Whereas most cases of NHL in adults arise in the lymph nodes, almost all cases in children are extranodal in origin and are histologically diffuse. The classification of the childhood tumors continues to evolve as more becomes known about the molecular biology of the different tumor cell types. The childhood NHL are currently divided into four groups (1,2):

Most lymphoblastic tumors are of T-cell origin. BL, BLL, and LBCL arise from B cells and fall on a continuous spectrum of histologic appearance. The principal histologic difference between BL and BLL is the degree of cellular pleomorphism. Anaplastic large cell lymphomas are T-cell or null cell derived. It is controversial whether there is also a B-cell–derived form of large cell lymphoma. Without question, it will be possible to subdivide these tumors further and classify them more accurately on the basis of more precise molecular and genetic differences.

In the United States, lymphoma is the third most common childhood neoplasm and accounts for about 10% of childhood cancers (3). NHL is rare in children younger than 5 years of age, and the incidence increases with age throughout life (2). For unknown reasons, the incidence in white children is twice that in blacks, and boys are affected twice as frequently as girls (2). Thirty percent to 40% of the cases of childhood NHL originate in the abdomen (3). In about one-half of these, the primary site is in the intestinal tract, most commonly in the small bowel and usually the ileum, although a precise figure is difficult to obtain because in extensive abdominal disease it is often impossible to know where the tumor originated.

Etiologic factors are not yet well understood, and, for unknown reasons, the incidence of NHL has been increasing over the last several decades in all geographic areas and in all age groups (4). In children, the increase has been greatest in teenagers (2). NHL is more common in other parts of the world, and the incidence of the different subtypes varies in different countries. The association between endemic BL and the Epstein-Barr virus (EBV) is well known, but the specific role of this virus, if any, in the pathogenesis of this disease remains unclear, especially in light of the much lower rate of association seen in the sporadic form. A role for other viruses is unproven. The association of African BL with areas of holoendemic malaria is also well known (5) and may relate either to the immunosuppressive effect of malaria, which could increase the number of EBV-infected B cells, or to malaria-induced B-cell hyperplasia, which could predispose to chromosomal translocation. Immunodeficiency syndromes,
including human immunodeficiency virus (HIV) infection, are associated with an increased incidence of NHL. Inherited genetic abnormalities may play a role, as evidenced by the identification in BL of mutations of the p53 gene and of members of the retinoblastoma family (6,7). The role of ionizing radiation alone is probably a small one. There is an increased risk for the development of NHL in patients who have been previously treated with combined modality therapy for Hodgkin’s disease or with chemotherapy for other solid tumors (8,9).

Almost all childhood lymphomas of the small bowel are of B-cell origin, either BL or BLL, and in the United States, 90% of these childhood lymphomas present in the abdomen (8). These tumors bear B-cell antigens, such as CD 19 and CD 20, as well as surface immunoglobulins, almost exclusively IgM (2). They are negative for terminal deoxynucleotidyl transferase, an enzyme that is almost invariably present in lymphoblastic lymphoma (2). B-cells first develop in the bone marrow, and immature B-cells then migrate to the periphery (lymph nodes, spleen, gut, liver) where maturation is completed (10). The small bowel lymphomas of childhood have the immmunophenotypic characteristics of a mature B cell, indicating that final malignant transformation occurs relatively late in the B-cell differentiation pathway.

In the majority of BL cases, the cells show a specific chromosomal translocation of a portion of the long arm of chromosome 8 to chromosome 14 (2,8). As a result of this molecular rearrangement, the c-myc oncogene from chromosome 8 comes to lie next to immunoglobulin heavy chain constant region sequences, resulting in abnormal c-myc activation. In a small proportion of cases, the translocation is from chromosome 2 or 22 to chromosome 8, which activates c-myc by putting it next to light chain constant region sequences (2,8). These translocations probably occur during the normal phase of immunoglobulin gene rearrangement. The subsequent inappropriate production of the c-myc protein presumably maintains the cell in a proliferating state rather than allowing it to enter a resting one [although normally this would lead to cell death via apoptosis (11), suggesting that other genetic modifications are also occurring]. Why these translocations occur is unknown, and it is also unclear whether they represent the primary or a secondary step in the development of the malignancy. A deficiency in DNA repair has been postulated to be a predisposing factor (8). The typical chromosome 8 break points are different in different regions of the world (2). Similar translocations may be seen in BLLs and LBCLs (2).

Mutations in the p53 tumor suppressor protein have been identified in about one-third of BLs, and the presence of mutation is independent of the geographic origin of the tumor, the 8;14 chromosomal break point locations, and the association of EBV (6,7). Mutations in members of the retinoblastoma family of proteins have also been reported (12). The exact role of the EBV in the development of BL is unknown (5). In 95% of African tumors and 40% to 80% of tumors in other developing countries, the cells carry the genome of this virus, but in North America only 15% of the tumors are positive. When EBV is present, it is unclear whether the virus plays an active, essential role in neoplastic transformation or merely predisposes to transformation by producing immortalized clones. The geographic differences in the rate of EBV association with NHL do not simply reflect the rate of exposure to the virus because even patients with negative tumors generally have serum antibodies to EBV (2). However, it may reflect the age of infection, which is typically much earlier in developing countries than it is in more affluent ones (2).

Small bowel lymphomas typically present with abdominal pain, bowel obstruction, gastrointestinal (GI) bleeding, or perforation. Perforation has been associated with an extremely poor prognosis (13). There may be a palpable mass, most commonly in the right lower quadrant, and in extensive cases ascites may occur. The intramural tumor can act as the lead point of an intussusception. In most cases, symptoms have been present for only a short time, and constitutional symptoms such as fever and weight loss are uncommon (3). Rarely, with extensive disease, there can be ureteric obstruction, symptoms of venous obstruction, or neurological impairment due to neuroforaminal invasion and spinal cord compression.

More than one-half of the patients with abdominal tumors come to urgent exploration as a result of their presentation with an acute abdomen. The differential diagnosis usually does not include lymphoma, and the operative findings are usually unexpected (14). In another group—those with a palpable or radiologically identified mass but without acute symptomatology—the diagnosis is made at the time of a planned laparotomy and biopsy. If ascites are present, paracentesis may yield the diagnosis, and in some patients with extensive tumor spread, bone marrow sampling or superficial lymph node biopsy may be diagnostic. The role of laparoscopy will likely increase in the evaluation of a number of these patients. Diagnosis requires obtaining adequate tissue and proper handling of the specimens to ensure the necessary immunotyping and cytogenetic studies can be performed in addition to routine histologic examination. Some patients present only with chronic, often vague, abdominal pain. In the absence of a palpable mass or obstruction, diagnosis of a small
bowel lesion can be difficult. A filling defect may be visible on a small bowel barium study, or a small mass may be identified on a computed tomography scan using oral contrast. However, when only nonspecific symptoms are present, even if studies are obtained, the diagnosis may prove elusive until other symptoms appear as a result of further disease progression.