, an apparent modulator of gene transcription. A more common abnormality than this, one observed in approximately 25% of patients with T-lymphoblastic lymphoma/T-cell acute lymphoblastic lymphoma (ALL), is a deletion in a regulatory region of the gene TAL1.

This deletion, which is too small to be detected with conventional cytogenetic techniques, leads to aberrant expression of Tal-1, another transcriptional regulator. Inactivation of the multiple tumor suppressor gene 1 (MTS-1/p16INK4 alpha/CDKN2) on chromosome 16 has been identified as a common genetic event in T-cell ALL; its frequency in T-lymphoblastic lymphoma is likely to be a significant factor. Of interest, the deletions or disruptions responsible for this inactivation are apparently related to illegitimate activity of the same V(D)J recombinase that mediates recombination of the TCR gene.20 Thus, even in the absence of a TCR translocation, similar molecular mechanisms may be responsible for disrupting other genes involved in normal control of the cell cycle. Some B-lineage LCLs have the same t(8;14)(q24;q32) translocation observed in Burkitt lymphoma. Compared with adults with B-LCL, this appears to be more common in children and may portend a worse prognosis.21 Alternatively, most anaplastic (T-lineage) LCLs in children involve a t(2;5)(p23;q35) translocation. This change joins the nucleophosmin gene (NPM) on chromosome 5 to a gene called anaplastic lymphoma kinase (ALK) on chromosome 2 and allows for the expression of an NPM/ALK fusion protein p80. Transcripts of NPM/ALK are also observed in about 20% of individuals with non-Hodgkin lymphoma lacking cytogenetic evidence of t(2;5); this finding reflects an occult or variant translocation.22 Patients with non-Hodgkin lymphomas expressing p80 may have a survival advantage over patients whose lymphomas lack p80.23

Workup
Laboratory Studies

Obtain a CBC count with differential and a platelet count in patients with non-Hodgkin lymphoma (NHL) to assess for possible involvement of the bone marrow and to determine the patient's transfusion requirements. Measure the prothrombin time, the activated partial thromboplastin time, fibrinogen, and the D-dimer level if the patient is febrile or if he or she has evidence of sepsis. The purpose is to assess for possible disseminated intravascular coagulation, which may require specific therapy. Obtain blood and urine cultures if patient has a fever, especially if it is associated with neutropenia. If indicated, also obtain stool and throat cultures. Analyze the measures listed below to assess the patient's renal and hepatic function and to monitor for possible tumor lysis syndrome. Of note, the level of lactate dehydrogenase at diagnosis had prognostic significance in many analyses of treatment outcomes. o Serum electrolytes o BUN o Creatinine o Uric acid o Lactate dehydrogenase o Bilirubin o Albumin o Total protein

Aspartate aminotransferase Alanine aminotransferase Calcium Magnesium Phosphorus Perform HIV serologic tests in patients who have risk factors for HIV exposure or in those with primary CNS lymphoma to exclude these possible predisposing factors.

o o o o o

Imaging Studies

Chest radiography: Obtain posteroanterior and lateral views to assess for possible mediastinal masses, to evaluate the airway, and to exclude pulmonary parenchymal lesions and associated pneumonia. Ultrasonography o Abdominal sonography helps in assessing the size of the kidneys and the patency of the urinary tract. o Abdominal sonography is useful particularly before chemotherapy in anticipation of prolonged excretion and excess toxicity, for example. o When symptoms are present, testicular ultrasonography aids in identifying additional sites of disease. Computed tomography o CT scans of the chest, abdomen, and pelvis can be used to stage lesions (see Staging). o If the patient is stable, chest CT scan is indicated to assess for the degree of tracheal compression. o Head CT scans assist in excluding mass lesions and possible meningeal involvement among individuals with CNS disease. Bone scanning and skeletal surveys: When additional symptoms are present, these tests help in identifying additional sites of disease. Gallium-67 scanning 67 o Gal scanning is highly recommended. o Some tumors are gallium avid, and their response to treatment can be assessed by using this modality. 67 o Occult sites of disease also may be identified on Gal scans. Positron emission tomography: Positron emission tomography (PET) has recently been used for purposes similar to those for67 Gal scanning.24,25

Histologic Findings Several classification systems for non-Hodgkin lymphoma are available. Examples are the Kiel classification and the NCI Working Formulation. At present, the Revised European-American Lymphoma (REAL) classification is gaining acceptance as the criterion standard for classifying adult non-Hodgkin lymphoma. For classifying childhood non-Hodgkin lymphoma, this system is overly complicated because it includes numerous diagnoses that are rarely or never observed in children.

