Williams Hematology



Definition and History
Etiology and Pathogenesis

Incidence and Epidemiology

Epidemiology and Etiology
Clinical Features

History and Physical Examination


Extranodal Lymphoma

B-Cell Lineage Indolent Lymphomas (Low Risk)

Intermediate-Grade Lymphomas

B-Cell Lineage Very Aggressive Lymphoma (High Risk)-Burkitt Lymphoma

T-Cell Lineage Indolent Lymphomas (Low Risk)

T-Cell Lineage Aggressive Lymphomas (Intermediate Risk)
Laboratory Features


Lymph Node Biopsy

Marrow Examination

Radiographic Studies
Therapy, Course, and Prognosis

General Prognostic Factors

Low-Grade Lymphomas

B-Cell Lineage Aggressive Lymphomas (Intermediate Risk)

B-Cell Lineage Very Aggressive Lymphoma (High Risk)

T-Cell Lineage Indolent Lymphomas (Low Risk)

T-Cell Lineage Aggressive Lymphomas (Intermediate Risk)

Extranodal Disease
Chapter References

The lymphomas are a heterogenous group of clonal (neoplastic) diseases that share the single characteristic of arising as the result of a somatic mutation(s) in a lymphocyte progenitor. The progeny of the affected cell usually carry the phenotype of a B, T, or NK cell as judged by immunophenotyping or gene rearrangement studies. Any site of the lymphatic system may be the primary site of origin of the disorder including lymph nodes, gut-associated lymphatic tissue, skin, or spleen. Any organ, e.g., thyroid, lung, bone, brain, gonads, etc. may be involved either by spread from lymphatic sites or as a manifestation of primary extranodal disease. The classification of the subtypes of disease has been difficult but newer systems couple immunologic phenotype with histopathologic and cytologic features to arrive at definition of subtypes. By historical convention, lymphocytic malignancies originating in the marrow are referred to as lymphocytic leukemia, whereas those originating in any other lymphoid site are referred to as lymphoma. In the former case, lymphoid sites may be involved and in the latter case the marrow may be involved. Diagnosis is usually made by histological examination of a biopsy specimen, supplemented by immunophenotyping and molecular analysis for clonal origin. Patients are often put through staging procedures that may involve imaging studies, other biopsies, and blood chemical studies. Treatment depends on the type of lymphoma and the distribution of clinically evident disease. Combinations of drugs are often required. Radiotherapy may be useful for localized disease. Perhaps the most exciting progress in the treatment of lymphomas has been for the follicular B cell lymphomas. Combinations of chemotherapies including fludarabine and mitoxantrone or cyclophosphamide have demonstrated responses in 75 to 95 percent of patients. The majority of these responses are complete responses, and many of them appear to be quite durable. Newer agents such as Rituximab, which is a human mouse chimeric monoclonal antibody that binds to the CD20 antigen, demonstrate responses in over 50 percent of patients. 131I- and 90Y-labeled anti-CD20 antibodies have also demonstrated outstanding responses in previously treated patients. The role of autologous and allogeneic bone marrow transplant is well established for intermediate-risk and high-risk lymphomas and is being better defined for patients with low-risk lymphoma. Better therapies clearly need to be defined for mantle zone cell lymphoma and adult T-cell leukemia lymphoma, neither of which consistently respond to any current therapeutic regimens.

Acronyms and abbreviations that appear in this chapter include: ACLC, anaplastic large-cell lymphoma; ALL, acute lymphoblastic leukemia; ALT, adult T-cell leukemia/lymphoma; CALGB, Cancer and Acute Leukemia Group B; CLL, chronic lymphocytic leukemia; CNS, central nervous system; CT scan, computed tomographic scan; DFS, disease-free survival; EBV, Epstein-Barr virus; EFS, event-free survival; FAB, French-American British; GELA, Groupe d’Etudes des Lymphomes des l’Adulte; HTLV-I, human T-cell leukemia-lymphoma virus I; IL-2, interleukin 2; IPI, International Lymphoma Prognostic Factor Index; KLH, keyhole limpet hemocyanin; LAK, lymphokine-activated killer; LDH, lactic dehydrogenase; MALT, mucosa-associated lymphoid tissue; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PFS, progression-free survival; PUVA, psoralen and ultraviolet A light; REAL, revised European-American classification of lymphoid neoplasm; SLVL, splenic lymphoma with villus lymphocytes; SWOG, Southwest Oncology Group; TdT, terminal deoxynucleotidyl transferase.

Lymphomas are a heterogeneous group of malignancies of B cells or T cells that usually originate in the lymph nodes but may originate in any organ of the body. Lymphoma previously was referred to as reticulum cell sarcoma, lymphosarcoma, or giant follicular lymphoma.1,2,3,4 and 5 In 1966, Rappaport published a classification system based on the patterns of lymphoma cell growth, size, and shape that attempted to correlate morphology with clinical outcome.6 The classification proved to have some inaccuracies, such as the term histiocytic to describe tumors of large transformed lymphocytes that were not derived from the macrophage lineage (see Chap. 101). Nonetheless, the Rappaport classification was an important milestone and became the most widely used classification in the United States. In 1974, Lukes and Collins proposed another classification system that incorporated morphology with immunologic subtype, which was endorsed by the Committee on Nomenclature.7 Another scheme, the Kiel classification, has been more popular in Europe.8 In 1982, a Working Formulation sponsored by the National Cancer Institute attempted to reconcile the large number of competing classifications then in use.9 The Working Formulation was very useful clinically and gained wide popularity. However, with advances in our understanding of the immune system, particularly the use of monoclonal antibodies to subdivide lymphoid cells, and increasing molecular and genetic advances, a new classification schema became necessary. In 1994, a revised European-American classification of lymphoid neoplasm (REAL) was proposed by the International Lymphoma Study Group10 and is presented in Chap. 101. This group distinguished three major categories of lymphoid malignancies which included B-cell, T-cell, and Hodgkin disease. Lymphomas were defined by current morphologic, immunologic, and genetic techniques. Many of the lymphomas were associated with distinct clinical presentations, and cases that did not fit into defined entities were left unclassified. Further subclassification11 divided each of the B- and T-cell lineages into: (1) indolent lymphomas (low risk), (2) aggressive lymphomas (intermediate risk), and (3) very aggressive lymphomas (high risk) (Table 103-1). Diseases presented in Table 103-1 that are not presented in this chapter are shown in brackets.


