Hodgkin’s and Non-Hodgkin’s Lymphomas.
Hodgkin’s Lymphoma (HL)
I. Epidemiology and etiology
A. Incidence. In
1. Age. HL demonstrates a bimodal age-incidence curve in the
2. Sex. About 85% of children with HL are boys. In adults, the nodular sclerosing subtype of HL shows slight women predominance, whereas the other histologic subtypes are more common in men.
B. Risk factors. In Western countries, the first
II. Pathology and natural history
A. Histology.
1. Reed-Sternberg (RS) cells are giant cells that have more than one nucleus and large, eosinophilic, inclusion-like nuclei. The lineage of these cells is probably B-cell lymphocytes. RS cells and the accompanying mononuclear Hodgkin’s cells are the neoplastic cells in HL, surrounded by a reactive cellular infiltrate. RS cells usually express CD15 (LeuM 1) and CD30 (Ki-1, an antigen that is also expressed in anaplastic large cell lymphoma). Infrequently, RS cells can coexpress CD20 or LCA (CD45).
a. Lymphocyte and histiocyte cells (L&H cells) are RS-like and were identified iodular lymphocyte-predominance HL. They manifest B-cell markers (CD20) and LCA (CD45). Although the L&H cells are believed to be of monoclonal origin, these B-cell infiltrates may be polyclonal.
b. The lacunar cell, a variant of the RS cell, characterizes nodular sclerosing HL and is often far more plentiful than classic RS cells in that subtype.
c. RS-like cells are found in a variety of infectious, inflammatory, and neoplastic disorders, including infectious mononucleosis, lymphoid hyperplasia associated with phenytoin therapy, and immunoblastic lymphomas.
2. The pathologic diagnosis of HL depends on the presence of RS cells and their variants in an appropriate pathologic milieu. The bulk of lymphatic tissue involved by HL is not composed of neoplastic cells but rather a variety of normal-appearing lymphocytes, plasma cells, eosinophils, neutrophils, and histiocytes existing in different proportions in the various histologic subtypes.
3. The
4. The World Health Organization (WHO) classification, which has not yet been correlated with clinical behavior, divides HL into nodular lymphocyte predominance HL and classic HL. Classic HL in this newer classification system comprises the lymphocyte-rich, NS, MC, and LD varieties.
a. Nodular LP HL is now clearly recognized to be an indolent B-cell NHL and not true HL. This variety has L&H cells that are positive for CD20 and other B-cell markers, but no typical RS cells. For that reason, nodular LPHL is distinguished from classic HL in the new WHO classification.
b. Diffuse LP HL in the
B. Mode of spread. HL almost always originates in a lymph node. Whenever a primary diagnosis of HL is made in an extranodal site without contiguous nodal involvement, the diagnosis should be highly suspect. For much of its natural history, HL appears to spread in an orderly fashion through the lymphatic system by contiguity. Histologic types other than NS, however, often skip the mediastinum, and disease appears in the neck and upper abdomen. Hematogenous dissemination occurs late in the course of disease and is characteristic of the LD subtype.
C. Sites of involvement. The axial lymphatic system is almost always affected in HL, whereas distal sites (e.g., epitrochlear and popliteal) are rarely involved.
1. Peripheral lymph nodes. Cervical or supraclavicular lymphadenopathy occurs in more than 70% of cases. Axillary and inguinal lymph nodes are less frequently involved. Generalized lymphadenopathy is atypical of HL. Left supraclavicular lymphadenopathy is more strongly associated with abdominal involvement than is right-sided disease.
2. Thoraxю: a. The anterior mediastinum is a prime location for NS HL; b. Mediastinal precedes hilar lymph node involvement. Lung involvement may occur by direct contiguity with hilar involvement in HL as well as by hematogenous dissemination; c. Pulmonary involvement by HL may produce discrete nodules and irregular, interstitial, or even lobar infiltrates; d. Pleural effusion may occur secondary to mediastinal compression of vascular-lymphatic drainage and by direct pleural involvement. Chylous effusions occasionally occur; e. Pericardial involvement may be found on CT scans, but overt cardiac tamponade is uncommon; f. Superior vena cava syndrome may occur in HL but is more frequent in NHL.
