Precursor Cell B Cell Neoplasms
Precursor B Cell Lymphoblastic Leukemia/Lymphoma
The most common cancer in childhood is B cell ALL. Although this disorder can also present as a lymphoma in either adults or children, presentation as lymphoma is rare.
The malignant cells in patients with precursor B cell lymphoblastic leukemia are most commonly of pre–B cell origin. Patients typically present with signs of bone marrow failure such as pallor, fatigue, bleeding, fever, and infection related to peripheral blood cytopenias. Peripheral blood counts regularly show anemia and thrombocytopenia but might show leukopenia, a normal leukocyte count, or leukocytosis based largely on the number of circulating malignant cells (Fig. 110-5). Extramedullary sites of disease are frequently involved in patients who present with leukemia, including lymphadenopathy, hepato- or splenomegaly, CNS disease, testicular enlargement, and/or cutaneous infiltration.
Acute lymphoblastic leukemia. The cells are heterogeneous in size, have round or convoluted nuclei, high nuclear/cytoplasmic ratio, and absence of cytoplasmic granules.
The diagnosis is usually made by bone marrow biopsy, which shows infiltration by malignant lymphoblasts. Demonstration of a pre–B cell immunophenotype (Fig. 110-2) and, often, characteristic cytogenetic abnormalities (Table 110–6) confirm the diagnosis. An adverse prognosis in patients with precursor B cell ALL is predicted by a very high white cell count, the presence of symptomatic CNS disease, and unfavorable cytogenetic abnormalities. For example, t(9;22), frequently found in adults with B cell ALL, has been associated with a very poor outlook. The bcr/abl kinase inhibitors have improved the prognosis.
Treatment: Precursor B Cell Lymphoblastic Leukemia
The treatment of patients with precursor B cell ALL involves remission induction with combination chemotherapy, a consolidation phase that includes administration of high-dose systemic therapy and treatment to eliminate disease in the CNS, and a period of continuing therapy to prevent relapse and effect cure. The overall cure rate in children is 90%, while ∼50% of adults are long-term disease-free survivors. This reflects the high proportion of adverse cytogenetic abnormalities seen in adults with precursor B cell ALL.
Precursor B cell lymphoblastic lymphoma is a rare presentation of precursor B cell lymphoblastic malignancy. These patients often have a rapid transformation to leukemia and should be treated as though they had presented with leukemia. The few patients who present with the disease confined to lymph nodes have a high cure rate.
Mature (Peripheral) B Cell Neoplasms
B Cell Chronic Lymphoid Leukemia/Small Lymphocytic Lymphoma
B cell CLL/small lymphocytic lymphoma represents the most common lymphoid leukemia, and when presenting as a lymphoma, it accounts for ∼7% of non-Hodgkin's lymphomas. Presentation can be as either leukemia or lymphoma. The major clinical characteristics of B cell CLL/small lymphocytic lymphoma are presented in Table 110–10.
Table 110–10 Clinical Characteristics of Patients with Common Types of Non-Hodgkin's Lymphomas (NHL) |Favorite Table|Download (.pdf)
Table 110–10 Clinical Characteristics of Patients with Common Types of Non-Hodgkin's Lymphomas (NHL)
|Disease||Median Age, years||Frequency in Children||% Male||Stage I/II vs III/IV, %||B Symptoms, %||Bone Marrow Involvement, %||Gastrointestinal Tract Involvement, %||% Surviving 5 years|
B cell chronic lymphocytic
leukemia/small lymphocytic lymphoma
|65||Rare||53||9 vs 91||33||72||3||51|
|Mantle cell lymphoma||63||Rare||74||20 vs 80||28||64||9||27|
|Extranodal marginal zone B cell lymphoma of MALT type||60||Rare||48||67 vs 33||19||14||50||74|
|Follicular lymphoma||59||Rare||42||33 vs 67||28||42||4||72|
|Diffuse large B cell lymphoma||64||~25% of childhood NHL||55||54 vs 46||33||16||18||46|
|Burkitt's lymphoma||31||~30% of childhood NHL||89||62 vs 38||22||33||11||45|
|Precursor T cell lymphoblastic lymphoma||28||~40% of childhood NHL||64||11 vs 89||21||50||4||26|
|Anaplastic large T/null cell lymphoma||34||Common||69||51 vs 49||53||13||9||77|
|Peripheral T cell non-Hodgkin's lymphoma||61||~5% of childhood NHL||55||20 vs 80||50||36||15||25|
The diagnosis of typical B cell CLL is made when an increased number of circulating lymphocytes (i.e., >4 × 109/L and usually >10 × 109/L) is found (Fig. 110-6) that are monoclonal B cells expressing the CD5 antigen. Finding bone marrow infiltration by the same cells confirms the diagnosis. The peripheral blood smear in such patients typically shows many “smudge” or “basket” cells, nuclear remnants of cells damaged by the physical shear stress of making the blood smear. If cytogenetic studies are performed, trisomy 12 is found in 25–30% of patients. Abnormalities in chromosome 13 are also seen.
Chronic lymphocytic leukemia. The peripheral white blood cell count is high due to increased numbers of small, well–differentiated, normal-appearing lymphocytes. The leukemia lymphocytes are fragile, and substantial numbers of broken, smudged cells are usually also present on the blood smear.
If the primary presentation is lymphadenopathy and a lymph node biopsy is performed, pathologists usually have little difficulty in making the diagnosis of small lymphocytic lymphoma based on morphologic findings and immunophenotype. However, even in these patients, 70–75% will be found to have bone marrow involvement and circulating monoclonal B lymphocytes are often present.
The differential diagnosis of typical B cell CLL is extensive (Table 110–1). Immunophenotyping will eliminate the T cell disorders and can often help sort out other B cell malignancies. For example, only mantle cell lymphoma and typical B cell CLL are usually CD5 positive. Typical B cell small lymphocytic lymphoma can be confused with other B cell disorders, including lymphoplasmacytic lymphoma (i.e., the tissue manifestation of Waldenström's macroglobulinemia), nodal marginal zone B cell lymphoma, and mantle cell lymphoma. In addition, some small lymphocytic lymphomas have areas of large cells that can lead to confusion with diffuse large B cell lymphoma. An expert hematopathologist is vital for making this distinction.