In 1998, the new cases of lymphoma in the United States are estimated to be 55,000 with 25,000 estimated deaths.12 This represents 4 percent of cancer incidence and 4 percent of all cancer-related deaths. The incidence of lymphoma has increased dramatically in the last half of the twentieth century. This increase has affected men and women, all age groups, and most histologic types and has been documented in industrialized countries in Europe as well as in the United States. The increase preceded the appearance of AIDS, but the latter has added to the effect somewhat. The increase in incidence, which was about 4 percent per year, slowed to about 1 percent in the 1990s, but the mortality rate continues to increase significantly. Case control studies have suggested that chemical lymphomagens in herbicides and pesticides may account for some of the increase. Large-scale studies are underway at the National Cancer Institute to examine possible environmental causal relationships. Variations in racial incidence, histology, and immunologic subtypes are found throughout the world. Lymphoma is more common in males than females and in whites than blacks. There exists a lower incidence of follicular lymphomas in China and Japan.13 The United States has a higher total incidence of lymphoma than does Japan, while the incidence of extranodal disease is higher in Japan.14 While there is a preadolescent peak in incidence, there is generally a logarithmic increase with age.15 Burkitt lymphoma occurs most frequently in tropical Africa, while T-cell leukemia lymphoma is most common in southwest Japan and the Caribbean basin.16 Cutaneous T-cell lymphoma is an uncommon malignancy in the United States, with about 1000 new cases reported per year.281 The average annual adjusted mortality rate is about 400 to 500 deaths per year.
An increased incidence of lymphoma has been reported among chemists, farmers, and individuals involved in rubber production and asbestos and arsenic processing.17,18,19,20,21,22,23,24,25 and 26 This increased incidence is attributed to exposure to a variety of agents, including benzene and herbicides. Studies regarding agent orange, a herbicide that was used as a defoliant during the Vietnam war, have been inconclusive.27 Small but significant increases in lymphoma have been associated with radiation exposure.28 Increased lymphomas were reported in survivors of the atomic bomb in Hiroshima who were exposed to 10 Gy or more.29,30 An increased incidence of lymphomas also has been reported for individuals radiated for ankylosing spondylitis.31 It is also well known that patients with Hodgkin disease who were patients with radiation therapy and chemotherapy have an increased incidence of lymphoma.
The most compelling evidence for a viral etiology of lymphoma is adult T-cell leukemia/lymphoma (ATL). A C-type RNA tumor virus was isolated from patients that was designated human T-cell leukemia-lymphoma virus I (HTLV-I).49 HTLV-I is an acquired retrovirus that is not related to other known animal retroviruses. HTLV-I was demonstrated to immortalize lymphoid cells in culture and induce malignancy in an infected human host. Incidence of infection with HTLV-I in endemic areas is very high, yet few of these patients develop ATL. HTLV-I also leads to a neurologic disorder called tropical spastic paraparesis.50 There appear to be host factors that affect transformation of lymphocytes by HTLV-I, and evidence suggests that there may be host-related genetic factors.51 Development of adult T-cell leukemia/lymphoma is associated with infection by the human T-cell leukemia virus I.390,391,392 and 393 Serum specimens from Japanese patients with adult T-cell leukemia/lymphoma were found to be positive for HTLV-I, as were serum samples from adult T-cell leukemia/lymphoma patients in the Caribbean, where adult T-cell leukemia/lymphoma was endemic.394,395 Moreover, the highest prevalence of adult T-cell leukemia/lymphoma in Japan is in the southern island of Kyushi, where 10 to 15 percent of the population have antibody to HTLV-I.395,396 On Japanese islands where adult T-cell leukemia/lymphoma is rare, the rate is less than 1 percent. It is apparent from these and additional data from the Caribbean, the southeastern United States, South America, and Africa that adult T-cell leukemia/lymphoma clusters in regions where HTLV-I is prevalent.395,396 and 397 It is not known how these regions are linked. One hypothesis is that HTLV-I was brought to the Americas from Africa by the slave trade, and then to the southern islands of Japan by trade with Japan and Africa.395
Several studies suggest that host susceptibility or a shared environmental exposure or both contribute to HTLV-I infection. The prevalence of HTLV-I antibodies in close family members is three to four times higher than in the corresponding normal population.398 In some instances, cell cultures of antibody-positive, clinically normal patients yielded HTLV-I isolates.399 Blood donors are routinely screened for antibodies to HTLV-I to prevent transmission by this route.
Some B-cell lymphomas may be caused by Epstein-Barr virus (EBV). EBV is a DNA virus in the herpes virus family that first was described in cultured lymphoblasts from patients with African Burkitt lymphoma.32 EBV binds to the CD21 antigen (also the receptor for the C3d component of complement) on B lymphocytes.33 It is capable of transforming B lymphocytes into lymphoblastoid cells that may proliferate perpetually in cell culture.34 EBV is present in over 95 percent of cases of endemic Burkitt lymphoma and in approximately 20 percent of cases of nonendemic Burkitt lymphoma.35,36 Malaria is holoendemic in the regions where endemic Burkitt lymphoma exists.37 A three-step process in the development of this lymphoma has been proposed.38,39 (1) EBV initiates a polyclonal proliferation of B cells; (2) malaria stimulates further the proliferating B cells; and (3) the transforming B cells incur specific reciprocal translations of chromosome 8, with either chromosomes 2, 14, or 22.
H. pylori can cause MALT lymphomas of the stomach and is probably the cause of some of the higher grade lymphomas, either from transformation of a MALT or de novo large cell lymphoma.151,152 and 153 This spiral gram-negative bacillus is the first bacterium demonstrated to cause a human neoplasm.
There exist a variety of examples of immunosuppressed individuals who develop lymphoma. AIDS-related lymphoma is discussed in Chap. 89. Individuals who are immunosuppressed by drugs following organ transplantation have a range of abnormalities from benign proliferations of EBV-infected polyclonal B cells to aggressive malignant lymphoma.40,41 Extranodal involvement is extremely common in post-transplant lymphomas. The incidence and rapidity of lymphomas has increased with the introduction of immunosuppressive agents such as cyclosporine and OKT3 (murine monoclonal anti-CD3).42,43 There has also been an increased incidence of lymphomas in recipients of mismatched T-cell-depleted marrow grafts. Individuals with inherited or acquired immunodeficiency also have B-cell lymphomas that are caused by EBV. The X-linked lymphoproliferative syndrome is an example of a genetic defect in immunoregulation that leads to an inability to generate an active anti-EBV immune response.44,45,46,47 and 48
Chromosomal abnormalities are common in lymphomas (see Chap. 10). For example, approximately 85 percent of follicle center lymphomas carry the chromosomal translocation t(14;18)(q32;q21) in which the BCL-2 oncogene on chromosome 18q21 is brought in continuity with the Ig heavy-chain loci on 14q32.156,157 The expression of the BCL-2 protein is increased.158,159 The accumulation of the BCL-2 protein permits accumulation of long-lived centrocytes, as BCL-2 protein inhibits programmed cell depth (apoptosis), leading to a longer cell life (see Chap. 11).160,161 The BCL-2 rearrangement may be detected by both Southern blot hybridization and the polymerase chain reaction. In Burkitt lymphoma the common genetic abnormality is the translocation of the C-MYC oncogene from chromosome 8 to either the immunoglobulin heavy-chain region on chromosome 14, t(8;14)(q24;q32) or, less commonly, the k region on chromosome 2 t(2;8)(p13;q24) or the l region on chromosome 22, t(8;22)(q24;q11). In the African endemic cases, the breakpoint on chromosome 14 includes the heavy-chain joining region, suggesting translocation occurs before complete immunoglobulin gene rearrangement in an early B cell. In nonendemic cases, the translocation involves the immunoglobulin heavy-chain switch region, suggesting the translocation occurs at a later stage of B-cell development.272,273 Epstein-Barr virus genomes are demonstrated in the tumor cells in most of the African cases, in approximately one-third of the cases associated with AIDS274,275 and 276 but less frequently in non-African, non-immune-deficient cases. The translocation t(2;5)(p23;q35) of anaplastic large cell lymphoma involves the NPM gene at 5p35 and the ALK gene at 2p23,375 leading to expression of a novel fusion protein p80.376 This translocation has been identified in approximately 50 percent of systemic cases and may be higher in children with ALCL.377,378 The t(2;5) is not common in primary cutaneous anaplastic large-cell lymphoma (ALCL).379 Several cytogenetic abnormalities have been reported in adult T-cell leukemia/lymphoma cells. The most common abnormalities are trisomy, or partial trisomy, of 3q, 6q, 14q, and inv.14 Less common cytogenetic abnormalities include loss of the X chromosome, 7(9;21), 5p, 2q+, 17q+, and trisomy 18.406,407,408,409,410,411 and 412 In some studies, survival correlates with karyotype abnormalities.
The cause of cutaneous T-cell lymphoma is not known. Environmental, infectious, and genetic influences may be important.283,284 and 285 Exposure to toxic chemicals and physical agents, and employment in manufacturing, particularly textiles, petrochemicals, and machinery, is associated with an increased incidence of cutaneous T-cell lymphoma, but this remains controversial.283,284 and 285 HTLV-I originally was isolated in the United States from patients thought to have cutaneous T-cell lymphoma.286 Seroepidemiologic studies, however, suggest that HTLV-I is associated with adult T-cell leukemia/lymphoma.287 Fewer than 1 percent of patients with cutaneous T-cell lymphoma in the United States have serologic evidence for prior infection with HTLV-I. In a series of CD25-negative cutaneous T-cell lymphoma patients from Italy, a new retrovirus, called HTLV-V, was isolated. The significance of this finding is not clear.288 Evidence for genetic factors in the cause of cutaneous T-cell lymphoma is less impressive. Cutaneous T-cell lymphoma is less common in African-Americans. Also, first-degree relatives of patients with cutaneous T-cell lymphoma may have an increased incidence of lymphoma or leukemia.289 Data conflict regarding whether there is an increased incidence of cutaneous T-cell lymphoma among family members.
It is important to ascertain whether the patient has night sweats, fever, or metabolic wasting resulting in loss of more than 10 percent of body weight within the preceding 6 months. The presence of such “B” symptoms has unfavorable prognostic significance.
An examination should be made of all lymph node areas. Involved nodes are typically nontender, firm, and rubbery. The throat should be examined for involvement of the oropharyngeal lymphoid tissue (Waldeyer ring). The aggressive lymphomas are more likely to involve extranodal sites such as the skin and the central nervous system (see “Extranodal Lymphoma”).
The staging procedures that may be used are shown in Table 103-2. Generally, staging laparotomy is not indicated. Surgery may be indicated to definitively treat low-grade lymphomas of the gastrointestinal tract and for the diagnosis of extranodal or nodal disease confined to the abdomen. The role of surgery for large intraabdominal masses (larger than 10 cm) is controversial and is not routinely recommended.


The Ann Arbor staging classification (Table 103-3) is not optimal for staging lymphoma52 but is still considered the gold standard and impacts patient survival. The staging system was created for Hodgkin disease, which spreads by contiguity from lymph node areas, rather than hematogenously as does lymphoma. For this reason, more than 80 percent of patients with low-grade lymphoma and more than 50 percent of patients with intermediate- or high-grade lymphoma present with stage III or stage IV disease. However, staging is critically important for patients that are truly stages I and II who are treated by potentially curative radiation therapy if they have low-risk follicle center lymphomas or a combination of radiation therapy and limited cycles of chemotherapy if they have an intermediate- or high-risk lymphoma.