3. Spleen, liver, and upper abdomen
a. The spleen, splenic hilar nodes, and celiac nodes are the earliest abdominal sites of involvement in infradiaphragmatic HL. Mesenteric lymph nodes are rarely involved by HL.
b. At least 25% of spleens not clinically enlarged harbor occult HL at laparotomy, and as many as half of spleens believed to be enlarged on physical examination or radiologic assessment are histologically normal.
c. Liver involvement is uncommon at diagnosis and is almost always associated with infiltration of the spleen.
4. Retroperitoneal lymph node involvement tends to occur relatively late in the course of supradiaphragmatic HL and after spleen, splenic hilar, and celiac nodal involvement. Periaortic involvement without splenic involvement is uncommon. The retroperitoneal nodes are, however, affected early in the course of inguinal presentations of HL.
5. The bone marrow is rarely involved at the time of diagnosis of HL. Patients with advanced-stage disease, systemic symptoms, and MC or LD histologies have a higher risk for bone marrow involvement. Biopsy is mandatory to evaluate the bone marrow because HL is difficult to diagnose on marrow aspirates.
6. Bone. Osseous involvement of HL usually produces an osteoblastic reaction mimicking prostatic carcinoma. Extradural masses may result in spinal cord compression. Sternal erosion by mediastinal NS HL may occur.
7. Other extranodal sites are rarely involved in HL. Skin involvement is rare and usually a late manifestation of disease. CNS involvement is uncommon with the exception of spinal cord compression. Clinical involvement of meninges, brain, Waldeyer’s ring, GI tract, kidney, and other extranodal sites is rare and suggests an alternative diagnosis.
D. Immune abnormalities and infections. Progressive loss of cell-mediated immunity with the development of cutaneous anergy, lymphocytopenia, and increased susceptibility to a variety of organisms is associated with advancing HL, even in the absence of therapy. Treatment with chemotherapy, corticosteroids, and radiation therapy (RT) accentuates these abnormalities. Late in the course of HL, hypogammaglobulinemia may also develop.
1. Infections associated with depressed cell-mediated immunity and therapy (particularly corticosteroids) includes Listeria, Toxoplasma, and Mycobacterium species, fungi, and slow viruses (such as progressive multifocal leukoencephalopathy). Patients treated with corticosteroids are at particularly increased risk for infections with Pneumocystis carinii and cytomegalovirus.
2. Herpes zoster appears in more than 25% of patients, particularly in patients with irradiated dermatomes and in those undergoing splenectomy. Generalized cutaneous involvement is not uncommon, but visceral involvement is rare.
3. Splenectomy-related infections involve encapsulated microorganisms, particularly pneumococci, and less commonly Haemophilus influenzae and Salmonella species, especially in children. Pneumococcal infection in an asplenic host can be rapidly fatal. Vaccination with polyvalent pneumococcal vaccine is recommended before splenectomy, although its effectiveness in this population is not certain. Early aggressive treatment with antibiotics of all febrile patients after splenectomy is mandatory.
III. Staging system and prognostic factors
A. Staging is the most crucial determinant of prognosis and treatment in HL. The
1. Cotswolds staging classification of HL
Stage Description
I Involvement of a single lymph node region or lymphoid structure
II Involvement of two or more lymph node regions on the same side of the diaphragm (the mediastinum is considered as a single site, whereas hilar lymph nodes are lateralized). The number of anatomical sites should be indicated by a subscript (e.g., II3)
III Involvement of lymph node regions or structures on both sides of the diaphragm
III1 With involvement of splenic hilar, celiac, or portal nodes
III2 With involvement of paraaoartic, iliac, and mesenteric nodes
IV Involvement of one or more extranodal sites in addition to a site for which the designation “E” has been used
2. Designations applicable to any disease stage
A No symptoms
B Fever (temperature higher than
X Bulky disease: mediastinal mass exceeding one third the maximum transverse diameter of the chest or the presence of a nodal mass with a maximal dimension greater than
E Involvement of a single extranodal site that is contiguous or proximal to a knowodal site
CS Clinical stage
PS Pathologic state (as determined by laparotomy or biopsy)
B. Prognostic factors
1. Stage is clearly the single most important prognostic factor in HL. Within each stage, the presence of B symptoms confers a poorer prognosis. About 60% of patients with HL in the
2. Histopathology was formerly closely related to prognosis. With advances in therapy, the value of histopathologic subtype as an independent prognostic variable (apart from stage) is less clearly defined.