Typical B cell CLL is often found incidentally when a complete blood count is done for another reason. However, complaints that might lead to the diagnosis include fatigue, frequent infections, and new lymphadenopathy. The diagnosis of typical B cell CLL should be considered in a patient presenting with an autoimmune hemolytic anemia or autoimmune thrombocytopenia. B cell CLL has also been associated with red cell aplasia. When this disorder presents as lymphoma, the most common abnormality is asymptomatic lymphadenopathy, with or without splenomegaly. The staging systems predict prognosis in patients with typical B cell CLL (Table 110–7). The evaluation of a new patient with typical B cell CLL/small lymphocytic lymphoma will include many of the studies (Table 110–11) that are used in patients with other non-Hodgkin's lymphomas. In addition, particular attention needs to be given to detecting immune abnormalities such as autoimmune hemolytic anemia, autoimmune thrombocytopenia, hypogammaglobulinemia, and red cell aplasia. Molecular analysis of immunoglobulin gene sequences in CLL has demonstrated that about half the patients have tumors expressing mutated immunoglobulin genes and half have tumors expressing unmutated or germ-line immunoglobulin sequences. Patients with unmutated immunoglobulins tend to have a more aggressive clinical course and are less responsive to therapy. Unfortunately, immunoglobulin gene sequencing is not routinely available. CD38 expression is said to be low in the better-prognosis patients expressing mutated immunoglobulin and high in poorer-prognosis patients expressing unmutated immunoglobulin, but this test has not been confirmed as a reliable means of distinguishing the two groups. ZAP-70 expression correlates with the presence of unmutated immunoglobulin genes, but the assay is not yet standardized and widely available.
Table 110–11 Staging Evaluation for Non-Hodgkin's Lymphoma |Favorite Table|Download (.pdf)
Table 110–11 Staging Evaluation for Non-Hodgkin's Lymphoma
Documentation of B symptoms
Complete blood counts
Liver function tests
Serum protein electrophoresis
CT scan of abdomen, pelvis, and usually chest
Bone marrow biopsy
Lumbar puncture in lymphoblastic, Burkitt's, and diffuse large B cell lymphoma with positive marrow biopsy
Gallium scan (SPECT) or PET scan in large cell lymphoma
Treatment: B Cell Chronic Lymphoid Leukemia/Small Lymphocytic Lymphoma
Patients whose presentation is typical B cell CLL with no manifestations of the disease other than bone marrow involvement and lymphocytosis (i.e., Rai stage 0 and Binet stage A; Table 110–7) can be followed without specific therapy for their malignancy. These patients have a median survival >10 years, and some will never require therapy for this disorder. If the patient has an adequate number of circulating normal blood cells and is asymptomatic, many physicians would not initiate therapy for patients in the intermediate stage of the disease manifested by lymphadenopathy and/or hepatosplenomegaly. However, the median survival for these patients is ∼7 years, and most will require treatment in the first few years of follow-up. Patients who present with bone marrow failure (i.e., Rai stage III or IV or Binet stage C) will require initial therapy in almost all cases. These patients have a serious disorder with a median survival of only 1.5 years. It must be remembered that immune manifestations of typical B cell CLL should be managed independently of specific antileukemia therapy. For example, glucocorticoid therapy for autoimmune cytopenias and γ globulin replacement for patients with hypogammaglobulinemia should be used whether or not antileukemia therapy is given.
Patients who present primarily with lymphoma and have a low IPI score have a 5-year survival of ∼75%, but those with a high IPI score have a 5-year survival of <40% and are more likely to require early therapy.
The most common treatments for patients with typical B cell CLL/small lymphocytic lymphoma have been chlorambucil or fludarabine, alone or in combination. Chlorambucil can be administered orally with few immediate side effects, while fludarabine is administered IV and is associated with significant immune suppression. However, fludarabine is by far the more active agent and is the only drug associated with a significant incidence of complete remission. The combination of rituximab (375–500 mg/m2 day 1), fludarabine (25 mg/m2 days 2–4 on cycle 1 and 1–3 in subsequent cycles), and cyclophosphamide (250 mg/m2 with fludarabine) achieves complete responses in 69% of patients, and those responses are associated with molecular remissions in half of the cases. Half the patients experience grade III or IV neutropenia. For young patients presenting with leukemia requiring therapy, regimens containing fludarabine are the treatment of choice. Because fludarabine is an effective second-line agent in patients with tumors unresponsive to chlorambucil, the latter agent is often chosen in elderly patients who require therapy. Bendamustine, an alkylating agent structurally related to nitrogen mustard, is highly effective and is vying with fludarabine as the primary treatment of choice. Patients who present with lymphoma (rather than leukemia) are also highly responsive to bendamustine and some patients will receive a combination chemotherapy regimen used in other lymphomas such as CVP (cyclophosphamide, vincristine, and prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab. Alemtuzumab (anti-CD52) is an antibody with activity in the disease, but it kills both B and T cells and is associated with more immune compromise than rituximab. Young patients with this disease can be candidates for bone marrow transplantation. Allogeneic bone marrow transplantation can be curative but is associated with a significant treatment-related mortality rate. Mini-transplants using immunosuppressive rather than myeloablative doses of preparative drugs are being studied (Chap. 114). The use of autologous transplantation in patients with this disorder has been discouraging.
Extranodal Marginal Zone B Cell Lymphoma of Malt Type
Extranodal marginal zone B cell lymphoma of MALT type (MALT lymphoma) makes up ∼8% of non-Hodgkin's lymphomas. This small cell lymphoma presents in extranodal sites. It was previously considered a small lymphocytic lymphoma or sometimes a pseudolymphoma. The recognition that the gastric presentation of this lymphoma was associated with H. pylori infection was an important step in recognizing it as a separate entity. The clinical characteristics of MALT lymphoma are presented in Table 110–10.
The diagnosis of MALT lymphoma can be made accurately by an expert hematopathologist based on a characteristic pattern of infiltration of small lymphocytes that are monoclonal B cells and CD5 negative. In some cases, transformation to diffuse large B cell lymphoma occurs, and both diagnoses may be made in the same biopsy. The differential diagnosis includes benign lymphocytic infiltration of extranodal organs and other small cell B cell lymphomas.