Lymphomas involving extranodal sites most commonly occur simultaneously with nodal involvement, either at the time of diagnosis or sometime during the course of disease. Where extranodal involvement occurs as the only evidence of lymphoma, it is referred to as primary extranodal lymphoma.
Between 5 and 10 percent of patients with nodal presentation of lymphoma may develop CNS involvement. These patients have a high incidence of marrow involvement and typically have aggressive histology.70,71 and 72 Epidural, testes,73,74 and paranasal sinus75 involvement commonly are associated with CNS disease. CNS presentation may include spinal cord compression, leptomeningeal spread, and/or intracerebral mass lesions. Spinal cord compression typically presents with back pain followed by extremity weakness, paresis, and paralysis. Leptomeningeal spread may present with cranial nerve palsies and signs of meningeal irritation. Intracerebral mass lesions may present with headaches, lethargy, papilledema, focal neurologic signs, or seizures.
Primary lymphomas originating and confined to the brain76,77 or spinal cord78 are rare. They almost always have an aggressive histology. Intracerebral tumors have increased dramatically in recent years because of the association with AIDS-related aggressive lymphomas (Chap. 89). Progressive multifocal leukoencephalopathy occurs as a result of polyoma virus infection in the brain and is characterized by demyelination; it is typically fatal.79 Paraneoplastic neurologic syndromes such as myasthenia gravis, cerebellar degeneration, peripheral neuropathies, and transverse myelopathy also may be associated with lymphomas.80
The most common presentation of ocular lesions is the periorbital soft tissues, in particular the conjunctival mucosal surfaces and the area surrounding the lacrimal gland.81 These lesions are typically low-risk and commonly have the histology of a mucosa-associated lymphoid tissue (MALT) or follicle center lymphoma. The preferred therapy is radiation in the range of 25 to 30 Gy, which is curative in the majority of patients.82 Bilateral involvement, particularly with MALT lymphomas, may be seen. In the rare situation where large-cell lymphoma involves the periorbital soft tissue, treatment follows the overall clinical picture.
Intraocular lymphomas are a rare presentation of lymphoma of the eye.83 Most cases are B-cell large-cell lymphomas, but they often have a unique indolent pattern. The diagnosis is established by a vitrectomy. There is approximately a 50 percent chance that the disease will be bilateral. Also, it is frequently associated with brain or leptomeningeal involvement. The mainstay of therapy is radiation, but most patients relapse within the eye or brain. Chemotherapeutic agents do not typically penetrate the eye or brain. Most patients are offered palliation with radiation and steroids, but recurrence is typical. These tumors behave much like large B-cell lymphomas of the brain, and consideration of more aggressive therapy would be reasonable.
Lymphomas may involve the frontal, maxillary, ethmoid, and sphenoid sinuses. These lymphomas typically involve bone and present with pain, upper airway obstruction, rhinorrhea, facial swelling, or epistaxis. Periorbital tumors may present with proptosis, visual loss, or dyplopia. These lymphomas are typically large-cell lymphomas.84 Following staging, treatment is planned in three phases that include systemic, local, and prophylaxis therapy to prevent spread to the CNS.81 With localized disease, three cycles of chemotherapy are recommended followed by involved field radiation. For more advanced disease, six to eight cycles of chemotherapy are recommended. Following standard therapy, six doses of intrathecal chemotherapy over 3 weeks are recommended because of the high incidence of CNS disease. Using this three-step approach to management, the majority of patients will be cured.81
Cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma typically involve the skin. Anaplastic large-cell lymphoma also commonly involves the skin. However, any lymphoma may secondarily infiltrate the skin. The lesions are typically reddish-purplish85 nodules and are more common with aggressive lymphomas, but low-grade lymphoma may also infiltrate the skin. Primary extranodal involvement of the skin is rarely seen in B-cell lymphomas and may have a more favorable prognosis.86
Pulmonary involvement is not common at diagnosis but may be seen with progressive disease.87 This typically is associated with lymphatic spread of tumor from hilar and mediastinal nodes. It may be seen in approximately 20 percent of cases at presentation. Primary lymphomas of the lung are rare and typically have a low-grade histology.88 Pleural effusions are quite common, occurring in approximately 25 percent of patients secondary to either central lymphatic obstruction or pleural seeding.
Approximately 15 percent of patients with nodal disease also have gastrointestinal involvement, and nearly half of patients have disease at autopsy.89 Patients may present with anorexia, nausea, vomiting, abdominal mass, or pain. Adjacent mesenteric nodes may be involved and may contribute to the symptoms.90 Intestinal involvement may be multifocal and may be associated with Waldeyer ring disease. The histologic pattern is usually that of an aggressive lymphoma.91 Ascites typically develops only late in the disease and is most commonly secondary. Primary involvement of the gastrointestinal tract is seen in approximately 5 percent of cases. The most frequent site of primary gastrointestinal lymphoma is the stomach, followed by the small intestine, rectum, and colon.92,93 Lymphoma of the stomach typically causes dyspeptic symptoms and sometimes anorexia or early satiety. Hemorrhaging is unusual but suggests a high-grade lymphoma. Diagnosis is typically made by gastroscopic biopsy. At gastroscopy, mild to severe gastritis is common. Adequate biopsies are critical at multiple sites so there is adequate material to determine the presence of H. pylori. MALT lymphoma is very common, but diffuse large B-cell lymphoma also may arise de novo or be found in the background of a MALT lymphoma. If both histologies are present, the treatment should be directed at the large-cell lymphoma.94,95,96 and 97
Lymphoma of the testis typically presents as a painless enlargement of the testis in an older man.98,99 and 100 It is typically a diffuse large B-cell lymphoma. At presentation, two-thirds of cases are localized to the testicle alone or the testicle and pelvic or abdominal lymph nodes. In the remaining cases, the testicle is one site of metastatic involvement in patients with widespread disease. After the orchiectomy has established the diagnosis, patients are staged with a special focus on the remaining testicle. If the sonography of the remaining testicle demonstrates a solid mass, it should be assumed to be lymphoma.
Hepatic involvement secondary to infiltration of the portal tract is more common in patients with low-risk lymphoma,101,102 whereas hepatic mass lesions are more commonly seen in patients with aggressive lymphomas.103 Liver involvement may not be associated with spleen involvement, as is typically seen in Hodgkin disease.104 Hepatomegaly and jaundice occur in about one-third of patients during the course of their disease. Primary lymphomas of the liver are quite rare and usually are associated with aggressive lymphomas.105
Splenic involvement is found in nearly half of patients with lymphoma.101,102 Primary involvement of the spleen is quite rare and may occur in all subtypes of lymphoma.106,107
Bone involvement in patients with nodal presentation is rare, as is primary bone involvement.104 Typically, this is restricted to aggressive lymphoma, and the lesions are usually lytic.108
Marrow involvement is very common in low-grade follicle center lymphomas and small lymphocytic lymphoma. Aggressive lymphomas that commonly are associated with marrow involvement include lymphoblastic lymphoma and small-noncleaved-cell lymphoma. Diffuse large-cell lymphoma involves the marrow in 10 percent of cases. Rarely, the marrow is the primary site of lymphoma involvement.109,110,111 and 112
Retroperitoneal urethral obstruction by lymph nodes is the most common urinary tract finding.113 This may be observed at diagnosis but more commonly is seen later in the course of the disease. While kidney involvement is common at autopsy, it rarely causes clinical overt disease. An unusual clinical manifestation is enlarged kidneys grossly involved with lymphoma; this rarely occurs at presentation. The nephritic syndrome is also unusual and may be due to renal vein occlusion, glomerulonephritis, or minimal change glomerulopathy. Glomerulopathy is more commonly associated with Hodgkin disease. Lymphomas involving the prostate,114 testes,73,74 or ovary115 are uncommon and typically have aggressive histology and clinical behavior.
Clinical disease related to cardiac involvement by lymphoma is very unusual. However, cardiac involvement may be found at autopsy in 20 percent of cases.103,116 Other uncommon sites include the salivary glands,117 adrenals,118 and thyroid.119 Thyroid lymphoma is usually associated with Hashimoto thyroiditis.
Small lymphocytic, or small lymphocytic lymphoma constitutes approximately 5 to 10 percent of all lymphomas.120,121 and 122 This lymphoma has a histologic appearance that is analogous to that of involved lymph nodes of patients with chronic lymphocytic leukemia (CLL).123 These neoplastic cells share the same morphologic and immunologic features, including low-intensity monoclonal surface immunoglobulin, gene rearrangement of heavy and light immunoglobulin chains, pan B-cell surface antigens (e.g., CD19 or CD20), and CD5124,125 (see Chap. 13). Similar to patients with CLL, the median age of patients with small lymphocytic lymphoma is 60 years. The disease tends to be indolent, with painless lymphadenopathy and eventual marrow involvement. Some patients with small lymphocytic lymphoma develop CLL. Staging is the same as that used in CLL and should include chest x-ray and a CT scan of the abdomen to determine if there are any lymph nodes compromising vital organs. Examination of the marrow should be performed to determine if there is tumor involvement and, if present, its histologic pattern (i.e., nodular versus diffuse) (see Chap. 98).
Fewer than 1 percent of patients with small lymphocytic lymphoma have lymphoma composed of neoplastic T cells rather than B lymphocytes.126,127 This represents an entirely different disease than that of B-cell small lymphocytic lymphoma and is often more aggressive. The cytogenetic abnormality inv (14)(q11;q32) has been observed in some cases, suggesting that at least some of these cases are the lymph node counterpart of T-prolymphocytic leukemia.128,129,130 and 131
Marginal zone B-cell lymphomas have cellular heterogeneity, including marginal zone cells, monocytoid B-cells, small lymphocytes, and plasma cells. The immunophenotype is that of mature B cells, with surface membrane immunoglobulin, IgM greater than IgG, and B-cell-associated antigens including CD19, CD20, CD22 without CD5, CD10, CD23, or CD11C.125 This is a tumor of adults with a slight female predominance.
A history of autoimmune disease such as Sjögren syndrome or Hashimoto thyroiditis is common. Most patients present with stage I or II extranodal disease of epithelial tissue, most frequently the stomach. Less common sites are small intestine, lung, salivary gland, thyroid, skin, and other soft tissues.132,133,134 and 135 Dissemination occurs in one-third of the cases, often in other extranodal sites with long disease-free intervals. It has been hypothesized that this disease may be multifocal. Abnormal karyotypes are observed commonly, often with rearrangements of chromosome 1p and numerical abnormalities of chromosomes 3 and 7.136 A t(11;18)(q21lq21) translocation was reported in a high frequency of patients with indolent MALT lymphoma.137 Staging studies are usually negative. Transformation to diffuse large B-cell lymphoma may occur.
The morphologic and immunophenotypic features of nodal marginal zone lymphoma is the same as MALT lymphoma. Most patients with nodal marginal zone monocytoid B-cell lymphoma have localized disease, commonly head and neck lymph nodes, and may have parotid gland involvement.138,139 and 140