Adult non-Hodgkin lymphomas are characterized as low, intermediate, or high grade, and they can have a diffuse or nodular appearance. In contrast, childhood non-Hodgkin lymphomas are almost always high grade and diffuse. In general, they can be divided into 3 major classes, or even 4 classes if one differentiates the 2 most common types of large cell lymphomas (LCLs), Bcell or T-cell LCLs. The 3 major classes are described below. For a particular tumor, achieving agreement among pathologists is sometimes difficult. However, synthesis of the histologic, immunohistochemical, cytogenetic, and clinical and/or anatomic data almost always results in a clear diagnosis. Lymphoblastic lymphomas Lymphoblastic lymphoma cells are indistinguishable from the lymphoblasts of acute lymphoblastic leukemia (ALL). The cells are monotonous and associated with a high nuclear-tocytoplasmic ratio. Their nuclei are often convoluted and contain finely stippled chromatin. Nucleoli are usually visible but are not prominent. Immunohistochemical analysis usually reveals T-cell markers, including CD5 and CD7. Common ALL antigen (CALLA) is occasionally observed. A minor subset of lymphoblastic lymphomas expresses the precursor B-cell phenotype typical of childhood ALL. This phenotype includes the surface antigens CALLA and B4 and the human leukocyte antigen (HLA)-DR. Small noncleaved cell lymphomas Small noncleaved cell lymphoma (SNCCLs) can be classified Burkitt or non-Burkitt (Burkittlike) lymphomas. The distinction may be subtle, and its clinical significance is unclear. Burkitt lymphoma cells are notably uniform in size and shape, and they usually contain multiple prominent nucleoli. In contrast, extensive cellular pleomorphism, or occasionally the presence of a single nucleolus in most cells, suggests a diagnosis of Burkittlike lymphoma. SNCCL cells have slightly more cytoplasm than do lymphoblastic lymphoma cells. The cytoplasm is basophilic and usually contains lipid-filled vacuoles. Macrophages often infiltrate the tumors, lending the classic starry-sky appearance. However, this observation is not pathognomic of Burkitt lymphoma. The tumor cells are mature B cells, as evidenced by the surface expression of immunoglobulin (usually immunoglobulin M), CD19, CD20, and HLA-DR. CALLA is usually present. Immunophenotyping results suggest that Burkittlike lymphoma cells are more likely than Burkitt lymphoma cells to express the BCL-6 oncogene, and they exhibit relatively low levels of apoptosis.28

Because of the features described, Burkittlike lymphoma appears to be biologically distinct from Burkitt lymphoma, and it is perhaps most closely related to the B-cell LCLs. Large cell lymphomas LCLs are a heterogeneous group. Most cases can be classified as B-cell or T-cell LCLs. The B-cellderived LCLs histologically merge with the SNCCLs. In terms of the expression of cell-surface proteins, these tumors are currently indistinguishable. If infiltrating macrophages are present, these cells can serve as a reference by which the tumor cells are measured. In B-cell LCLs, many or most of the tumoral nuclei are larger than those of the macrophages. Anaplastic LCLs are more common than B-cell LCLs and are derived from T cells, as evidenced by their TCR gene rearrangements. However, anaplastic LCLs may express few T-cell surface markers. Their hallmark is the expression of CD30, or Ki-1+, an antigen first recognized on Hodgkin lymphoma cells. Aberrant expression of myeloid markers CD13 and CD33 has more recently been reported as a sensitive (but not specific) marker of ALK+ anaplastic LCL.29 Other cell surface markers that may be observed are HLA-DR and the interleukin-2 receptor. Finally, a small number of LCLs do not exhibit a clear T-cell or B-cell phenotype. At least some of these tumors are of histiocytic origin. Staging Several systems for classifying non-Hodgkin lymphomas have been proposed. The St Jude system (ie, the Murphy system) has gained the widest acceptance.30 This system is as follows:

Stage I - Single extranodal tumor or single anatomic area (nodal), excluding the mediastinum or abdomen Stage II - Single extranodal tumor with regional node involvement; primary GI tumor with or without associated involvement of mesenteric nodes, with gross total resection; or, on same side of diaphragm, 2 or more nodal areas, or 2 single (extranodal) tumors with or without regional node involvement Stage III - Any primary mediastinal, pleural, or thymic intrathoracic tumor; any extensive and unresectable abdominal tumor; any primary paraspinous or epidural tumor regardless of other sites; or, on both sides of the diaphragm, 2 or more nodal areas, or 2 single (extranodal) tumors with or without regional node involvement Stage IV - Any of the above with initial CNS or marrow (<25%) involvement