Introduction
Non-Hodgkin's Lymphoma (NHL) results from the malignant proliferation of cells of lymphocytic lineage. Although malignant lymphomas are generally restricted to lymphoid tissue such as lymph nodes and spleen, it is not uncommon to find bone marrow involvement in children.
Incidence And Epidemiology
Incidence
- NHL accounts for 5-7% of malignant diseases in childhood (Europe, United States). It is the third most common childhood malignancy
- The incidence of NHL is higher in the Middle East, Nigeria, and Uganda (15 of 100,000 children under 5-10 years of age).
- NHL accounts for 60% of all childhood lymphomas
- Isolated cases of familial NHL have been known to occur.
Epidemiology
Sex: M:F= 2.5:1
Age: Peak age 5-15 years
Risk factors
Genetic: Immunological defects (Bruton's type of sex-linked agammaglobulinemia, common variable agammaglobulinemia, ataxia telangiectasia, Wiskott-Aldrich syndrome, severe combined immune deficiency)
Post-transplant immunosuppression: Post-bone marrow transplantation (especially with use of T-cell depleted marrow); post-liver or post-heart transplantation.
Drugs: Diphenylhydantoin
Radiation: Children treated with chemo-radiotherapy for Hodgkin's disease
Virus: Epstein-Barr virus (EBV), human immune deficiency virus (HIV)
Pathologic Classification
Table 1 presents the Revised European - American Lymphoma (REAL) classification from the International Lymphoma Study Group. This classification for NHL is based on the currently recognized histologic (morphologic), immunologic, and genetic features; their clinical presentation, and course. Currently, the REAL classification is the preferred classification for NHL.
Table 1: Revised European-American Lymphoma Classification from the International Lymphoma Study Group
B-cell neoplasms
Precursor B-cell neoplasms
Precursor B-lymphoblastic leukemia/lymphoma
Peripheral B-cell neoplasms
- B-cell CLL/PLL/SLL
- Lymphoplasmacytoid lymphoma/immunocytoma
- Mantle cell lymphoma
Follicle center lymphoma, follicular
- Provisional cytologic grades: I (small), II (mixed), III (large)
- Provisional subtype: diffuse, predominantly small cell
Marginal zone B-cell lymphoma
- Extranodal (MALT ± monocytoid B cells)
- Provisional category: nodal (± monocytoid B cells)
- Provisional entity: splenic marginal zone lymphoma
Hairy cell leukemia
Plasmacytoma/myeloma
Diffuse large B-cell lymphoma
Burkitt's lymphoma
- Provisional entity: high-grade B-cell lymphoma, Burkitt-type
T-cell and putative natural killer (NK) cell neoplasms
Precursor T-cell neoplasms
Precursor T-lymphoblastic lymphoma/leukemia
Peripheral T-cell and NK cell neoplasms
- T-cell CLL/PLL
- Large granular lymphocyte leukemia
- Mycosis fungoides/Sezary syndrome
- Peripheral T-cell lymphomas, unspecified
Provisional categories: medium, mixed, large, lymphoepitheloid
Provisional subtypes:
- Hepatosplenic T-cell lymphoma
Subcutaneous panniculitic T-cell lymphoma
- Adult T-cell lymphoma/leukemia
- Angioimmunoblastic T-cell lymphoma
- Angiocentric lymphoma
- Intestinal T-cell lymphoma (± enteropathy)
- Anaplastic large cell lymphoma (T/null)
- Provisional ALCL Hodgkin's-like
Note: CLL, chronic lymphocytic leukemia; PLL prolymphocytic leukemia; SLL, small lymphocytic lymphoma, MALT,mucosal-associated lymphoid tissue lymphoma; ALCL, anaplastic large cell lymphoma
From Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKS, Cleary ML, Delsol G et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group, Blood 1994, 84: 1361-92.
Fifty percent of NHL in children are small noncleaved, 30% lymphoblastic, and 20% large cell types.
Presentation
The presenting symptoms of NHL depend mainly on the location of the tumor. It may present in a variety of ways, occasionally providing a major diagnostic dilemma because of the protean manifestations of its presentation.
Burkitt's lymphoma may be of the endemic or sporadic variety. Table 2 lists the epidemiologic, immunologic, and molecular features of these two varieties.
Table 2 Epidemiologic, Immunologic, and Molecular Features of Endemic and Sporadic Burkitt's Lymphoma
Features | Endemic | Sporadic |
Epidemiologic
Population affected | African | Worldwide |
Age affected | Children(peak age, 7 years) | Young adults (peak age, 11 years) |
Organ involvement | Jaw, paraspinal, ovary | Marrow, abdomen, nasopharynx, ovary |
Epstein-Barr virus | Present in more than 97% of cases | Present in less than 30% of cases |
CNS involvement | More frequent than bone marrow involvement | As frequent as bone marrow involvement |
Immunologic IgM secretion |
Little or none
|
Prominent
|
Fc and C3 | + | - |
CALLA | + | - |
IgH gene rearrangement | DH or JH | IgH switch region |
Molecular Breakpoints on chromosome 8 |
Upstream of C-myc
|
Within C-myc
|
Site of cell origin | Germinal center of lymph node | Bone marrow |
The frequency of involvement, according to primary sites and tumor distribution of NHL at the time of diagnosis, is as follows.
Abdomen:
The primary site in 35% of cases is abdominal - the ileocecal region, appendix, ascending colon, or some combination of these sites. These patients usually present with:
- Abdominal pain
- Vomiting and diarrhea
- Abdominal distension
- Palpable mass
- Intussusception
- Peritonitis
- Ascites
- Acute gastrointestinal (GI) bleeding
- Obstructive jaundice
- Hepatosplenomegaly
Bleeding and perforation of the intestine occur infrequently in patients with Burkitt's lymphoma. Lymphoma is the most frequent anatomic lesion causing intussusception in children over 6 years of age. When this disease presents insidiously, it may clinically and radiologically resemble Crohn's disease.
Head and Neck:
In 13% of cases, the head and neck are involved, causing enlargement of the cervical node(s) and parotid gland, jaw swelling, and unilateral tonsillar hypertrophy. The disease may present with nasal obstruction, rhinorrhea, hypoacousia, and cranial nerve palsies.
Mediastinum
The frequency of involvement of the mediastinum is 26%. A large anterior mediastinal mass may produce superior vena cava syndrome (distended neck veins, edema of the neck and face, marked dyspnea, orthopnea, dizziness, headache, dysphagia, epistaxis, altered mental status, and syncope associated with bending). In this condition, a large anterior mediastinal mass compresses the superior vena cava (SVC) because of the thinness of its wall and its close apposition to the vertebral column. The rapid growth of the mass does not permit enough time to develop effective collateral circulation to compensate and results in signs and symptoms of SVC compression.
Tumors of the mediastinum have a marked tendency to involve the bone marrow, transform to acute lymphoblastic leukemia, and develop meningeal and gonadal involvement. Many of these tumors is composed of cells of T-lymphocytes lineage. Pleural effusion may be produced by direct pleural involvement and/or may result from the compression of lymphatics by the mediastinal mass. The presence of pericardial effusion may cause cardiac tamponade.
Other Primary Sites
Other sites involved (11%) include skin and subcutaneous tissue, orbit, thyroid, bone (with or without hypercalcemia), kidney, epidural space, breast, and gonads. The peripheral nodes are affected in 14% of cases.