Approximately 15 percent of such patients have Sjögren syndrome.141,142 Similar to patients with low-grade B-cell lymphomas of MALT, most patients with this lymphoma respond to local therapy. This is likely the nodal equivalent of MALT lymphoma or a closely related condition. Transformation to large cell lymphoma may occur.
Splenic marginal zone lymphoma appears to be morphologically and clinically distinct from extranodal MALT lymphomas and nodal marginal zone B-cell lymphomas.143,144 There is overlap between this entity and splenic lymphoma with villous lymphocytes (SLVL).145 The spleen pathology appears to be identical between these identities with involvement of both mantle and marginal zones of the splenic white pulp usually with a central residual germinal center and involvement of red pulp. The malignant cells range from small lymphocytes in the mantle zone to larger cells with irregular nuclei and pale cytoplasm in the marginal zones. The immunophenotype is identical to MALT and nodal marginal zone lymphomas. At presentation, the patients typically have marrow and blood involvement, usually without peripheral lymphadenopathy. A small M component may be present. These patients typically have a very indolent course.
Follicle center lymphoma, follicular are tumors composed of follicle center cells, usually a mixture of cleaved follicle center cells (centrocytes) and large noncleaved follicle center cells (centroblasts). Diffuse areas may be present and, in fact, may even predominate, but follicles exist. Sclerosis also may be seen in diffuse areas. The REAL classification proposes that the term follicle center lymphoma, follicular encompasses most of the tumors that were previously classified by pattern as follicular center lymphomas in the Working Formulation and, by cytology, follicular center cell lymphoma in the Lukes and Collins classification, or centroblastic/centrocytic in the Kiel classification. Follicle center lymphoma, follicular show a wide variation in the number of large cells, and it is difficult to sharply divide the distinct subtypes. The REAL classification proposes the term follicle center lymphoma, follicular grade I, grade II, or grade III to distinguish predominantly small-cell, mixed small and large cell, and large-cell respectively. Grade I or II are treated similarly, while grade III disease is treated the same as diffuse large B-cell lymphoma.
The disease is typically widespread at diagnosis and has an indolent course. Clinical involvement tends to be systemic with lymph nodes, marrow, liver, and spleen involvement. Progression to large-cell lymphoma is common. Tumor cells typically express surface immunoglobulin and CD10, but not CD5, CD23, CD43, and CD11c.125
This tumor typically involves the thymus at presentation and is composed of large cells resembling centroblasts, large centrocytes, or multilobated cells.230,231 In some cases the predominant cells are immunoblast, and Reed-Sternberg-like cells may also be present. Sclerosis is a common feature. The cells typically do not express surface immunoglobulin but have the typical B-cell-associated antigens, including CD19, CD20, and CD22, and may have weak expression of CD30.232,233 They have no specific genetic abnormality. This disease is predominantly found in women with a median age at presentation of 40 years.234,235 These patients typically present with a locally invasive anterior mediastinal mass originating from the thymus. Patients may have airway compromise or superior vena cava syndrome. Upon relapse, patients tend to have extranodal disease. While the disease is aggressive, it responds well to therapy with a similar outcome as diffuse large B-cell lymphoma.
This tumor is defined in the Kiel classification as centrocytic lymphoma. The tumor is typically composed of small to medium lymphocytes with irregular or “cleaved” nuclei.255 A small proportion of cases have larger nuclei with more dispersed chromatin, referred to as the blastic variant. The pattern of mantle zone cell lymphoma is usually diffuse or vaguely nodular. Some cases involve the mantle zone of reactive follicles, but rarely does a purely mantle zone pattern occur. The immunophenotype has some similarities to CLL/SLL in that the lymphoma cells express surface IgM and IgD and the B-cell-associated antigens CD19 and CD20 along with CD5.256,257 However, in contrast to CLL/SLL, mantle zone cell lymphoma express CD22 but not CD23 or CD11c. The chromosomal translocation of t(11;14)(q13;q32) involving the BCL-1 locus at chromosome 11 and the immunoglobulin heavy-chain locus on chromosome 14 occurs in about 50 percent of cases.258,259,260,261,262,263 and 264 This results in overexpression of the gene known as PRAD1, which encodes cyclin D1, a cell cycle protein that is not normally expressed in lymphoid cells. Patients with mantle cell lymphoma are predominantly males and have a median age of 60 years.265,266,267,268 and 269 The disease is typically widespread at diagnosis involving lymph nodes, spleen, Waldeyer ring, marrow, blood, and extranodal sites, especially the gastrointestinal tract (lymphomatous polyposis).
These cases are rare lymphomas composed of cells that resemble centrocytes, with minor components with centroblasts, but are entirely diffuse. They represent the diffuse counterpart of the follicle center lymphoma.10 In some cases, this may be a sampling problem as additional biopsies may show follicular elements. These cases have been called diffuse small-cleaved-cell lymphoma by the Working Formulation. The immunophenotype is identical to other follicle center lymphomas. A large retrospective study270 demonstrated that the vast majority of cases previously referred to as diffuse small-cleaved-cell lymphoma when reevaluated were predominantly marginal cell lymphomas and mantle cell lymphomas (SWOG).
In the Working Formulation, this disease entity was called small noncleaved cell, non-Burkitt. The International Lymphoma Study Group noted that often these cases were confused with large-cell lymphomas and suggested that many of the cases had been designated undifferentiated, non-Burkitt in the Rappaport classification, and small noncleaved cell, non-Burkitt-type in the Working Formulation.10 Some cases classified as small noncleaved non-Burkitt type, lacked the C-MYC rearrangement but often had the BCL-2 rearrangement, suggesting that they were not Burkitt lymphoma. This classification, therefore, represents cases in which the cell size and nuclear morphology are intermediate between Burkitt lymphoma and typical large-cell lymphoma, in which there is a high proliferative index with or without a starry-sky pattern. The Study Group emphasizes that this is not a reproducible category and likely does not represent a single-disease entity. The tumors typically expressed surface immunoglobulin-positive and B-cell-associated antigens, but not CD5 or CD10. The C-MYC rearrangement is rare, and one-third of cases have the BCL-2 rearrangement. This disease occurs mostly in adults and may or may not be associated with immunosuppression. Involvement of lymph nodes is more common than extranodal sites. In children, the disease appears to behave very much as classic Burkitt lymphoma. In adults, it appears to be a highly aggressive disease.
Under the Working Formulation, Burkitt lymphoma is small noncleaved cell, Burkitt’s type. The cells are monomorphic, with round nucleoli, and are intermediate in size between small-cell lymphomas and large-cell lymphomas. When these cells are present in the blood, the patient may be classified as having L3 acute lymphoblastic leukemia (ALL) by the French-American-British (FAB) criteria (see Chap. 97). Cytoplasmic lipid vacuoles are typically present. This tumor has an extremely high proliferative index and high rate of spontaneous cell death. The classic starry-sky pattern is secondary to macrophages that have ingested remnants of the tumor cells. Immunophenotypically, the cells express surface IgM and B-cell-associated antigens CD19, CD20, CD22, and CD10 but not CD5 or CD23.271
Burkitt lymphoma is commonly a disease of children, but the adult cases are predominantly in the AIDS population. The male:female ratio is approximately 2:1. In the endemic cases, facial bones and, most particularly, the jaws are involved, while in the nonendemic cases, the jaw tumors are less common, and the majority of cases present with disease in the abdomen, most commonly in the distal ileum cecum, and/or mesentery, or other abdominal organs.277
Cutaneous T-cell lymphoma consists of mycosis fungoides and the Sézary syndrome. These disorders are malignant proliferations of T lymphocytes of the helper phenotype. In 1938, Sézary and Bouvrain described a syndrome of pruritus, generalized exfoliative erythroderma, and abnormal hyperconvoluted lymphoid cells in the blood.282 Today this is referred to as Sézary syndrome, a syndrome seen in a subset of patients with mycosis fungoides. Sézary syndrome has biological features similar to the other forms of mycosis fungoides. Most patients with generalized erythroderma have varying numbers of circulating Sézary cells. One-fourth of those with plaque or tumor stage also have circulating Sézary cells.
Cutaneous T-cell lymphoma occurs more commonly in males, with a 2:1 ratio. The median age at diagnosis is 55 years. Initial skin lesions are clinically and histologically nonspecific, and it may take many years before the diagnosis is confirmed.
The initial clinical manifestation of cutaneous T-cell lymphoma is cutaneous infiltration, and the diagnosis is usually established by skin biopsy. Early lesions may show polymorphic infiltrations compatible with several benign diseases as well as cutaneous T-cell lymphoma. Characteristically, the malignant infiltrate in early cutaneous T-cell lymphoma is epidermotrophic, with exocytosis of single or clusters of convoluted cutaneous T-cell lymphoma cells. Epidermal clusters of these cells are termed Pautrier microabscesses. The epidermis also may show parakeratosis and acanthosis. A bandlike infiltrate in the upper dermis is composed of lymphocytes, neutrophils, eosinophils, plasma cells, and histiocytes in early lesions. The atypical, convoluted lymphocytes are present in clusters. In more advanced stages, the infiltrate is less polymorphic with a predominance of atypical cells extending deeper into the dermis; epidermotrophism may be lost. Lymph nodes that drain affected areas may show partial or complete effacement of normal architecture with a monomorphic infiltrate of cutaneous T-cell lymphoma cells. In most lymph nodes, the architecture is not effaced, and dermatopathic changes with varying numbers of atypical lymphocytes in the T-cell paracortical areas of the node are present. The cytologic appearance of the malignant cells in visceral organs is similar to that in the skin.290
Most cases of cutaneous T-cell lymphoma progress through distinct stages of skin involvement. These stages begin with a premycotic, erythematous, or eczematoid stage, progress to an infiltrative plaque stage, and eventuate in the tumor stage.291 Progression is variable but commonly occurs over several years.292 The premycotic or erythematous stage of cutaneous T-cell lymphoma is nonspecific; it is characterized by localized or widespread areas of erythema or dry eczema.291 Lesions may be associated with pruritus. Histologic features also are nonspecific, and a definitive diagnosis is often not possible. This stage may last for months to years before progression. The plaque stage is distinguished by palpable, pruritic, indurated lesions. The tumor stage is characterized by large lesions; these may develop in previously normal skin or in premycotic lesions or plaques. The lesions occur most often on the face and in body folds, often in a “bathing trunk” distribution. Tumors are often generalized, and ulceration is common. Pruritus is absent.
The erythrodermic form of cutaneous T-cell lymphoma is manifested by generalized erythroderma and may precede the appearance of other cutaneous T-cell lymphoma lesions by many years. It also may be preceded by premycotic lesions or may appear simultaneously with plaques or tumors. Two common types of erythroderma are exfoliative erythroderma, characterized by intense scaling, and “I’homme rouge” or “red-man” syndrome, in which redness rather than scaling predominates. Transition between forms is common. Lymphadenopathy and alopecia are frequent manifestations.
