Non-Hodgkin's Lymphoma

Malignant monoclonal proliferation of lymphoid cells in sites of the immune system,

including lymph nodes, bone marrow, spleen, liver, and GI tract.

In the USA, the annual age-adjusted incidence of non-Hodgkin's lymphomas (NHLs)

ranges from 2.6 to 5.8/100,000. Increasing incidence with age is similar to that of acute
leukemia. At age 80, the annual incidence is about 40/100,000.

The NHLs are a heterogeneous group of lymphoid malignancies that share certain features.
Classification of NHLs is controversial and has undergone many revisions. Currently, there
are two complementary approaches: one based on descriptions of lymph node architecture
and histologic features (see Table 74-4) and the other based on the use of immunologic
markers. A new classification based on immunologic markers and histologic features is
shown in Table 74-5.

Etiology and Pathophysiology

The cause of most NHLs is unknown. However, immunosuppressed patients (eg, renal
transplant patients) and patients with abnormally high immune function (eg, those with
collagen-vascular disease) are at greater risk, as are those taking hydantoin drugs (eg,
phenytoin), suggesting that the immune system plays a role. A virus is involved in at least
some cases. Burkitt's lymphoma, endemic in Central Africa, is associated with Epstein-Barr
virus infection. An aggressive T-cell leukemia-lymphoma is associated with human T-cell
lymphotropic virus type I (HTLV-I) infection in Japan and the Caribbean. Patients with
HIV often develop aggressive NHL.

In the pathophysiology of NHL, normal lymphoid tissue is replaced by the malignant

lymphoma, resulting in immunodeficiency and infections. The bone marrow may be
replaced, resulting in pancytopenia and subsequent bleeding and infection. Tumor bulk may
obstruct or invade organs, ultimately causing death.

Symptoms and Signs

NHL appears to be multicentric in origin and is often widespread at presentation. A

leukemic phase, detectable by peripheral blood testing, may occur. Most patients initially
seek medical care because of cervical or inguinal lymph node enlargement. However, the
skin, GI tract, bone, liver, and central nervous system constitute up to 10 to 20% of the
primary sites of lymphoma at presentation. Occasionally, splenomegaly, bone marrow
failure, autoimmune hemolytic anemia, and autoimmune thrombocytopenia are presenting
features. Systemic symptoms (fever, night sweats, loss of weight, pruritus) are not as
common as in Hodgkin's disease. Waldeyer's tonsillar lymphatic ring is commonly
involved in patients with GI lesions. Hypercalcemia is prominent in HTLV-I-related NHL
but is rare in other types. Hypogammaglobulinemia may occur. However, occasionally a
monoclonal serum M spike is found on serum protein electrophoresis and on
immunoelectrophoresis.

Diagnosis

The diagnosis is made by a biopsy of a lymphatic site revealing the histologic features of
malignant lymphoma. Clinical staging of NHL is similar to that of Hodgkin's disease,
although a staging laparotomy is rarely required because the illness is usually disseminated
when discovered. After a complete physical examination, CBC, blood chemistry profile,
bone marrow aspirate, lymph node biopsy, chest x-ray, and abdominal CT scan, about 90%
of patients are found to have stage III or IV disease. Other studies (eg, serum protein
electrophoresis, skeletal x-rays, IV urography) are sometimes useful.

Prognosis and Treatment

In NHL, indicators of a good prognosis are nodular histologic pattern, limited stage, low
number of extranodal sites, and younger age. Marrow involvement is a poor prognostic
sign for high-grade lymphomas but not for low- or intermediate-grade lymphomas. Other
poor prognostic signs are poor performance status, bulky abdominal disease, Hb < 12 g/dL,
and serum LDH > 250 U/L. The rapidity of response to chemotherapy also predicts
survival.

Chemotherapy has the potential to cure only patients with intermediate- and high-grade
lymphomas. Paradoxically, aggressive therapy does not even prolong survival of patients
with low-grade lymphomas, even though these tumors are extremely sensitive to
chemotherapy. Therefore, therapy should be minimal with low-grade tumors and aggressive
with intermediate- and high-grade tumors. Hemolymphopoietic growth factors may also be
used.

Low-grade lymphomas: In stage I or II disease, often no therapy is indicated. The

disease at these stages usually is asymptomatic, except in patients with lymphadenopathy.
The clinical course of low-grade NHL is identical to that of chronic lymphocytic leukemia.
Particularly in the elderly, a practical approach is to withhold treatment and to monitor
closely until problems of progressive disabling constitutional symptoms clearly due to the
NHL develop (ie, progression to stages III and IV). Regional radiation can be used in stage
I or II disease to reduce the local bulky nodes and any resulting compromise of vital
organs. Since most of these patients relapse despite regional radiotherapy, chemotherapy
may be indicated to prevent relapses and to reduce disabling constitutional symptoms.
However, even without chemotherapy, the disease is usually so indolent that it does not
recur for 5 to 10 years.

In stages III and IV, most patients experience only lymphadenopathy. Although most
patients respond to chemotherapy, the relapse rate is 10 to 20% annually. Even though 80 to
90% of patients with favorable prognostic histologic findings achieve a complete
remission, only 10 to 20% are without disease after 10 years. Thus, it seems wise to avoid
both the serious systemic toxicity inherent in aggressive combination chemotherapy and the
risk of acute nonlymphocytic leukemia caused by chronic low-dose alkylating agents.
Chemotherapeutic treatment is reserved for patients with progressive disabling
constitutional symptoms. Most oncologists use a single alkylating agent (eg, chlorambucil
0.4 mg/kg as a single dose for 1 day every 28 days). This so-called pulse therapy has less
myelotoxicity and, perhaps, less leukemogenic potential. Some physicians use relatively
mild combination chemotherapy regimens (see Table 74-6). Local radiation can be used to
reduce bulky nodes.

Intermediate- and high-grade lymphomas: These aggressive NHLs are rapidly

growing tumors with a short natural history. In elderly patients with intermediate- and high-
grade lymphomas who have good functional status and normal organ function, curative
combination chemotherapy is generally feasible. In those elderly patients with poor
functional status and cardiopulmonary, renal, or central nervous system impairment,
chemotherapy is poorly tolerated and rarely successful. Clearly, the physician must weigh
all of these factors before recommending chemotherapy.

Regimens developed specifically for the elderly are available. One such regimen, as shown
in Table 74-6, uses cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine,
and prednisone (CAP/BOP). However, doxorubicin is not well tolerated by the elderly (nor
is methotrexate because it causes renal complications). Nearly identical complete remission
rates were found for patients > 60 and those < 60 treated with this regimen. The toxicity
was the same in both age groups, as was the duration of remission. Overall survival was
62% for those < 60 but only 35% for those > 60. However, most of the excess morbidity
was related to factors other than lymphoma.