3. Age greater than 60 years, anemia, elevated ESR, bone marrow involvement, bulk of disease, and poor Karnofsky’s scale performance status are so closely correlated with stage, systemic symptoms, and histopathology that it is difficult to prove independent prognostic importance.
4. Adverse prognostic factors were evaluated by an international group in a multivariate retrospective analysis of 4,695 patients, mostly with extensive disease. Patients with no adverse factors had an 84% freedom from progression, whereas the presence of each factor depressed the freedom from progression curve plateau by about 8%. Interestingly, neither tumor bulk nor histology emerged as independent factors. The seven independent prognostic factors identified were as follows: Male sex (1.35); Age ≥ 45 years (1.39); Stage IV disease (1.26); Hemoglobin < 10.5 g/dL (1.35); White cell count (WBC) > 15,000/µL (1.41); Lymphocytes: (1.38): Count < 600/µL or < 8% of WBC; Serum albumin < 4 g/dL (1.49).
IV. Diagnosis
Clinical evaluation. Staging evaluation
1. Adequate surgical biopsy reviewed by experienced hematopathologist.
2. Thorough history and physical examination
3. Laboratory tests: CBC, serum chemistries, protein electrophoresis, ESR, urinalysis
4. CT scan of chest (include neck), abdomen, and pelvis with contrast
5. Bone marrow aspiration and biopsy (bilateral iliac crest) unless clinical stage IA to IIA with no anemia or other blood count depression
6. Bone scan in presence of bone pain, or elevated serum alkaline phosphatase or calcium level
7. 67Ga scans, particularly with high-dose single photon emission computed tomography scans (SPECT), and positron emission tomography (PET) scans are optional but are useful in follow-up of residual masses on chest radiograph or CT scan after therapy.
8. Bone radiographs to corroborate findings on bone scan or in presence of bone pain
Definition of an adequate staging laparotomy:
a. Wedge and needle biopsies of both lobes of the liver
b. Splenectomy with removal of splenic hilar lymph nodes
c. Biopsies of random celiac, iliac, portal, and mesenteric nodes; any node that is enlarged or feels abnormal; and equivocal or abnormal nodes on LAG. Radiopaque clips are used to delineate sites of biopsies and large masses for treatment planning.
d. Open iliac crest bone marrow biopsy
e. Oophoropexy for young women, but the declining use of pelvic radiation has virtually eliminated this indication.
Potential complications of staging laparotomy. The operative mortality rate should be less than 0.5% and the significant morbidity rate less than 5% to justify this procedure. The most common anticipated complications include pneumonitis, pulmonary embolism, pancreatitis, and subdiaphragmatic abscess. Overwhelming pneumococcal sepsis is also a potential complication; patients who have undergone splenectomy should carry penicillin and must report any incident of fever or chills to a physician immediately.
V. Management: primary therapy
A. Treatment philosophy. More than one treatment approach may be used in the management of cases of HL. The challenge is to determine a course of therapy that preserves cure while minimizing long-term neoplastic and nonneoplastic complications.
B. Surgery is limited to diagnosis, possibly laparotomy, and splenectomy for the rare patient with hypersplenism, and laminectomy for spinal cord compression.