MALT lymphoma may occur in the stomach, orbit, intestine, lung, thyroid, salivary gland, skin, soft tissues, bladder, kidney, and CNS. It may present as a new mass, be found on routine imaging studies, or be associated with local symptoms such as upper abdominal discomfort in gastric lymphoma. Most MALT lymphomas are gastric in origin. At least two genetic forms of gastric MALT exist: one (accounting for ∼50% of cases) characterized by t(11;18)(q21;q21) that juxtaposes the amino terminal of the API2 gene with the carboxy terminal of the MALT1 gene creating an API2/MALT1 fusion product, and the other characterized by multiple sites of genetic instability including trisomies of chromosomes 3, 7, 12, and 18. About 95% of gastric MALT lymphomas are associated with H. pylori infection, and those that are do not usually express t(11;18). The t(11;18) usually results in activation of NF-κB, which acts as a survival factor for the cells. Lymphomas with t(11;18) translocations are genetically stable and do not evolve to diffuse large B cell lymphoma. By contrast, t(11;18)-negative MALT lymphomas often acquire BCL6 mutations and progress to aggressive histology lymphoma. MALT lymphomas are localized to the organ of origin in ∼40% of cases and to the organ and regional lymph nodes in ∼30% of patients. However, distant metastasis can occur—particularly with transformation to diffuse large B cell lymphoma. Many patients who develop this lymphoma will have an autoimmune or inflammatory process such as Sjögren's syndrome (salivary gland MALT), Hashimoto's thyroiditis (thyroid MALT), Helicobacter gastritis (gastric MALT), C. psittaci conjunctivitis (ocular MALT), or Borrelia skin infections (cutaneous MALT).
Evaluation of patients with MALT lymphoma follows the pattern (Table 110–11) for staging a patient with non-Hodgkin's lymphoma. In particular, patients with gastric lymphoma need to have studies performed to document the presence or absence of H. pylori infection. Endoscopic studies including ultrasound can help define the extent of gastric involvement. Most patients with MALT lymphoma have a good prognosis, with a 5-year survival of ∼75%. In patients with a low IPI score, the 5-year survival is ∼90%, while it drops to ∼40% in patients with a high IPI score.
Treatment: Mucosa-Associated Lymphoid Tissue Lymphoma
MALT lymphoma is often localized. Patients with gastric MALT lymphomas who are infected with H. pylori can achieve remission in the 80% of cases with eradication of the infection. These remissions can be durable, but molecular evidence of persisting neoplasia is not infrequent. After H. pylori eradication, symptoms generally improve quickly but molecular evidence of persistent disease may be present for 12–18 months. Additional therapy is not indicated unless progressive disease is documented. Patients with more extensive disease or progressive disease are most often treated with single-agent chemotherapy such as chlorambucil. Combination regimens that include rituximab are also highly effective. Coexistent diffuse large B cell lymphoma must be treated with combination chemotherapy (see below). The additional acquired mutations that mediate the histologic progression also convey Helicobacter independence to the growth.
Mantle cell lymphoma makes up ∼6% of all non-Hodgkin's lymphomas. This lymphoma was previously placed in a number of other subtypes. Its existence was confirmed by the recognition that these lymphomas have a characteristic chromosomal translocation, t(11;14), between the immunoglobulin heavy chain gene on chromosome 14 and the bcl-1 gene on chromosome 11, and regularly overexpress the BCL-1 protein, also known as cyclin D1. Table 110–10 shows the clinical characteristics of mantle cell lymphoma.
The diagnosis of mantle cell lymphoma can be made accurately by an expert hematopathologist. As with all subtypes of lymphoma, an adequate biopsy is important. The differential diagnosis of mantle cell lymphoma includes other small cell B cell lymphomas. In particular, mantle cell lymphoma and small lymphocytic lymphoma share a characteristic expression of CD5. Mantle cell lymphoma usually has a slightly indented nucleus.
The most common presentation of mantle cell lymphoma is with palpable lymphadenopathy, frequently accompanied by systemic symptoms. The median age is 63 years and men are affected four times as commonly as women. Approximately 70% of patients will be stage IV at the time of diagnosis, with frequent bone marrow and peripheral blood involvement. Of the extranodal organs that can be involved, gastrointestinal involvement is particularly important to recognize. Patients who present with lymphomatosis polyposis in the large intestine usually have mantle cell lymphoma. Table 110–11 outlines the evaluation of patients with mantle cell lymphoma. Patients who present with gastrointestinal tract involvement often have Waldeyer's ring involvement, and vice versa. The 5-year survival for all patients with mantle cell lymphoma is ∼25%, with only occasional patients who present with a high IPI score surviving 5 years and ∼50% of patients with a low IPI score surviving 5 years.
Treatment: Mantle Cell Lymphoma
Current therapies for mantle cell lymphoma are evolving. Patients with localized disease might be treated with combination chemotherapy followed by radiotherapy; however, these patients are exceedingly rare. For the usual presentation with disseminated disease, standard lymphoma treatments have been unsatisfactory, with the minority of patients achieving complete remission. Aggressive combination chemotherapy regimens followed by autologous or allogeneic bone marrow transplantation are frequently offered to younger patients. For the occasional elderly, asymptomatic patient, observation followed by single-agent chemotherapy might be the most practical approach. An intensive combination chemotherapy regimen originally used in the treatment of acute leukemia, HyperC-VAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, and methotrexate), in combination with rituximab, seems to be associated with better response rates—particularly in younger patients. Alternating two regimens, HyperC-VAD with rituximab added (R-HyperC-VAD) and rituximab plus high-dose methotrexate and cytarabine can achieve complete responses in >80% of patients and 8-year survival of 56%, comparable to regimens employing high-dose therapy and autologous hematopoietic stem cell transplantation. Bortezomib, temsirolimus, and bendamustine are single agents that induce transient partial responses in a minority of patients and are being added to primary combinations.
Follicular lymphomas make up 22% of non-Hodgkin's lymphomas worldwide and at least 30% of non-Hodgkin's lymphomas diagnosed in the United States. This type of lymphoma can be diagnosed accurately on morphologic findings alone and has been the diagnosis in the majority of patients in therapeutic trials for “low-grade” lymphoma in the past. The clinical characteristics of follicular lymphoma are presented in Table 110–10.