Cutaneous lesions are classified by using the T staging system. T1 (limited plaque stage) consists of erythematous patches and plaques covering less than 10 percent of the body. Plaques covering 10 percent of the skin surface are designated T2. Cutaneous tumors are designated T3, and generalized erythroderma, T4. Patients with limited plaque disease have an intermediate prognosis; those with tumor or erythroderma have the worst prognosis.293
Lymphadenopathy is present in about half of patients and increases with progressive cutaneous involvement.294 Lymphangiograms were formerly used to assess pretreatment involvement of intraabdominal lymph nodes. CT scans are less invasive, however, and reveal similar information.281,295,296 In most cases the cells express CD3, CD5, and CD4, a phenotype associated with mature helper-inducer T lymphocytes297,298 and 299 (see Chap. 13). These cells function as helper T lymphocytes in in vitro assays.300 The CD7 antigen, expressed by more than 85 percent of normal circulating T lymphocytes, also is present on mycosis fungoides cells in the skin but not on circulating Sézary cells.301 The cells are generally negative for markers of T-cell activation, such as HLA-DR or CD25 (IL-2 receptor). Like most malignant T cells, the cutaneous T-cell lymphoma cells stain for acid phosphatase, alpha-naphthyl acetate esterase, and beta glucoronidase. They are generally negative for peroxidase, alkaline phosphatase, and esterase. PAS-positive granules are present in some cases. Rearrangement of the T-cell receptor beta gene can be identified.
A wide range of chromosomal abnormalities are described in cutaneous T-cell lymphoma302 (see Chap. 10). Chromosomes 1 and 6 are frequently involved in structural abnormalities, whereas chromosomes 7, 11, 21, and 22 frequently are involved in numeric abnormalities. Rearrangement of chromosome 10 was common in one study.303 Chromosomal abnormalities often correlate with extent of disease and survival.
Circulating Sézary cells have been thought to increase with advancing disease. These cells are particularly prominent in patients with generalized erythroderma. Malignant cells also can be detected using sensitive techniques such as cytogenetics or T-cell receptor gene-rearrangement studies.304,305,306,307 and 308 Patients with blood involvement have a higher likelihood of lymphadenopathy, visceral involvement, and shorter survival. Marrow infiltration is infrequently detected by biopsy despite circulating malignant cells; it is identified at autopsy in 30 to 40 percent of cases. Using a highly sensitive PCR technique, one group reported a high frequency of clonal T cells in the blood of early mycosis fungoides, suggesting that early systemic disease is quite common.309
Smoldering adult T-cell leukemia/lymphoma has a number of clinical features similar to cutaneous T-cell lymphoma, but it usually can be distinguished by the presence of antibodies to HTLV-1 and by its regional occurrence. Pagetoid reticulosis is a rare skin disorder consisting of solitary or localized cutaneous plaques. The involved areas show a prominent atypical mononuclear cell infiltrate with hyperplastic epidermis.310
Although this disease is usually indolent and localized, some patients present with a disseminated form referred to as the Ketron-Goodman variant.311 Studies have demonstrated that this is a disease of an activated T lymphocyte that only occasionally expresses the helper T-cell CD4 antigen.312 Like cutaneous T-cell lymphoma, the neoplastic cells have T-cell receptor gene rearrangements.
Many of the large T-cell lymphomas cannot be specifically diagnosed and, therefore, are grouped under this heading.10 These peripheral T-cell lymphomas typically are made up of a mixture of small and large atypical lymphocytes. In the Working Formulation, they have been identified as either diffuse mixed small- and large-cell type or the large-cell immunoblastic. They are extremely heterogeneous and uncommon in the Western world. The International Lymphoma Study Group suggested that, until they can further subclassify this entity, they will be under this current heading.10 Immunophenotypically, they have T-cell-associated antigens, but many of these antigens may be absent. The cases are predominantly CD4-positive but may be CD8-positive or may be CD4/CD8-negative. The cells lack B-cell antigens. T-cell receptor genes are usually rearranged. Clinically, the cases represent approximately 10 percent of the cases in the United States but appear to be more common in other parts of the world. It is typically a disease of adults who present with systemic disease occasionally with eosinophilia, pruritus, or a hemophagocytic syndrome. Clinical course is typically aggressive, although potentially curable, but relapses are more common than are seen in large B-cell lymphomas. The treatment is identical for large B-cell lymphomas.
Lymphoepithelioid lymphoma was first described by Lennert346 and later by Lennert and Mestdagh347 and was believed to be a variant of Hodgkin disease. It is now believed that Lennert lymphoma is a distinct lymphoma with a multifocal epithelioid histiocytic reaction.348 The neoplasms are composed of small and large atypical lymphoid cells, some resembling Reed-Sternberg cells, reactive lymphocytes, or epithelioid histiocytes. They are typically mature T-cells with a helper T-cell immunophenotype and T-cell receptor chain gene rearrangement.349,350 Cytogenetic studies show a variety of chromosome abnormalities, especially involving chromosome 3351,352 (see Chap. 10). Lennert lymphoma is most often placed in the diffuse, mixed small- and large-cell category of the Working Formulation. However, patients tend to be older and to have disseminated disease that commonly involves the lung, spleen, lymph nodes, and marrow.348 Lymphoma involvement of Waldeyer ring is common, as are B symptoms. The clinical course is variable, some patients having a rapidly progressive course. The more aggressive form of the disease is treated with combination chemotherapy, while the indolent form is treated similar to low-grade lymphomas.
Angiocentric immunoproliferative lesions previously were termed polymorphic reticulosis and lymphomatoid granulomatosis.353,354 They are composed of atypical lymphoid cells mixed with histiocytes and plasma cells that invade and destroy blood vessels. The atypical lymphoid cells express T-cell antigens but usually do not have T-cell receptor gene rearrangements.355,356 and 357 Angiocentric immunoproliferative lesions are classified into three groups based on the degree of cytologic atypia and number of large lymphoid cells. Grade I lesions have the least atypia and fewest large cells, while grade III have the most and are termed angiocentric lymphoma. Grade II is intermediate. The lower-grade lesions often progress to frank lymphoma. Association of EBV within the tumor cells of grade III lesions suggests a role for EBV in the pathogenesis of this disease.355,356,358 Grade III patients often respond with durable complete responses to chemotherapy with CHOP, while grades I and II patients who progress to grade III generally do not.357
Angioimmunoblastic lymphadenopathy is a rare disease predominantly seen in elderly patients who typically have fever, chills, night sweats, and malaise, generalized lymphadenopathy, hepatospenomegaly, pruritic skin rash, polyclonal hypergammaglobulinemia, anemia (often with a positive Coombs’ test), and eosinophilia.359 Histologically there is loss of lymphoid architecture with a polymorphous infiltrate, including medium-size lymphocytes, plasma cells, esoinophils, and immunoblasts. A hallmark of the disease is arborizing proliferation of small blood vessels and absence of lymphoid follicles.
Approximately 30 percent of patients with angioimmunoblastic lymphadenopathy develop angioimmunoblastic lymphadenopathy-like lymphoma. The neoplasms are either diffuse mixed or large-cell immunoblastic. The tumors of most patients have T-cell surface antigens, as well as T-cell receptor b gene rearrangement360,361 and 362 and nonrandom chromosomal abnormalities.363,364 Some angioimmunoblastic lymphadenopathy-like lymphoma patients develop B-cell lymphomas that may be related to EBV.365 Many consider angioimmunoblastic lymphadenopathy-like lymphoma to be a preneoplastic disorder causing abnormalities of the immune system and predisposing to either B- or T-cell malignancies.
This disease is a T-cell lymphoma of the intestines and typically presents with jejunal ulcers which may be multiple and may have perforations.10,368 The tumors contain an admixture of small, medium, large, or anaplastic lymphocytes.10 Immunophenotypically, the cells are CD3-positive, CD7-positive, sometimes CD8-positive, CD4-negative, and CD103-positive. The TCR beta chain genes are rearranged. This is a disease of adults who often have a history of gluten-sensitive enteropathy. They may have as the initial event typical histologic features of sprue in the resected intestine. This is a very uncommon disease in the United States and Europe but is seen in areas where gluten-sensitive enteropathies are common. The typical presentation is abdominal pain, often associated with jejunal perforation. Other areas of the gastrointestinal tract are less commonly involved. The course is aggressive, and death usually occurs from intestinal perforation.
Anaplastic large-cell lymphoma, formally referred to as Ki-1 lymphoma, is now a world-recognized pathologic entity that accounts for 2 to 8 percent of all lymphomas. It was first noted that the cells from large-cell lymphomas reacted with the anti-Ki-1 antibody, a monoclonal antibody raised against the Reed-Sternberg cells of Hodgkin disease patients.369,370 and 371 Pathologically, the lymph nodes are partially involved and the B-cell follicles are spared, but the sinuses are infiltrated by tumor cells.10 There exists a proliferation of pleomorphic large neoplastic lymphoid cells usually growing in a cohesive pattern and peripherally spreading in the lymph node sinuses. The majority of ALCL cases express antigens of the T-cell lineage; however, many cases may lack lymphoid antigens and others may express B-cell antigens.10,372,373 and 374 The REAL classification includes the B-cell type of ALCL among the morphologic variants of diffuse large B-cell lymphoma, limiting ALCL to T-cell and null-cell types.10
The two distinct clinical forms of primary ALCL are cutaneous and systemic. The primary cutaneous form of ALCL is uncommon before age 20, may undergo spontaneous regression, and has a favorable prognosis. The systemic form is common in children and adolescents, has a bimodal age distribution, and has an aggressive clinical course, frequently presenting with systemic symptoms, advanced disease, and extranodal localization of disease. While response to treatment and overall survival of systemic ALCL in children is good, prognosis in adults is controversial. In one study373 comparing 146 adult patients with primary systemic ALCL to 1695 cases of nonanaplastic diffuse large-cell lymphoma, a number of conclusions were drawn. Patients with ALCL were more likely to be male, were younger, and had more frequent B-cell symptoms. Skin and lung involvement was more frequent in ALCL, while bone marrow involvement was identical. The immunophenotype was rather equally divided between B-cell, T-cell, and null-cell phenotypes. Response to chemotherapy, event-free survival, and overall survival were superior for ALCL.
Clinically, lymphoblastic lymphoma is very similar to acute lymphoblastic leukemia. It is an aggressive lymphoma that frequently spreads to the CNS. The published experience in adult patients is relatively limited.
