Non-Hodgkin's Lymphomas

The non-Hodgkin's lymphomas are a group of cancers of the lymphocytes. The disorders are variable in clinical
presentation and course, varying from indolent disease to rapidly progressive devastating illnesses.
Results of studies using techniques of molecular biology have provided clues to the pathogenesis of these
disorders. The best-studied example is Burkitt's lymphoma, in which a characteristic cytogenetic abnormality of
translocation between the long arms of chromosomes 8 and 14 has been identified. The proto-oncogene c-myc is
translocated from its normal position on chromosome 8 to the heavy chain locus on chromosome 14. Cells
committed to B cell differentiation are likely to have enhanced expression of this heavy chain locus, and it is
likely that overexpression of c-myc (in its new anomalous position) is related to malignant transformation. In the
follicular lymphomas, translocations of a possible oncogene bcl-2 from chromosome 8 to the heavy chain locus
on chromosome 14 may play a similar role.
Classification of the lymphomas is a controversial area still undergoing evolution. Recently, the National Cancer
Institute characterizes these lymphomas according to their biologic behavior, whether indolent or aggressive
(Table 13–16).

Table 13–16. Classification of lymphomas:

Low-grade
Small lymphocytic
Small lymphocytic, plasmacytoid
Follicular small cleaved cell
Follicular mixed cell
Intermediate-grade
Follicular large cell
Diffuse small cleaved cell
Diffuse mixed cell
Diffuse large cell
High-grade
Immunoblastic
Small noncleaved (Burkitt’s)
Small noncleaved (non-Burkitt’s)
Lymphoblastic
True histiocytic
Other
Cutaneous T cell (mycosis fungoides)
Adult T cell leukemia/lymphoma
T g lymphocytosis

Clinical Findings
A. Symptoms and Signs: Patients with indolent lymphomas usually present with painless lymphadenopathy,
which may be isolated or widespread. Involved lymph nodes may be present in the retroperitoneum, mesentery,
and pelvis. However, the indolent lymphomas are often disseminated at the time of diagnosis, and bone marrow
involvement is frequent.
Patients with intermediate and high-grade lymphomas may present with adenopathy or with constitutional
symptoms such as fever, drenching night sweats, or weight loss. On examination, lymphadenopathy may be
isolated, or extranodal sites of disease (skin, gastrointestinal tract) may be found. Patients with Burkitt's
lymphoma frequently present with abdominal pain or abdominal fullness because of the predilection of the
disease for the abdomen. Patients with HIV disease also have an increased incidence of non-Hodgkin's
lymphoma; it may be isolated to the central nervous system in such individuals.
Once a pathologic diagnosis is established, the patient should be staged. Physical examination is supplemented by
chest x-ray and CT scan of the abdomen and pelvis. The bone marrow should be biopsied, and—in selected cases
such as high-risk morphology—a lumbar puncture should be performed.
B. Laboratory Findings: The peripheral blood is usually normal, but a number of lymphomas may present in a
"leukemic" phase. In these situations, the distinction between leukemia and lymphoma is arbitrary, as the
malignant cell has the same characteristics. Examples of the diseases that may present as lymphoma or leukemia
are small cell lymphoma (chronic lymphocytic leukemia), small cell plasmacytic lymphoma (Waldenstrom's
Waldenström's macroglobulinemia), follicular small cleaved cell lymphoma (lymphosarcoma cell leukemia),
cutaneous T cell lymphoma (Sezary Sézary syndrome), lymphoblastic lymphoma (T cell acute lymphoblastic
leukemia), and Burkitt's lymphoma (B cell acute lymphoblastic leukemia).
Bone marrow involvement is usually manifested as paratrabecular lymphoid aggregates. In some high-grade
lymphomas, the meninges may be involved and the spinal fluid may contain malignant cells. The chest radiograph
may show a mediastinal mass in lymphoblastic lymphoma.
The serum LDH level is useful in evaluating the extent of disease and the aggressiveness of tumor behavior, with
higher levels indicating more widespread disease.
The diagnosis of lymphoma is made by tissue biopsy. Needle aspiration may yield suspicious results, but usually a
lymph node biopsy (or biopsy of involved extranodal tissue) is required.

Treatment
The indolent lymphomas are usually not curable and are approached with palliative therapy. If patients are
asymptomatic, no initial treatment may be necessary. However, in 1–3 years, the disease will usually progress
and require treatment. Treatment decisions are individualized depending on the patient's age and performance
status and the extent of disease. Initial therapy is based on the alkylating agents. Appropriate regimens include
chlorambucil, 0.6–1 mg/kg every 3 weeks, or combination therapy with cyclophosphamide, vincristine, and
prednisone (CVP). Patients with more aggressive or resistant disease may require more intensive therapy, and
allogeneic bone marrow transplantation may be appropriate for selected younger patients. The role of autologous
transplantation for indolent lymphomas is controversial at this time. Those with apparently localized disease may
be treated initially with local radiation. Low-grade MALT (mucosa-associated lymphoid tissue) lymphomas may
be related to Helicobacter pylori infection, and disease confined to the stomach has responded completely to
antibiotic therapy.
Patients with intermediate and high-grade lymphomas should be treated with curative intent. Irradiation is
occasionally used for localized disease (supplemented by brief intensive chemotherapy), but the mainstay of
therapy is combination chemotherapy. The traditional treatment regimen has been cyclophosphamide,
doxorubicin, vincristine, and prednisone (CHOP) (see Tables 4–2 and 4–3). It remains to be proved that newer
and more intensive regimens produce superior results. For patients who relapse following initial treatment with
chemotherapy, the treatment of choice is autologous stem cell (or bone marrow) transplantation. The role of
autologous transplantation or initial therapy for high-risk patients is promising.

Prognosis
The median survival of patients with indolent lymphomas is 6–8 years. These diseases ultimately become
refractory to chemotherapy. This often occurs at the time of histologic progression of the disease to a more
aggressive form of lymphoma. The prognosis of patients with high-grade lymphomas depends on their response
to chemotherapy. Depending on the initial pathologic subtype and initial bulk of disease, these patients are
variably curable.
With appropriate therapy, approximately 50% of patients with disseminated large-cell lymphomas may be cured.
Results are better in those who are young, are in good clinical condition, and have less advanced stages of
disease. Salvage therapy with autologous bone marrow transplantation may be effective in 50% of cases if the
disease is still responsive to chemotherapy and the patient comes to transplant in good condition and with
minimal tumor bulk.
10130:28:1 The International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for
aggressive non-Hodgkin's lymphoma. N Engl J Med 1993;329:987. (International index and age-adjusted
international index based on tumor stage, serum LDH, and performance status among others useful in predicting
survival.)
10130:28:2 Philip T et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in
relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995;333:1540.
10130:28:3 Roggero E et al: Eradication of Helicobacter pylori infection in primary low-grade gastric
lymphoma of mucosa-associated lymphoid tissue. Ann Intern Med 1995;122:767.