Evaluation of an adequate biopsy by an expert hematopathologist is sufficient to make a diagnosis of follicular lymphoma. The tumor is composed of small cleaved and large cells in varying proportions organized in a follicular pattern of growth (Fig. 110-7). Confirmation of B cell immunophenotype and the existence of the t(14;18) and abnormal expression of BCL-2 protein are confirmatory. The major differential diagnosis is between lymphoma and reactive follicular hyperplasia. The coexistence of diffuse large B cell lymphoma must be considered. Patients with follicular lymphoma are often subclassified into those with predominantly small cells, those with a mixture of small and large cells, and those with predominantly large cells. While this distinction cannot be made simply or very accurately, these subdivisions do have prognostic significance. Patients with follicular lymphoma with predominantly large cells have a higher proliferative fraction, progress more rapidly, and have a shorter overall survival with simple chemotherapy regimens.
Follicular lymphoma. The normal nodal architecture is -effaced by nodular expansions of tumor cells. Nodules vary in size and contain predominantly small lymphocytes with cleaved nuclei along with variable numbers of larger cells with vesicular chromatin and prominent nucleoli.
The most common presentation for follicular lymphoma is with new, painless lymphadenopathy. Multiple sites of lymphoid involvement are typical, and unusual sites such as epitrochlear nodes are sometimes seen. However, essentially any organ can be involved, and extranodal presentations do occur. Most patients do not have fevers, sweats, or weight loss, and an IPI score of 0 or 1 is found in ∼50% of patients. Fewer than 10% of patients have a high (i.e., 4 or 5) IPI score. The staging evaluation for patients with follicular lymphoma should include the studies included in Table 110–11.
Treatment: Follicular Lymphoma
Follicular lymphoma is one of the malignancies most responsive to chemotherapy and radiotherapy. In addition, tumors in as many as 25% of the patients undergo spontaneous regression—usually transient—without therapy. In an asymptomatic patient, no initial treatment and watchful waiting can be an appropriate management strategy and is particularly likely to be adopted for older patients with advanced-stage disease. For patients who do require treatment, single-agent chlorambucil or cyclophosphamide or combination chemotherapy with CVP or CHOP are most frequently used. With adequate treatment, 50–75% of patients will achieve a complete remission. While most patients relapse (median response duration is ∼2 years), at least 20% of complete responders will remain in remission for >10 years. For the rare patient (15%) with localized follicular lymphoma, involved field radiotherapy produces long-term disease-free survival in the majority.
A number of therapies have been shown to be active in the treatment of patients with follicular lymphoma. These include cytotoxic agents such as fludarabine, biologic agents such as interferon α, monoclonal antibodies with or without radionuclides, and lymphoma vaccines. In patients treated with a doxorubicin-containing combination chemotherapy regimen, interferon α given to patients in complete remission seems to prolong survival, but interferon toxicities can affect quality of life. The monoclonal antibody rituximab can cause objective responses in 35–50% of patients with relapsed follicular lymphoma, and radiolabeled antibodies appear to have response rates well in excess of 50%. The addition of rituximab to CHOP and other effective combination chemotherapy programs is beginning to show prolonged overall survival and a decreased risk of histologic progression. Complete remissions can be noted in 85% or more of patients treated with R-CHOP and median remission durations can exceed 6 or 7 years. Maintenance intermittent rituximab therapy can prolong remissions even further, though it is not completely clear that overall survival is prolonged. Some trials with tumor vaccines have been encouraging. Both autologous and allogeneic hematopoietic stem cell transplantation yield high complete response rates in patients with relapsed follicular lymphoma, and long-term remissions can occur in 40% or more of patients.
Patients with follicular lymphoma with a predominance of large cells have a shorter survival when treated with single-agent chemotherapy but seem to benefit from receiving an anthracycline-containing combination chemotherapy regimen plus rituximab. When their disease is treated aggressively, the overall survival for such patients is no lower than for patients with other follicular lymphomas, and the failure-free survival is superior.
Patients with follicular lymphoma have a high rate of histologic transformation to diffuse large B cell lymphoma (5–7% per year). This is recognized ∼40% of the time during the course of the illness by repeat biopsy and is present in almost all patients at autopsy. This transformation is usually heralded by rapid growth of lymph nodes—often localized—and the development of systemic symptoms such as fevers, sweats, and weight loss. Although these patients have a poor prognosis, aggressive combination chemotherapy regimens can sometimes cause a complete remission in the diffuse large B cell lymphoma, at times leaving the patient with persisting follicular lymphoma. With more frequent use of R-CHOP to treat follicular lymphoma at diagnosis, it appears that the rate of histologic progression is decreasing.
Diffuse Large B Cell Lymphoma
Diffuse large B cell lymphoma is the most common type of non-Hodgkin's lymphoma, representing approximately one-third of all cases. This lymphoma makes up the majority of cases in previous clinical trials of “aggressive” or “intermediate-grade” lymphoma. Table 110–10 shows the clinical characteristics of diffuse large B cell lymphoma.
The diagnosis of diffuse large B cell lymphoma can be made accurately by an expert hematopathologist (Fig. 110-8). Cytogenetic and molecular genetic studies are not necessary for diagnosis, but some evidence has accumulated that patients whose tumors overexpress the BCL-2 protein might be more likely to relapse than others. Patients with prominent mediastinal involvement are sometimes diagnosed as a separate subgroup having primary mediastinal diffuse large B cell lymphoma. This latter group of patients has a younger median age (i.e., 37 years) and a female predominance (66%). Subtypes of diffuse large B cell lymphoma, including those with an immunoblastic subtype and tumors with extensive fibrosis, are recognized by pathologists but do not appear to have important independent prognostic significance.
Diffuse large B cell lymphoma. The neoplastic cells are heterogeneous but predominantly large cells with vesicular chromatin and prominent nucleoli.
Diffuse large B cell lymphoma can present as either primary lymph node disease or at extranodal sites. More than 50% of patients will have some site of extranodal involvement at diagnosis, with the most common sites being the gastrointestinal tract and bone marrow, each being involved in 15–20% of patients. Essentially any organ can be involved, making a diagnostic biopsy imperative. For example, diffuse large B cell lymphoma of the pancreas has a much better prognosis than pancreatic carcinoma but would be missed without biopsy. Primary diffuse large B cell lymphoma of the brain is being diagnosed with increasing frequency. Other unusual subtypes of diffuse large B cell lymphoma such as pleural effusion lymphoma and intravascular lymphoma have been difficult to diagnose and associated with a very poor prognosis.
Table 110–11 shows the initial evaluation of patients with diffuse large B cell lymphoma. After a careful staging evaluation, ∼50% of patients will be found to have stage I or II disease and ∼50% will have widely disseminated lymphoma. Bone marrow biopsy shows involvement by lymphoma in ∼15% of cases, with marrow involvement by small cells more frequent than by large cells.