C. RT alone is used in the
1. Radiation dose. HL may be locally sterilized in almost all cases with 3500 to 4500 cGy given at a rate of about 1000 cGy per week. 2. Radiation fields: a. Mantle field encompasses the cervical, supraclavicular, infraclavicular, axillary, hilar, and mediastinal lymph nodes to the level of the diaphragm. Preauricular fields are added for patients with high cervical lymph adenopathy. The lungs and much of the heart are shielded by lead blocks, although many radiotherapists administer some radiation (1500 cGy or less) to the lung on the involved side, if hilar lymph nodes are enlarged. The whole heart may be treated if the pericardium is involved. A small gap must be left between the inferior border of the mantle field and the superior border of the periaortic field to obviate potential severe spinal cord injury caused by overlap; b. Inverted-Y field includes the spleen or splenic pedicle and the celiac, periaortic, iliac, inguinal, and femoral lymph nodes. The kidneys, much of the pelvic marrow, and the testes are shielded.
c. Spade and pelvic fields. The inverted-Y field may be divided into a spade field encompassing the splenic pedicle (or spleen) and periaortic nodes, and a pelvic field, including the iliac, inguinal, and femoral lymph nodes.
d. Subtotal nodal or subtotal lymphoid irradiation consists of mantle and spade fields.
e. Total nodal or total lymphoid irradiation is uncommonly used and consists of mantle and inverted-Y fields.
f. Involved-field radiation therapy (IFRT) consists of sites of known disease only and is used with curative intent only in combination with chemotherapy. It has become the most common use of RT in HL.
D. Combination chemotherapy is used for stage III, stage IV, and bulky disease. Chemotherapy is preferable for patients with early-stage disease and B symptoms, usually in combination with RT. The selection among the available regimens is often guided by the desire to avoid long-term toxici-ties associated with specific treatments. The advent of the nonleukemogenic, gonadal-sparing ABVD chemotherapy regimen expanded the use of chemotherapy to patients with earlier stages and obviated the need for laparotomy.
1. Useful chemotherapy regimens for HL. Different regimens must be strictly followed because delays in therapy or reduction in dosages not indicated by the protocol can clearly compromise results. The total dose and dose rate (dose intensity) are important in achieving cure.
2. MOPP regimen. The National Cancer Institute (NCI) recommends that vincristine should not be limited to a 2-mg maximum dosage in this regimen, but most clinicians sustain the 2-mg limit.
a. MOPP therapy is administered in 28-day cycles for two additional cycles beyond the attainment of a restaged complete response (CR) and a minimum of six cycles (months).
b. The CR rate using the MOPP regimen is between 70% and 80% for stages III and IV HL. About 60% to 70% of CR cases are durable, with relapses rare after 42 months. Half of patients are cured, with some deaths caused by treatment-related or unrelated disease. More than 80% of patients with stage IIIA or IVA disease survive 10 years without disease. Histologic subtype appears to have little effect on results with MOPP.
c. Maintenance therapy beyond the initial complete course is unnecessary and not recommended.
d. The MOPP regimen is associated with significant toxicities, including hematosuppression, nausea, neuropathy, leukemogenesis, and infertility.
3. ABVD regimen is at least as effective as and probably superior to the MOPP regimen but has much less reported leukemogenesis and infertility. Potential cardiac toxicity caused by doxorubicin and potential pulmonary toxicity caused by bleomycin have been infrequent problems using this schedule but are of concern, especially when combined with RT. ABVD-based treatment has replaced MOPP as the standard regimen for HL.
a. Generally, the same therapeutic rules as with the MOPP regimen apply: six to eight monthly cycles are usually administered, and at least two cycles beyond maximum response.
b. Pulmonary function should be monitored. If dyspnea, pneumonitis, or significant reduction of more than 40% of lung diffusion capacity is noted, bleomycin should be discontinued. Bleomycin pneumonitis usually responds to corticosteroids.
c. Cardiac function should be monitored in patients with preexisting heart disease and in those receiving high cumulative doses of doxorubicin.
VI. Special clinical problems in HL
A. Sequelae and complications of therapy
1. Hypothyroidism. Overt hypothyroidism can be expected in 10% to 20% of patients and elevation of serum TSH in up to 50% of patients treated with mantle-field RT. Replacement therapy corrects the problem.