This is a disease caused by lymphoblasts with round or convoluted nuclei, fine chromatin, scant cytoplasm, and an inconspicuous nucleoli.10 These cells have an identical morphology to that of precursor B lymphoblastic neoplasms. However, the cells have a distinguishing immunophenotype in that they typically express CD7 and CD3. Cytoplasmic CD3 is typically present even if surface membrane CD3 is absent. The expression of other T-cell-associated antigens is variable, and the expression of CD4 and CD8 is quite variable with double positives, double negatives, or either CD4 or CD8 alone.125,380,381 and 382 TdT is positive, and B-cell-associated antigens are negative. The rearrangement of the T-cell receptor gene is variable, depending on the maturity of the cells.383
Patients are typically young adult males. This disease constitutes 40 percent of childhood lymphomas and 15 percent of acute lymphoblastic leukemias.384 The typical presentation is a rapidly enlarging thymic mass and/or peripheral adenopathy. It is a rapidly fatal disease if untreated and usually terminates in acute leukemia with central nervous system involvement.
Adult T-cell leukemia/lymphoma is a T-cell lymphoproliferative syndrome first described in Japan in 1977 and later identified in the United States, the Caribbean, and other countries.385,386,387,388 and 389 Adult T-cell leukemia/lymphoma is characterized by pleomorphic neoplastic cells with membrane features of mature helper T lymphocytes. Presenting features include lymphadenopathy, hepatomegaly, splenomegaly, cutaneous infiltration, hypercalcemia (with or without lytic bone lesions), and interstitial pulmonary infiltrate.
Patients with adult T-cell leukemia/lymphoma have varied clinical presentations, including an aggressive acute syndrome with leukemia, a lymphoma without lymphocytosis, a chronic process with a modest leukemia phase, and a smoldering condition.400 The median age of patients with the aggressive acute type of adult T-cell leukemia/lymphoma is 40 years. Typical presentation includes an elevated leukocyte count, ranging from 5000 to 100,000/µl (5 to 100 × 109/liter) with circulating malignant lymphocytes.385,386 Anemia and thrombocytopenia are uncommon at presentation. Onset of symptoms is typically acute, with rapidly developing cutaneous lesions, hypercalcemia, or both. The appearance of skin lesions is variable. Some patients have discrete tumors, and others have confluent smaller nodules. Some patients present with plaques, papules, nonspecific erythematous patches, or erythroderma. Patients with hypercalcemia typically have weakness, lethargy, confusion, polyuria, and polydipsia.
Lymph node enlargement occurs in all patients, although the nodes are initially small in some. Many have generalized lymphadenopathy, and most have retroperitoneal adenopathy. Hilar adenopathy is common, but a mediastinal mass is rare. The patient’s marrow may be infiltrated with leukemia cells. Additional sites of disease include the lung, liver, skin, gastrointestinal tract, and central nervous system. In addition, adult T-cell leukemia/lymphoma is associated with lymphomas of several histologic subtypes, including diffuse, poorly differentiated small-cell; mixed large- and small-cell; and large-cell immunoblastic. No apparent correlation exists between clinical course and lymph node morphology. Opportunistic infections are common in patients with adult T-cell leukemia/lymphoma. Pneumocystis carinii infection is common, as is cryptococcal meningitis. Bacterial and fungal infections are also common.
Cutaneous involvement occurs in about two-thirds of patients with adult T-cell leukemia/lymphoma. Focal epidermal infiltration with adult T-cell leukemia/lymphoma cells, or Pautrier microabscesses, is seen in most patients with cutaneous involvement. Pautrier microabscesses were thought to be pathognomonic of cutaneous T-cell lymphoma, but they also can also be found in some patients with adult T-cell leukemia/lymphoma. The absence of a chronic premycotic phase in most patients with adult T-cell leukemia/lymphoma distinguishes it from typical cutaneous T-cell lymphoma. Furthermore, serologic studies in cases of cutaneous T-cell lymphoma show no association with HTLV-I infection, although rare patients with cutaneous T-cell lymphoma are HTLV-I positive.
An important pathologic feature of adult T-cell leukemia/lymphoma is the presence of pleomorphic lymphoid cells in the blood. Not all patients have blood involvement at diagnosis, even though circulating leukemia cells are identified in most cases eventually. Adult T-cell leukemia/lymphoma cells have moderately condensed nuclear chromatin, inconspicuous nucleoli, and a markedly irregular nuclear contour that divides the nucleus into several lobes. These cells are characteristic of HTLV-I-associated disease and can be distinguished from Sézary cells and cells of other mature and immature T-cell malignancies. In about 20 percent of the cases, nuclear irregularities are less extreme, and the cells may be difficult to distinguish from Sézary cells.
The malignant cells from patients with adult T-cell leukemia/lymphoma typically have the phenotype of mature helper T cells401 and express the CD2, CD3, and CD4 antigens (see Chap. 13). They also express CD25, the p55 subunit of the IL-2 receptor. Clonal rearrangements of the T-cell receptor b chain are present.402,403,404 and 405 Leukemia cells have been reported to suppress B-cell immunoglobulin secretion by a complex mechanism involving induction of suppressor cells after activation of normal suppressor cell precursors.401
Radionuclide bone scans of patients with the acute adult T-cell leukemia/lymphoma syndrome typically show a diffuse increased uptake throughout the skeleton, most prominent in the joints and skull. These scans are referred to as “super” scans and are unusual in other patients with malignant lymphomas. Isolated lytic bone lesions also may occur. Typically, the serum alkaline phosphatase level is elevated.
Laboratory tests include standard chemistry and hematology studies. The indolent lymphomas are more likely to involve the blood. If anemia or reticulocytosis is present at diagnosis, a Coombs’ test should be obtained to determine whether autoimmune hemolytic anemia is present. Thrombocytopenia may be related to marrow replacement, hypersplenism, or autoimmune destruction. Marrow involvement, as well as autoimmune complications, is more common with low-grade lymphomas. Elevation of serum lactic dehydrogenase (LDH) is common and suggests a poorer prognosis.
A biopsy is essential to establish the diagnosis of lymphoma. This usually involves excisional biopsy of an affected lymph node. If the disease is extranodal, then a surgical biopsy of the site of involvement is necessary. A needle aspiration biopsy is not adequate for the initial diagnosis, except in unusual circumstances.
A portion of the biopsy specimen should be placed in formalin for histology, and another portion frozen for immunologic and molecular studies that may be necessary. Special studies such as immunoglobulin and T-cell receptor gene rearrangement studies, polymerase chain reaction (PCR) for the BCL-1 or BCL-2 oncogene rearrangements, cytogenetics, flow cytometry, and immunohistochemistry may be critical for diagnosis in a minority of cases or may support the diagnosis in other cases.
Evaluation of the marrow of patients with suspected or newly diagnosed lymphoma may assist in establishing the diagnosis or in staging the extent of disease respectively. Because the marrow involvement by most lymphomas is spotty, patients generally should undergo bilateral posterior iliac crest biopsies. Except in Burkitt lymphoma and lymphoblastic lymphoma, the incidence of marrow involvement is higher in indolent lymphomas (20 to 95 percent) than in the more aggressive lymphomas (10 percent). Lymphoma involvement of the marrow can be detected by morphologic evaluation if there is 5 percent or greater infiltration by malignant cells. Additional techniques, such as flow cytometry, Southern Blot analysis, or evaluation for clonal excess, may detect lymphoma cells in the marrow when they constitute a smaller proportion of marrow cells, e.g., greater than 1 percent. The polymerase chain reaction can be used to detect abnormalities, such as the t(14;18) translocation involving BCL-2, in the range of one lymphoma cell in 105 to 106 normal cells. PCR is not entirely reliable, as 10 to 20 percent of patients with follicular lymphomas do not have a PCR-amplified breakpoint. PCR also may have a role in detecting minimal residual disease following therapy. However, PCR cannot be considered a standard tool unless the results of the PCR changes our approach to therapy. Patients who have intermediate- or high-grade lymphoma in the marrow have a higher likelihood of central nervous system disease and should undergo a spinal tap.
Chest roentgenograms should be performed in all patients found to have lymphoma. A computed tomographic (CT) scan of the chest is indicated if the chest roentgenogram is abnormal or questionable. A CT scan of the abdomen and pelvis should be performed to evaluate for abdominal or pelvic nodes and masses. Lymphangiography has been abandoned for this purpose. Gallium scan may be very useful in the setting of large masses to follow responses to therapy and to evaluate residual tumor in a large mass that has responded to treatment. Ultrasonography and magnetic resonance imaging (MRI) may clarify abnormalities found on other studies. Lymphoma involvement of Waldeyer ring is commonly associated with lymphoma in the gastrointestinal tract, and vice versa. Therefore, patients who have Waldeyer ring involvement should be evaluated with an upper gastrointestinal series that includes a small-bowel follow-through and a barium enema. Such barium contrast studies also should be performed if any abnormality involving the gastrointestinal tract is suspected from the history or physical examination.
One important prognostic factor is the histologic subtype. This is described in detail below and divides the lymphomas into different risk groups. Low-risk lymphomas may transform over a number of years to intermediate- or high-risk lymphomas that typically have a more aggressive clinical course than de novo intermediate- or high-risk disease. Advanced stage is associated with poorer survival. Systemic B symptoms generally are considered adverse,53 although some studies have not confirmed this finding.54 Age is considered a prognostic factor. Patients over 60 years of age have a poorer survival,55,56 although this is disputed by some investigators.57 This may be related to the lower tolerance of the elderly for chemotherapeutic drugs.58 Extranodal disease is considered an adverse prognostic factor, particularly in CNS disease. Primary CNS disease usually is associated with more aggressive histologies and has a high incidence in individuals with AIDS. The testes are another extranodal site, and radiation of the uninvolved testis generally is recommended because of the high incidence of recurrent disease. As described above, patients with Waldeyer ring involvement have an increased risk of gastrointestinal lymphoma.
Tumor bulk and growth rate also have been associated with prognosis. Tumor masses larger than 10 cm generally have been considered a poor prognostic factor.59,60 and 61 Elevated serum LDH is an unfavorable prognostic factor as it reflects increased tumor burden.62 Some studies have reported that a T-cell phenotype in advanced aggressive disease is an adverse prognostic factor,63,64 although this remains controversial.65 A high proliferative index as measured by the Ki-67 antigen was associated with a poor prognosis in one study.66 Nonrandom chromosomal abnormalities also have been associated with a poorer prognosis.67
The International Lymphoma Prognostic Factor Index (IPI) is a predictive model for aggressive lymphoma.68 The project was undertaken to develop a model for predicting outcome in patients with aggressive lymphoma on the basis of patients’ clinical characteristics before treatment, because the Ann Arbor classification was inconsistent in distinguishing between patients. Five risk factors were identified as poor prognostic factors (Table 103-4). These included age greater than 60 years, elevated serum LDH concentration, poor performance status, stage III or IV disease, and more than one extranodal disease site. Based on these factors, four risk groups were identified with 5-year survival rates of 73 percent, 51 percent, 43 percent, and 26 percent (Table 103-5).