Treatment: Diffuse Large B Cell Lymphoma
The initial treatment of all patients with diffuse large B cell lymphoma should be with a combination chemotherapy regimen. The most popular regimen in the United States is CHOP plus rituximab, although a variety of other anthracycline-containing combination chemotherapy regimens appear to be equally efficacious. Patients with stage I or nonbulky stage II disease can be effectively treated with three to four cycles of combination chemotherapy with or without subsequent involved field radiotherapy. The need for radiation therapy is unclear. Cure rates of 70–80% in stage II disease and 85–90% in stage I disease can be expected.
For patients with bulky stage II, stage III, or stage IV disease, six to eight cycles of CHOP plus rituximab are usually administered. A large randomized trial showed the superiority of CHOP combined with rituximab over CHOP alone in elderly patients. A frequent approach would be to administer four cycles of therapy and then reevaluate. If the patient has achieved a complete remission after four cycles, two more cycles of treatment might be given and then therapy discontinued. Using this approach, 70–80% of patients can be expected to achieve a complete remission, and 50–70% of complete responders will be cured. The chances for a favorable response to treatment are predicted by the IPI. In fact, the IPI was developed based on the outcome of patients with diffuse large B cell lymphoma treated with CHOP-like regimens. For the 35% of patients with a low IPI score of 0–1, the 5-year survival is >70%, while for the 20% of patients with a high IPI score of 4–5, the 5-year survival is ∼20%. The addition of rituximab to CHOP has improved each of those numbers by ∼15%. A number of other factors, including molecular features of the tumor, levels of circulating cytokines and soluble receptors, and other surrogate markers, have been shown to influence prognosis. However, they have not been validated as rigorously as the IPI and have not been uniformly applied clinically.
Because a number of patients with diffuse large B cell lymphoma are either initially refractory to therapy or relapse after apparently effective chemotherapy, 30–40% of patients will be candidates for salvage treatment at some point. Alternative combination chemotherapy regimens can induce complete remission in as many as 50% of these patients, but long-term disease-free survival is seen in ≤10%. Autologous bone marrow transplantation is superior to salvage chemotherapy at usual doses and leads to long-term disease-free survival in ∼40% of patients whose lymphomas remain chemotherapy-sensitive after relapse.
Burkitt's lymphoma/leukemia is a rare disease in adults in the United States, making up <1% of non-Hodgkin's lymphomas, but it makes up ∼30% of childhood non-Hodgkin's lymphoma. Burkitt's leukemia, or L3 ALL, makes up a small proportion of childhood and adult acute leukemias. Table 110–10 shows the clinical features of Burkitt's lymphoma.
Burkitt's lymphoma can be diagnosed morphologically by an expert hematopathologist with a high degree of accuracy. The cells are homogeneous in size and shape (Fig. 110-9). Demonstration of a very high proliferative fraction and the presence of the t(8;14) or one of its variants, t(2;8) (c-myc and the λ light chain gene) or t(8;22) (c-myc and the κ light chain gene), can be confirmatory. Burkitt's cell leukemia is recognized by the typical monotonous mass of medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm with cytoplasmic vacuoles. Demonstration of surface expression of immunoglobulin and one of the above-noted cytogenetic abnormalities is confirmatory.
Burkitt's lymphoma. The neoplastic cells are homogeneous, medium-sized B cells with frequent mitotic figures, a morphologic correlate of high growth fraction. Reactive macrophages are scattered through the tumor and their pale cytoplasm in a background of blue-staining tumor cells give the tumor a so-called starry sky appearance.
Three distinct clinical forms of Burkitt's lymphoma are recognized; endemic, sporadic, and immunodeficiency-associated. Endemic and sporadic Burkitt's lymphomas occur frequently in children in Africa, and the sporadic form in Western countries. Immunodeficiency-associated Burkitt's lymphoma is seen in patients with HIV infection.
Pathologists sometimes have difficulty distinguishing between Burkitt's lymphoma and diffuse large B cell lymphoma. In the past, a separate subgroup of non-Hodgkin's lymphoma intermediate between the two was recognized. When tested, this subgroup could not be diagnosed accurately. Distinction between the two major types of B cell aggressive non-Hodgkin's lymphoma can sometimes be made based on the extremely high proliferative fraction seen in patients with Burkitt's lymphoma (i.e., essentially 100% of tumor cells are in cycle) caused by c-myc deregulation.
Most patients in the United States with Burkitt's lymphoma present with peripheral lymphadenopathy or an intraabdominal mass. The disease is rapidly progressive and has a propensity to metastasize to the CNS. Initial evaluation should always include an examination of cerebrospinal fluid to rule out metastasis in addition to the other staging evaluations noted in Table 110–11. Once the diagnosis of Burkitt's lymphoma is suspected, a diagnosis must be made promptly and staging evaluation must be accomplished expeditiously. This is the most rapidly progressive human tumor, and any delay in initiating therapy can adversely affect the patient's prognosis.
Treatment: Burkitt's Lymphoma
Treatment of Burkitt's lymphoma in both children and adults should begin within 48 h of diagnosis and involves the use of intensive combination chemotherapy regimens incorporating high doses of cyclophosphamide. Prophylactic therapy to the CNS is mandatory. Burkitt's lymphoma was one of the first cancers shown to be curable by chemotherapy. Today, cure can be expected in 70–80% of both children and young adults when effective therapy is administered precisely. Salvage therapy has been generally ineffective in patients failing the initial treatment, emphasizing the importance of the initial treatment approach.
Other B Cell Lymphoid Malignancies
B cell prolymphocytic leukemia involves blood and marrow infiltration by large lymphocytes with prominent nucleoli. Patients typically have a high white cell count, splenomegaly, and minimal lymphadenopathy. The chances for a complete response to therapy are poor.
Hairy cell leukemia is a rare disease that presents predominantly in older males. Typical presentation involves pancytopenia, although occasional patients will have a leukemic presentation. Splenomegaly is usual. The malignant cells appear to have “hairy” projections on light and electron microscopy and show a characteristic staining pattern with tartrate-resistant acid phosphatase. Bone marrow is typically not able to be aspirated, and biopsy shows a pattern of fibrosis with diffuse infiltration by the malignant cells. Patients with this disorder are prone to unusual infections, including infection by Mycobacterium avium intracellulare, and to vasculitic syndromes. Hairy cell leukemia is responsive to chemotherapy with interferon α, pentostatin, or cladribine, with the latter being the usually preferred treatment. Clinical complete remissions with cladribine occur in the majority of patients, and long-term disease-free survival is frequent.