2. Sterility. RT poses problems for female patients who receive pelvic irradiation. The testes are shielded during irradiation. MOPP and similar therapies produce near-universal sterility in male patients and can be anticipated to produce sterility in women in their late 20s or older. ABVD is not associated with sterility. Sperm banking is encouraged in male patients about to receive MOPP or similar therapies, or autologous stem cell transplantation.
3. Lung damage
a. Radiation pneumonitis. Mantle-field irradiation routinely produces a paramediastinal fibrosis that is usually not clinically significant. When large ports are necessitated by large mediastinal-hilar masses, the potential for more severe reaction exists. In addition, patients given MOPP who have a prior history of mantle-field irradiation may experience an abrupt episode of pneumonitis, presumably secondary to steroid withdrawal. Therefore, prednisone is omitted from MOPP after mantle-field irradiation, even if the radiation was administered years earlier.
b. Bleomycin pulmonary toxicity. Almost all patients treated with bleomycin (in ABVD and the like) experience a reduction in their lung diffusion capacity. This reduction is usually asymptomatic and slowly improves after treatment. Severe idiopathic pulmonary toxicity is occasionally seen at bleomycin doses of more than 50 mg, although it usually does not occur until cumulative doses exceed 200 mg/m2. More severe pulmonary toxicity (pulmonary infiltrates, restrictive defects, exertional dyspnea) is reported when bleomycin is given in combination with mediastinal RT. These adverse effects depend partly on the total dose of bleomycin and the radiation field. Because the pulmonary toxicity of the combination of ABVD and RT can be fatal rarely, some recommend the use of ABVD alternating with MOPP if a full course of chemotherapy and mediastinal irradiation is planned.
4. Cardiac damage
a. Radiation. The risk for radiation pericarditis is relatively small when modern anteroposterior weighted radiation ports are used and when large portions of the heart are not radiated. Radiation pericarditis with or without pericardial effusion or tamponade can develop, however. Constrictive pericarditis is a rare complication ofRT.
b. Chemotherapy. Doxorubicin, which is a component of ABVD and related regimens, is a well-known cardiotoxic agent. The incidence of cardiotoxicity is related to the cumulative dose and probably to peak serum levels. The cumulative dose of doxorubicin in ABVD is usually 300 mg/m2, below the clinically significant cardiotoxic level when given without radiation. Administration of mediastinal RT, however, increases the chance of cardiomyopathy, pericarditis, or coronary artery disease as well as the potential for delayed cardiomyopathy.
5. Aseptic necrosis of the femoral heads has been reported and is probably secondary to prednisone therapy in MOPP.
6. Depressed cellular immunity
7. Secondary neoplasms
a. Acute myelogenous leukemia, often preceded by a prodrome of myelodysplastic syndrome, develops in 2% to 10% of patients treated with MOPP or similar combined-modality therapy. The problem appears to be greatest in patients older than 40 years of age and may be increased in patients undergoing splenectomy. The leukemia generally occurs between 3 and 10 years after treatment, is often associated with total or partial deletion of chromosomes 5 and 7, and has an extremely poor prognosis. Acute leukemia is extremely uncommon in patients treated with RT alone and appears to be rare in patients treated with ABVD.
b. NHL may occur during the course of HL and may represent an evolution of the natural history of disease rather than a treatment complication. Most reported cases are high-grade B-cell tumors, with a particularly high incidence in cases of LP HL (especially the nodular variant). High-grade peripheral T-cell lymphomas have also complicated HL, particularly the NS type.
c. Epithelial tumors and sarcomas are being increasingly reported as complications of RT and possibly of combined-modality therapy, and actuarial statistics suggest a rate of second neoplasms exceeding 20% with prolonged follow-up. Tumors may include breast cancer, sarcoma, melanoma, lung cancer, and other solid tumors. The relative risk for cancer appears to be higher for younger patients and synergistic to other predisposing factors. This significant risk applies to a patient population treated in the 1960s and 1970s; modern strategies limiting radiation exposure may reduce this risk.