While the original classification was identified for patients with aggressive lymphoma, it was later demonstrated that the same model could predict prognosis for a variety of histologic types of lymphoma.69 Interestingly, the histologic diagnosis of anaplastic large-cell lymphoma was associated with good survival even with a high prognostic index.
Treatment of small lymphocytic lymphoma is similar to that for CLL and is presented in Chap. 98. Systemic therapy is initiated with single agent chlorambucil, fludarabine, or cladrabine but is not curative.123 Some investigators consider fludarabine the treatment of choice for previously untreated patients.131
The rare T-cell variant of small lymphocytic leukemia may be more aggressive and require therapeutic intervention earlier. Doxorubicin-based regimens often are initiated, although pentostatin (deoxycoformycin) might be a reasonable alternative.129 There exists no standard therapy for the T-cell variant.
MALT lymphoma and monocytoid B-cell lymphoma often are localized and may be cured by surgery or local radiation, depending on the site of disease.146,147 and 148 Single-agent chemotherapy also has been recommended.149 Unless there is residual disease, there are no data to support the use of postoperative radiation therapy. It has been suggested that the lymphoma may be multifocal and that patients should have frequent follow-up with endoscopy and biopsy of suspicious lesions. Disseminated disease may be followed without therapy until necessary to relieve symptoms. When therapy is indicated, it usually is initiated with an alkylating agent or multiagents including an anthracycline.149,150
Successful treatment of the H. pylori frequently leads to complete regression of the MALT lymphoma.154,155 The diagnosis of H. pylori-associated MALT lymphoma requires biopsy proof of both the lymphoma and the presence of H. pylori. The patient is then treated with antibiotics effective against H. pylori. If the H. pylori is not eradicated, which appears in approximately 10 percent of the cases, a second course of antibiotics is indicated. Even if the H. pylori is eliminated, the MALT lymphoma may persist. This should be followed with serial endoscopies as there may be a gradual regression of the MALT lymphoma. If the MALT lymphoma does not continue to decrease in size or persists beyond 6 months, further antilymphoma therapy should be initiated with either single-agent chlorambucil or cyclophosphamide or upper abdominal radiation. Biopsies should rule out coexistant large-cell lymphoma.
Follicle center lymphomas grade III are more aggressive than the small cleaved or mixed small cleaved and large cell lymphomas and represents 10 percent of the total cases. The cells may be cleaved or noncleaved. They more commonly present with localized tumors, as compared to grade I and grade II tumors. However, despite the early clinical stage at diagnosis, they have the least favorable prognosis of the follicle center lymphomas, with frequent recurrences and progression to diffuse large-cell lymphoma. The number of centroblasts and the size of the centrocytes appear to correlate with the prognosis.162,163 Controversy exists over whether cases classified as follicular mixed cell type may be curable with aggressive therapy, while the small cleaved cell variant is not considered curable with therapy. The proportion of the tumor that has a follicular pattern also is correlated with prognosis.164,165 The rare purely diffuse cases appear to have the worse prognosis.166 Progression to diffuse large B-cell lymphoma may occur.
Over time the follicular pattern tends to progress to a diffuse pattern, and the fraction of tumor cells that are large cleaved or noncleaved increases. The growth fraction increases with the number of large cells in the tumor, and the number of cytogenetic abnormalities increases with acceleration of the disease. The ability to obtain durable responses to initial therapy, however, also increases as a function of the number of large cells in the tumor.
Patients with follicle center lymphoma grades I and II are treated in a similar fashion. There are data to suggest that patients with grade II disease may have a more durable response to therapy. However, the approach to therapy is the same. However, patients with grade III disease are treated similarly to patients with diffuse large B-cell lymphoma and are not included in this section.
Patients who have stage I or stage II disease represent fewer than 20 percent of all cases. These patients often are treated with involved-field radiation therapy alone. Between 50 and 75 percent of such patients are cured. There is no evidence that adjuvant chemotherapy in this setting improves survival or diminishes the risk for recurrent disease. A retrospective review of 177 patients with stage I and stage II disease with either follicle center lymphomas grade I or grade II demonstrated a median survival of 14 years following radiation therapy as a single modality.167 Most of these patients received either involved- or extended-field radiation therapy ranging from 35 to 50 Gy. Approximately 50 percent of the patients were relapse-free at 5 to 10 years, but only 5 of 47 patients who reached 10 years without relapse subsequently developed recurrence.
The concept of “watch and wait” for patients with stage III or IV disease proposes that patients are followed without therapy until they develop progressive disease or systemic symptoms. Some untreated patients have spontaneous remissions and are spared chemotherapy. The median survival of patients so managed was reported to be over 7 years in one study168 and 4 years in another.169 In another trial, patients were randomized to a watch-and-wait protocol or to a protocol of combined therapy with prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide, then mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE/MOPP) followed by total nodal irradiation.170 The overall survival rates for the two groups were similar. However, the number of complete remissions and the disease-free survival rates were longer in the patients treated with combined modality therapy. Responses to single-agent therapy such as chlorambucil or a nucleoside (Table 103-6) range from 75 to 90 percent of patients.171,172,173,174,175,176 and 177 All patients eventually relapse. In randomized trials, single-agent alkylating therapy was compared to CVP. Patients treated with CVP had more complete responses and shorter median time to complete response than patients treated with single-agent therapy but did not have significantly longer overall survival rates.171,173,174,178,179,180 and 181 Similarly, intensive combination regimens including doxorubicin also have demonstrated excellent responses for patients with follicle center lymphoma, but there is no evidence that such treatment prolongs survival.182,183,184 and 185