Splenic marginal zone lymphoma involves infiltration of the splenic white pulp by small, monoclonal B cells. This is a rare disorder that can present as leukemia as well as lymphoma. Definitive diagnosis is often made at splenectomy, which is also an effective therapy. This is an extremely indolent disorder, but when chemotherapy is required, the most usual treatment has been chlorambucil.
Lymphoplasmacytic lymphoma is the tissue manifestation of Waldenström's macroglobulinemia (Chap. 111). This type of lymphoma has been associated with chronic hepatitis C virus infection, and an etiologic association has been proposed. Patients typically present with lymphadenopathy, splenomegaly, bone marrow involvement, and occasionally peripheral blood involvement. The tumor cells do not express CD5. Patients often have a monoclonal IgM protein, high levels of which can dominate the clinical picture with the symptoms of hyperviscosity. Treatment of lymphoplasmacytic lymphoma can be aimed primarily at reducing the abnormal protein, if present, but will usually also involve chemotherapy. Chlorambucil, fludarabine, and cladribine have been utilized. The median 5-year survival for patients with this disorder is ∼60%.
Nodal marginal zone lymphoma, also known as monocytoid B cell lymphoma, represents ∼1% of non-Hodgkin's lymphomas. This lymphoma has a slight female predominance and presents with disseminated disease (i.e., stage III or IV) in 75% of patients. Approximately one-third of patients have bone marrow involvement, and a leukemic presentation occasionally occurs. The staging evaluation and therapy should use the same approach as used for patients with follicular lymphoma. Approximately 60% of the patients with nodal marginal zone lymphoma will survive 5 years after diagnosis.
Mature (Peripheral) T Cell Disorders
Mycosis fungoides is also known as cutaneous T cell lymphoma. This lymphoma is more often seen by dermatologists than internists. The median age of onset is in the midfifties, and the disease is more common in males and in blacks.
Mycosis fungoides is an indolent lymphoma with patients often having several years of eczematous or dermatitic skin lesions before the diagnosis is finally established. The skin lesions progress from patch stage to plaque stage to cutaneous tumors. Early in the disease, biopsies are often difficult to interpret, and the diagnosis may only become apparent by observing the patient over time. In advanced stages, the lymphoma can spread to lymph nodes and visceral organs. Patients with this lymphoma may develop generalized erythroderma and circulating tumor cells, called Sézary's syndrome.
Rare patients with localized early-stage mycosis fungoides can be cured with radiotherapy, often total-skin electron beam irradiation. More advanced disease has been treated with topical glucocorticoids, topical nitrogen mustard, phototherapy, psoralen with ultraviolet A (PUVA), extracorporeal photopheresis, retinoids (bexarotene), electron beam radiation, interferon, antibodies, fusion toxins, histone deacetylase inhibitors, and systemic cytotoxic therapy. Unfortunately, these treatments are palliative.
Adult T Cell Lymphoma/Leukemia
Adult T cell lymphoma/leukemia is one manifestation of infection by the HTLV-I retrovirus. Patients can be infected through transplacental transmission, mother's milk, blood transfusion, and by sexual transmission of the virus. Patients who acquire the virus from their mother through breast milk are most likely to develop lymphoma, but the risk is still only 2.5% and the latency averages 55 years. Nationwide testing for HTLV-I antibodies and the aggressive implementation of public health measures could theoretically lead to the disappearance of adult T cell lymphoma/leukemia. Tropical spastic paraparesis, another manifestation of HTLV-I infection (Chap. 188), occurs after a shorter latency (1–3 years) and is most common in individuals who acquire the virus during adulthood from transfusion or sex.
The diagnosis of adult T cell lymphoma/leukemia is made when an expert hematopathologist recognizes the typical morphologic picture, a T cell immunophenotype (i.e., CD4 positive), and the presence in serum of antibodies to HTLV-I. Examination of the peripheral blood will usually reveal characteristic, pleomorphic abnormal CD4-positive cells with indented nuclei, which have been called “flower” cells (Fig. 110-10).
Adult T cell leukemia/lymphoma. Peripheral blood smear showing leukemia cells with typical "flower-shaped" nucleus.
A subset of patients have a smoldering clinical course and long survival, but most patients present with an aggressive disease manifested by lymphadenopathy, hepatosplenomegaly, skin infiltration, pulmonary infiltrates, hypercalcemia, lytic bone lesions, and elevated LDH levels. The skin lesions can be papules, plaques, tumors, and ulcerations. Lung lesions can be either tumor or opportunistic infection in light of the underlying immunodeficiency in the disease. Bone marrow involvement is not usually extensive, and anemia and thrombocytopenia are not usually prominent. Although treatment with combination chemotherapy regimens can result in objective responses, true complete remissions are unusual, and the median survival of patients is ∼7 months. A small phase II study reported a high response rate with interferon plus zidovudine and arsenic trioxide.
Anaplastic Large T/Null Cell Lymphoma
Anaplastic large T/null cell lymphoma was previously usually diagnosed as undifferentiated carcinoma or malignant histiocytosis. Discovery of the CD30 (Ki-1) antigen and the recognition that some patients with previously unclassified malignancies displayed this antigen led to the identification of a new type of lymphoma. Subsequently, discovery of the t(2;5) and the resultant frequent overexpression of the anaplastic lymphoma kinase (ALK) protein confirmed the existence of this entity. This lymphoma accounts for ∼2% of all non-Hodgkin's lymphomas. Table 110–10 shows the clinical characteristics of patients with anaplastic large T/null cell lymphoma.
The diagnosis of anaplastic large T/null cell lymphoma is made when an expert hematopathologist recognizes the typical morphologic picture and a T cell or null cell immunophenotype with CD30 positivity. Documentation of the t(2;5) and/or overexpression of ALK protein confirm the diagnosis. Some diffuse large B cell lymphomas can also have an anaplastic appearance but have the same clinical course or response to therapy as other diffuse large B cell lymphomas.