8. Neurologic complications
a. Lhermitte’s sign, which follows thoracic irradiation for HL, is an innocuous but worrisome finding for the patient. It consists of shock-like sensations down the back and legs, often precipitated by flexing the neck, and it gradually disappears.
b. Transverse myelopathy is a rare but serious complication of RT that is usually caused by failure to leave an appropriate gap between the mantle and abdominal ports.
9. Retroperitoneal fibrosis has been described as a complication of HL treatment.
B. Synchronous neoplasms. HL is said to be associated with an increased risk for simultaneous Kaposi’s sarcoma, leukemia, NHL, and myeloma.
C. Nephrotic syndrome, as a remote effect of malignancy, occurs most often in patients with HL. Lipoid nephrosis is typical
D. Pregnancy in HL.
1. Limit staging procedures that may expose the fetus to radiation. When lymphangiography would affect treatment, it may be performed after the first trimester; the important modification is that only one abdominal film is taken 24 hours after injection of dye (fetal dose is less than 1 cGy).
2. If the disease is diagnosed during the first trimester, either perform a TAB (therapeutic abortion) and proceed as usual or delay chemotherapy or RT until later in the pregnancy.
3. If the disease is diagnosed during the second or third trimester:
a. Try to delay therapy until delivery if the mother’s outcome will not be adversely affected.
b. If therapy is necessary, proceed with proper counseling regarding possible growth and developmental abnormalities.
c. Very limited-field RT has been largely successful. Internal scatter from standard mantle field RT can result in fetal exposure of 50 to 250 cGy.
4. Non-Hodgkin lymphoma is generally a more virulent disease and poses a greater risk to the mother and secondarily to the fetus than does HL. Therapeutic recommendations parallel HL, except for the possibility of protracted delay of treatment with indolent lymphomas.
E. Genetic counseling. Retrospective studies and case reports of patients who were treated for malignancy in childhood or adolescence and bore children later show a 4% rate of major malformations in offspring. This rate is similar to the risk borne by the general population. The late effects of cancer treatment on infants exposed in utero are unknown. Female survivors of cancer who later become pregnant, particularly those who have had abdominal radiation, have an increased rate of preterm delivery and low-birthweight infants.
F. Ichthyosis. Adult-onset ichthyosis is associated with HL in 75% of cases
Non-Hodgkin’s Lymphoma (NHL)
I. Epidemiology and etiology
A. Incidence. In
NHL occurs roughly eight times as frequently as HL, with about 57,000 new cases annually in the
B. Age and sex. Small lymphocytic lymphomas occur in the elderly. Lymphoblastic lymphoma has a predilection for male adolescents and young adults. Follicular lymphomas occur mainly in middle-adult life. Burkitt lymphoma occurs in children and young adults.
C. Etiology. Viral etiology and abnormal immune regulation have been implicated in the development of lymphomas. The two mechanisms may be interrelated. An etiologic agent, however, can be identified in only a minority of cases.
1. Pathogens: a. RNA viruses. The human T-cell lymphotrophic virus type 1 (HTLV-1) is associated with adult T-cell leukemia-lymphoma (ATLL). HIV produces AIDS, and the resultant immune deficiency is associated with high-grade B-cell lymphomas. Chronic hepatitis C virus infection has been associated with indolent B-cell lymphoma.
b. DNA viruses. EBV has been found in the genome of African Burkitt lymphoma cells. This virus has also been associated with lymphomas in situations characterized by reduced immune surveillance, such as in patients with the X-linked lymphoproliferative syndrome, organ transplantation, and, in many instances, HIV-associated lymphoma.
c. Chronic H. pylori infection of the gastric mucosa is clearly associated gastric lymphoma. Eradication of the infection produces remission in more than two thirds of patients.
2. Immunodeficiency or immune dysregulation states associated with development of lymphomas include the following:
a. AIDS; b. Organ transplant recipients; c. Congenital immunodeficiency syndromes (e.g., agammaglobulinemia, ataxia-telangiectasia, Wiskott-Aldrich syndrome); d. Autoimmune disorders (e.g., SjÖgren’s syndrome, rheumatoid disease, lupus erythematosus, Hashimoto’s thyroiditis). Diphenylhydantoin may cause a spectrum from benign lymphoproliferation to frank lymphoma.