Patients with anaplastic large T/null cell lymphoma are typically young (median age, 33 years) and male (∼70%). Some 50% of patients present in stage I/II, and the remainder with more extensive disease. Systemic symptoms and elevated LDH levels are seen in about one-half of patients. Bone marrow and the gastrointestinal tract are rarely involved, but skin involvement is frequent. Some patients with disease confined to the skin have a different and more indolent disorder that has been termed cutaneous anaplastic large T/null cell lymphoma and might be related to lymphomatoid papulosis.
Treatment: Anaplastic Large T/Null Cell Lymphoma
Treatment regimens appropriate for other aggressive lymphomas, such as diffuse large B cell lymphoma, should be utilized in patients with anaplastic large T/null cell lymphoma, with the exception that the B cell–specific antibody, rituximab, is omitted. Surprisingly, given the anaplastic appearance, this disorder has the best survival rate of any aggressive lymphoma. The 5-year survival is >75%. While traditional prognostic factors such as the IPI predict treatment outcome, overexpression of the ALK protein is an important prognostic factor, with patients overexpressing this protein having a superior treatment outcome. The ALK inhibitor crizotinib appears highly active as well.
Peripheral T Cell Lymphoma
The peripheral T cell lymphomas make up a heterogeneous morphologic group of aggressive neoplasms that share a mature T cell immunophenotype. They represent ∼7% of all cases of non-Hodgkin's lymphoma. A number of distinct clinical syndromes are included in this group of disorders. Table 110–10 shows the clinical characteristics of patients with peripheral T cell lymphoma.
The diagnosis of peripheral T cell lymphoma, or any of its specific subtypes, requires an expert hematopathologist, an adequate biopsy, and immunophenotyping. Most peripheral T cell lymphomas are CD4+, but a few will be CD8+, both CD4+ and CD8+, or have an NK cell immunophenotype. No characteristic genetic abnormalities have yet been identified, but translocations involving the T cell antigen receptor genes on chromosomes 7 or 14 may be detected. The differential diagnosis of patients suspected of having peripheral T cell lymphoma includes reactive T cell infiltrative processes. In some cases, demonstration of a monoclonal T cell population using T cell receptor gene rearrangement studies will be required to make a diagnosis.
The initial evaluation of a patient with a peripheral T cell lymphoma should include the studies in Table 110–11 for staging patients with non-Hodgkin's lymphoma. Unfortunately, patients with peripheral T cell lymphoma usually present with adverse prognostic factors, with >80% of patients having an IPI score ≥2 and >30% having an IPI score ≥4. As this would predict, peripheral T cell lymphomas are associated with a poor outcome, and only 25% of the patients survive 5 years after diagnosis. Treatment regimens are the same as those used for diffuse large B cell lymphoma (omitting rituximab), but patients with peripheral T cell lymphoma have a poorer response to treatment. Because of this poor treatment outcome, hematopoietic stem cell transplantation is often considered early in the care of young patients.
A number of specific clinical syndromes are seen in the peripheral T cell lymphomas. Angioimmunoblastic T cell lymphoma is one of the more common subtypes, making up ∼20% of T cell lymphomas. These patients typically present with generalized lymphadenopathy, fever, weight loss, skin rash, and polyclonal hypergammaglobulinemia. In some cases, it is difficult to separate patients with a reactive disorder from those with true lymphoma.
Extranodal T/NK cell lymphoma of nasal type has also been called angiocentric lymphoma and was previously termed lethal midline granuloma. This disorder is more frequent in Asia and South America than in the United States and Europe. EBV is thought to play an etiologic role. Although most frequent in the upper airway, it can involve other organs. The course is aggressive, and patients frequently have the hemophagocytic syndrome. When marrow and blood involvement occur, distinction between this disease and leukemia might be difficult. Some patients will respond to aggressive combination chemotherapy regimens, but the overall outlook is poor.
Enteropathy-type intestinal T cell lymphoma is a rare disorder that occurs in patients with untreated gluten-sensitive enteropathy. Patients are frequently wasted and sometimes present with intestinal perforation. The prognosis is poor. Hepatosplenic γδ T cell lymphoma is a systemic illness that presents with sinusoidal infiltration of the liver, spleen, and bone marrow by malignant T cells. Tumor masses generally do not occur. The disease is associated with systemic symptoms and is often difficult to diagnose. Treatment outcome is poor. Subcutaneous panniculitis-like T cell lymphoma is a rare disorder that is often confused with panniculitis. Patients present with multiple subcutaneous nodules, which progress and can ulcerate. Hemophagocytic syndrome is common. Response to therapy is poor. The development of the hemophagocytic syndrome (profound anemia, ingestion of erythrocytes by monocytes and macrophages) in the course of any peripheral T cell lymphoma is generally associated with a fatal outcome.
Classical Hodgkin's Disease
Hodgkin's disease occurs in 8000 patients in the United States each year, and the disease does not appear to be increasing in frequency. Most patients present with palpable lymphadenopathy that is nontender; in most patients, these lymph nodes are in the neck, supraclavicular area, and axilla. More than half the patients will have mediastinal adenopathy at diagnosis, and this is sometimes the initial manifestation. Subdiaphragmatic presentation of Hodgkin's disease is unusual and more common in older males. One-third of patients present with fevers, night sweats, and/or weight loss—B symptoms in the Ann Arbor staging classification (Table 110–8). Occasionally, Hodgkin's disease can present as a fever of unknown origin. This is more common in older patients who are found to have mixed-cellularity Hodgkin's disease in an abdominal site. Rarely, the fevers persist for days to weeks, followed by afebrile intervals and then recurrence of the fever. This pattern is known as Pel-Ebstein fever. Hodgkin's disease can occasionally present with unusual manifestations. These include severe and unexplained itching, cutaneous disorders such as erythema nodosum and ichthyosiform atrophy, paraneoplastic cerebellar degeneration and other distant effects on the CNS, nephrotic syndrome, immune hemolytic anemia and thrombocytopenia, hypercalcemia, and pain in lymph nodes on alcohol ingestion.
The diagnosis of Hodgkin's disease is established by review of an adequate biopsy specimen by an expert hematopathologist. In the United States, most patients have nodular sclerosing Hodgkin's disease, with a minority of patients having mixed-cellularity Hodgkin's disease. Lymphocyte-predominant and lymphocyte-depleted Hodgkin's disease are rare. Mixed-cellularity Hodgkin's disease or lymphocyte-depletion Hodgkin's disease are seen more frequently in patients infected by HIV (Fig. 110-11). Hodgkin's disease is a tumor characterized by rare neoplastic cells of B cell origin (immunoglobulin genes are rearranged but not expressed) in a tumor mass that is largely polyclonal inflammatory infiltrate, probably a reaction to cytokines produced by the tumor cells. The differential diagnosis of a lymph node biopsy suspicious for Hodgkin's disease includes inflammatory processes, mononucleosis, non-Hodgkin's lymphoma, phenytoin-induced adenopathy, and nonlymphomatous malignancies.
Mixed-cellularity Hodgkin's disease. A Reed-Sternberg cell is present near the center of the field; a large cell with a bilobed nucleus and prominent nucleoli giving an "owl's eyes" appearance. The majority of the cells are normal lymphocytes, neutrophils, and eosinophils that form a pleomorphic cellular infiltrate.
The staging evaluation for a patient with Hodgkin's disease would typically include a careful history and physical examination; complete blood count; erythrocyte sedimentation rate; serum chemistry studies including LDH; chest radiograph; CT scan of the chest, abdomen, and pelvis; and bone marrow biopsy. Many patients would also have a PET scan or a gallium scan. Although rarely utilized, a bipedal lymphangiogram can be helpful. PET and gallium scans are most useful to document remission. Staging laparotomies were once popular for most patients with Hodgkin's disease but are now done rarely because of an increased reliance on systemic rather than local therapy.
Treatment: Classical Hodgkin's Disease
Patients with localized Hodgkin's disease are cured >90% of the time. In patients with good prognostic factors, extended-field radiotherapy has a high cure rate. Increasingly, patients with all stages of Hodgkin's disease are treated initially with chemotherapy. Patients with localized or good-prognosis disease receive a brief course of chemotherapy followed by radiotherapy to sites of node involvement. Patients with more extensive disease or those with B symptoms receive a complete course of chemotherapy. The most popular chemotherapy regimens used in Hodgkin's disease include doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), or combinations of the drugs in these two regimens. Today, most patients in the United States receive ABVD, but a weekly chemotherapy regimen administered for 12 weeks called Stanford V is becoming increasingly popular, but includes radiation therapy, which has been associated with life-threatening late toxicities such as premature coronary artery disease and second solid tumors. In Europe, a high-dose regimen called BEACOPP incorporating alkylating agents has become popular and might have a better response rate in very high risk patients. Long-term disease-free survival in patients with advanced disease can be achieved in >75% of patients who lack systemic symptoms and in 60–70% of patients with systemic symptoms.
Patients who relapse after primary therapy of Hodgkin's disease can frequently still be cured. Patients who relapse after initial treatment with only radiotherapy have an excellent outcome when treated with chemotherapy. Patients who relapse after an effective chemotherapy regimen are usually not curable with subsequent chemotherapy administered at standard doses. However, patients with a long initial remission can be an exception to this rule. Autologous bone marrow transplantation can cure half of patients who fail effective chemotherapy regimens.
Because of the very high cure rate in patients with Hodgkin's disease, long-term complications have become a major focus for clinical research. In fact, in some series of patients with early-stage disease, more patients died from late complications of therapy than from Hodgkin's disease itself. This is particularly true in patients with localized disease. The most serious late side effects include second malignancies and cardiac injury. Patients are at risk for the development of acute leukemia in the first 10 years after treatment with combination chemotherapy regimens that contain alkylating agents plus radiation therapy. The risk for development of acute leukemia appears to be greater after MOPP-like regimens than with ABVD. The risk of development of acute leukemia after treatment for Hodgkin's disease is also related to the number of exposures to potentially leukemogenic agents (i.e., multiple treatments after relapse) and the age of the patient being treated, with those aged >60 years at particularly high risk. The development of carcinomas as a complication of treatment for Hodgkin's disease has become a major problem. These tumors usually occur ≥10 years after treatment and are associated with use of radiotherapy. For this reason, young women treated with thoracic radiotherapy for Hodgkin's disease should institute screening mammograms 5–10 years after treatment, and all patients who receive thoracic radiotherapy for Hodgkin's disease should be discouraged from smoking. Thoracic radiation also accelerates coronary artery disease, and patients should be encouraged to minimize risk factors for coronary artery disease such as smoking and elevated cholesterol levels. Cervical radiation therapy increases the risk of carotid atherosclerosis and stroke.
A number of other late side effects from the treatment of Hodgkin's disease are well known. Patients who receive thoracic radiotherapy are at very high risk for the eventual development of hypothyroidism and should be observed for this complication; intermittent measurement of thyrotropin should be made to identify the condition before it becomes symptomatic. Lhermitte's syndrome occurs in ∼15% of patients who receive thoracic radiotherapy. This syndrome is manifested by an “electric shock” sensation into the lower extremities on flexion of the neck. Infertility is a concern for all patients undergoing treatment for Hodgkin's disease. In both women and men, the risk of permanent infertility is age-related, with younger patients more likely to recover fertility. In addition, treatment with ABVD rather than MOPP increases the chances to retain fertility.
Nodular Lymphocyte-Predominant Hodgkin's Disease
Nodular lymphocyte-predominant Hodgkin's disease is now recognized as an entity distinct from classical Hodgkin's disease. Previous classification systems recognized that biopsies from a subset of patients diagnosed as having Hodgkin's disease contained a predominance of small lymphocytes and rare Reed-Sternberg cells (Fig. 110-11). A subset of these patients have tumors with nodular growth pattern and a clinical course that varied from that of patients with classical Hodgkin's disease. This is an unusual clinical entity and represents <5% of cases of Hodgkin's disease.
Nodular lymphocyte-predominant Hodgkin's disease has a number of characteristics that suggest its relationship to non-Hodgkin's lymphoma. These include a clonal proliferation of B cells and a distinctive immunophenotype; tumor cells express J chain and display CD45 and epithelial membrane antigen (EMA) and do not express two markers normally found on Reed-Sternberg cells, CD30 and CD15. This lymphoma tends to have a chronic, relapsing course and sometimes transforms to diffuse large B cell lymphoma.
The treatment of patients with nodular lymphocyte-predominant Hodgkin's disease is controversial. Some clinicians favor no treatment and merely close follow-up. In the United States, most physicians will treat localized disease with radiotherapy and disseminated disease with regimens utilized for patients with classical Hodgkin's disease. Regardless of the therapy utilized, most series report a long-term survival of >80%.