3. Treatment related. The potential role of chemotherapy or RT in the development of NHL after HL and myeloproliferative disorders remains uncertain.
II. Pathology and natural history
A. Classification systems for NHL.
Grade Malignant lymphoma type
Low-grade A. Small lymphocytic
CLL-type
Plasmacytoid
B. Follicular, small cleaved cell
C. Fallicular, mixed (small cleaved and large cell)
Intermediate-grade D. Follicular, large cell
E. Diffuse, small cleaved cell
F. Diffuse, mixed cell (small and large cell)
High-grade G. Diffuse, large cell
H. Immunoblastic (large cell)
I. Lymphoblastic
J. Small, non-cleaved
Burkitt
Non-Burkitt
There is subclassification of disease:
B-cell
Largecell/Immunoblastic
Favorable
Unfavorable
Mantle cell
Burkitt’s
T-cell
Peripheral
Anaplastic
Lymphoblastic
III. Staging system and prognostic factors
A. The
B. Survival
1. Low-grade lymphomas are rarely curable and appear to cause a steady percentage of deaths annually. It is possible that the rare, early stages of low-grade NHL (stage I or II) may be curable in some cases, but even this is uncertain. Survival time averages between 6 and 10 years for follicular lymphomas.
2. Intermediate-grade and high-grade lymphoma survival curves generally display two components: a rapid fall off in the first 1 to 2 years followed by an eventual plateau representing a presumptively cured population. About 80% to 90% of patients with stage I or early stage II disease and 30% to 40% with stage III or IV intermediate/high-grade lymphomas may be curable.
C. Prognostic factors
1. Low-grade lymphomas
a. Sensitivity to therapy is a prognostic sign in that the attainment of a CR or an excellent partial response (PR) identifies patients who are likely to do well.
b. Early stage. Stage I and II cases constitute less than 15% of all patients with low-grade lymphoma. In one small series, 80% of stage I and II patients younger than 40 years of age who were treated with RT were disease free 10 years after diagnosis.
c. Follicular mixed (small cleaved and large cell) lymphomas. Although these lymphomas are probably rarely curable, extremely long-term remissions have been reported by some institutions using regimens both with and without doxorubicin. Other authorities believe that there is little difference, if any, in responsiveness to treatment or duration of remission between follicular small cleaved and mixed NHL.
2. Intermediate/high-grade lymphoma. Stage I or II presentations, constituting 30% to 40% of these lymphomas, are highly curable (about 80%), although tumor bulk (more than
a. Age (older than 60 years of age, adverse)
b. Stage I or II versus III or IV (III and IV, adverse)
c. Number of extranodal sites (more than 1 site, adverse)
d. Performance status (low status, adverse)
e. Serum LDH (elevated level, adverse)
IV. Management
A. Surgery is limited to the following indications:
1. Biopsy for diagnosis. Staging laparotomy is rarely conducted.
2. Splenectomy for large spleens and significant hypersplenism.
3. Resection may be indicated in primary GI lymphoma.
B. Therapy for indolent lymphomas
1. True stage I and II disease (15% cases): RT to a dose of 3500 to 4000 cGy may be administered to all known sites of disease (including draining lymph nodes in E presentation). Large RT fields do not increase the cure rate and may decrease tolerance to chemotherapy later. Prolonged disease-free survival has been reported in some patients.
2. Stage III and IV disease
a. No treatment. Most patients with advanced indolent disease may be observed with no therapy and without adverse influence on survival. Therapy is instituted in the presence of any systemic symptoms, rapid nodal growth, or imminent complications of the disease, such as obstructive phenomena or effusions. The median times to “requiring therapy” vary from 16 months for the follicular, mixed group, to 48 months for the follicular, small cleaved group, to 72 months for the small lymphocytic group. Spontaneous remissions may occur during the period of no therapy.
b. Single-agent therapy with chlorambucil or cyclophosphamide gives good responses that may develop slowly in indolent NHL. Cyclophosphamide has the disadvantages of alopecia and hemor-rhagic cystitis. Data suggest that the purine analogues, fludarabine and cladribine, may exhibit activity rivaling the alkylating agents, but relatively few previously untreated patients have been reported. Up to 40% to 50% of patients with previously treated low-grade lymphomas respond to these purine analogues. Dosages are as follows:
(1) Chlorambucil, 4 to 6 mg/m2
(2) Fludarabine, 25 mg/m2 IV daily for 5 days every 4 weeks
(3) Cladribine, 0.14 mg/kg per day IV over 2 hours for 5 days every 4 weeks, or 0.1 mg/kg/day by continuous IV infusion for 7 days every 4 weeks
c. Combination chemotherapy. Multiagent therapy may be used if a rapid response is required. Chlorambucil or cyclophosphamide plus corticosteroids in pulse doses, and fludarabine plus mitox-antrone combinations are commonly used regimens. Single-agent or combination chemotherapy produces CRs or excellent PRs 60% to 80% of patients. Doxorubicin-containing regimens have no clear advantages for low-grade NHL and are often reserved for later stages of the disease or adverse presentations. Treatment is generally continued until a maximum response is achieved. Maintenance chemotherapy does not appear to prolong survival, may compromise further treatment, and is potentially leukemogenic.
d. IFN-α has demonstrable activity in the follicular lymphomas. No clear-cut dose schedule is superior, and doses as low as 2 to 3 million U three times weekly may produce responses in up to 40 to 60% of patients. The place of IFN-α in the routine management of follicular lymphoma is not clear. It has been used in several randomized studies as part of either induction or maintenance therapy for previously untreated patients. Results of some of these series suggest a potentiation of response rates, a prolongation of remission duration, and possibly an effect of IFN-α on survival.
e. RT
(1) Palliative RT is used for sites of bulky disease and to relieve obstruction or pain. RT alone may be used when most of the disease sites do not require treatment but one or two areas are troublesome. However, multiple courses of RT exhaust the marrow and are discouraged when chemotherapy is an effective alternative.
(2) “Limited” stage III. Although some series have observed long-term disease-free survival with total lymphoid radiation for highly selected stage III presentations (e.g., no bulky disease, asymptomatic, fewer than five involved sites), this approach is not generally accepted for most patients.
Burkitt lymphoma (BL) is a specific subtype of the small noncleaved cell high-grade NHL. The cells in BL are very uniform with round or oval nuclei, two to five prominent nucleoli, and cytoplasm rich in RNA. The cells are of B lineage, expressing monoclonal surface IgM. A consistent series of cytogenetic translocations and explosive growth characterizes BL.
1. Epidemiology and etiology
a. BL is endemic in certain regions of equatorial
b. EBV has been found in the genome of endemic BL but rarely in the sporadic form. Very high EBV antibody titers are seen in the endemic form.
2. Staging system. A variety of systems have been proposed. The NCI system is as follows:
Stage Disease distribution
A Single solitary extra-abdominal site
B Multiple extra-abdominal sites
C Intra-abdominal tumor
D Intra-abdominal plus one or more extra-abdominal sites
AR Intra-abdominal: more than 90% of tumor resected
3. Prognosis. Before effective treatment, only 30% of sporadic cases survived. Using combination chemotherapy and CNS prophylaxis, the survival rate is at least 60%. Children and young adults with limited (A, B, AR) disease have an excellent prognosis with a 90% survival rate. Bone marrow and CNS involvement carry a poor prognosis. Adult cases of BL, particularly those of advanced stage, do more poorly than childhood cases.
4. Treatment
a. Cyclophosphamide therapy alone has been curative for many localized presentations in
b. Multiagent, aggressive regimens are necessary for the sporadic form as well as for Burkitt-like NHL. One such program combines cyclophosphamide, vincristine (Oncovin), methotrexate, and prednisone (COMP) with CNS prophylaxis.
c. Because of the extremely rapid growth rate, massive acute destruction of tumor with initial chemotherapy usually results in tumor lysis syndrome.
Prepared by Prof. G.S. Moroz