Approximately 90 percent of relapsed follicle center lymphoma patients responded to fludarabine, mitoxantrone, and dexamethasone with 50 percent complete responses.186 Twenty-seven of 27 previously untreated follicle center lymphoma patients responded to a combination of cyclophosphamide and fludarabine with over 90 percent complete responses.187 Similar responses were reported with three courses of full-dose fludarabine followed by six to eight courses of cyclophosphamide, mitoxantrone, vincristine, and prednisone with 96 percent responses, and 65 percent complete responses.188
Rituximab, an anti-CD20 human-mouse chimeric monoclonal antibody, has been approved by the U.S. Food and Drug Administration for the treatment of follicle center lymphoma.189,190 Response rates of 50 percent are reported following a dose of 375mg/m2 given weekly for four doses to previously treated patients. The majority of responses were partial responses but tended to be very durable with a median time to progression of 13 months. 131I- and 90Y-labeled murine monoclonal anti-CD20 antibody trials have demonstrated excellent responses in previously treated patients treated with either a one-time low-dose of 131I- or 90Y-labeled antibody191,192 or a marrow ablative dose of 131I-labeled antibody.193,194 Previously untreated patients with follicle center lymphomas were treated with 75 cGy delivered on 35mg of anti-CD20 murine monoclonal antibody with 100 percent response rates and predominantly complete responses.195 The major toxicity was moderate reversible myelosuppression.
Autologous and allogeneic stem cell transplantation is an additional therapeutic approach for patients with follicle center lymphoma (see Chap. 18). In most studies, patients were treated for recurrent disease. Similar survival outcomes are reported for autologous and allogeneic transplantation, although allogeneic transplant has a much higher incidence of treatment-related death, while autologous transplants have a higher incidence of disease recurrence. In one large retrospective study of 113 follicle center lymphoma patients that received allografts, the 3-year probability of disease-free survival was 49 percent.196 Allografts should likely be considered for younger patients with follicle center lymphoma who do not have an initial conventional chemotherapy-induced remission.
Autografts are more popular than allografts because of age and donor limitations. Some investigators have used monoclonal antibodies specific for B-cell surface antigens for ex vivo “purging” of tumor cells from autologous marrow. In one study, detection of residual lymphoma by PCR for the BCL-2 oncogene rearrangement in the purged marrow proved to be the most important predictor of early relapse following transplantation.197 Several investigators have failed to show benefit from purging in low-grade lymphoma; however, large randomized studies have not been reported.198,199 and 200 Unfortunately, while high-dose therapy may prolong disease-free survival, there is no definitive evidence to date that it prolongs overall survival compared with conventional approaches. Furthermore, there is no evidence that blood stem cells are superior to marrow, stem cells, that regimens which include total body irradiation are superior to drug-only regimens, or that outcome of patients with follicle center lymphoma, grade II (mixed cellularity) is superior to that of patients with grade I (small cleaved cell) disease.198
An aggressive approach to follicle center lymphoma is autologous marrow transplantation in first remission. In one study, 83 patients with previously untreated follicle center lymphoma were treated with anthracycline-based chemotherapy and 77 were eligible for stem cell transplantation.201 Forty-three patients entered complete remissions at a median follow-up of 45 months. The 3-year estimated disease-free survival was 63 percent, and the overall survival at 3 years was 89 percent. A patient whose marrow was PCR-negative after purging had a significantly longer freedom from recurrence than patients who were PCR-positive.
High-dose interferon-a is active in heavily pretreated patients with follicle center lymphoma.202,203 Based on these results, studies were designed to determine the role of interferon-a both in the induction phase of treatment as well as in maintenance therapy. A number of phase III trials were designed to address these issues. Two of four trials included doxorubicin-based regimens, one included cyclophosphamide, vincristine, and prednisone, and one had cyclophosphamide as a single agent.204,205,206,207 and 208 These studies included relatively low doses of interferon given intermittently, ranging from 2 to 6 million U/m2. In one of the studies, disease-free survival and overall survival were improved.204 In two studies, there was increased remission duration without an improvement in overall survival.205,206 and 207 A fourth study demonstrated interferon to have no impact on remission or survival.208 Five large randomized trials evaluated interferon-a as postinduction therapy.205,209,210,211 and 212 Patients were randomized to relatively low-doses of interferon-a three times per week following chemotherapy (2 to 5 million U/m2). The duration of remission was improved in three of the five trials, but it is not clear that there was an impact on overall survival. These studies demonstrate activity for interferon-a in follicle center lymphoma. However, it is not clear that there is a survival benefit.
Interleukin-2 (IL-2) has been used to treat patients with low-grade lymphoma. In one study, IL-2 and exogenous lymphokine-activated killer (LAK) cells had no activity in patients with advanced low-grade or intermediate-grade lymphoma.213 In another study IL-2, alone or in combination with interferon-a, also demonstrated no activity in patients with lymphoma.214 A subsequent study, using higher doses of IL-2 with exogenous LAK cells, observed objective responses in 3 of 6 patients with low-grade lymphoma.215 However, considering the toxicity and modest activity of this regimen, it is difficult to envision a major role for IL-2 in the treatment of this disease.
B-cell malignancies are clonal; All cells within the tumor express immunoglobulin with the same variable region structure that can be recognized uniquely by anti-idiotype antibodies. Therefore, an anti-idiotype antibody raised against patients’ tumor cells may recognize a “tumor-specific” antigen. Infusion with murine monoclonal anti-idiotype antibodies, either combined with interferon-a, chlorambucil, or antibody alone have demonstrated approximately 50 percent response rates in patients with advanced follicle center lymphoma.216,217 and 218 Several problems have been identified with the anti-idiotype antibody therapy, including the high cost of generating custom-made antibodies for each patient’s tumor and the fact that idiotype variants within the tumor may be selected during treatment that are nonresponsive to subsequent therapy with the original anti-idiotype antibodies.219 Current studies are focused on idiotype vaccines. Isolating the idiotypic protein and coupling it to keyhole limpet hemocyanin (KLH) combined with an immunologic adjuvant generates specific immune responses in approximately 50 percent of patients treated.220 There appeared to be an improved clinical outcome for those patients who generated a specific immune response against the idiotype.221,222 In more recent studies, autologous dendritic cells were pulsed ex vivo with tumor-specific idiotype protein, and 4 of 4 patients with follicle center lymphoma developed measurable antitumor cellular immune responses measured by T-cell proliferation, and 3 of these 4 patients demonstrated clinical responses.223
Monoclonal antibody specific for tumor-associated antigens may be conjugated to toxins producing immunotoxins. Such immunotoxins may directly deliver toxin to tumor cells. The most common toxin used in clinical studies is ricin. Ricin is a heterodimeric protein that inhibits protein synthesis with the action of its cytotoxic A chain. The A chain is linked covalently to a B chain that binds galactose, a sugar found in glycoproteins of virtually all mammalian cells. By removing or chemically blocking the B chain, the cell-binding activity of ricin is eliminated. Conjugating this modified ricin to monoclonal antibody allows for specific delivery of the toxic A chain to cells recognized by the monoclonal antibody. Clinical trials with antibody conjugated to either ricin A chain or using the whole ricin with the B chain chemically blocked have demonstrated modest responses.224,225 and 226
Early-Stage Disease Clinical data from the 1960s and 1970s indicated that about half of all patients with localized diffuse large-cell lymphoma could be cured with involved- or extended-field radiation therapy. The patients who relapsed had undetected microscopic disease at distinct sites. Early phase II pilot studies demonstrated that higher cure rates were noted for patients treated with combination chemotherapy, with or without involved-field radiation.238 Such systemic therapy also obviated staging laparotomy, thereby reducing the morbidity and mortality of the initial patient evaluation. National cooperative group studies have evaluated the optimal number of cycles of chemotherapy for such patients and whether local radiation therapy is necessary. Investigators demonstrated that nonbulky patients with stage I or II disease had a superior overall survival when treated with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy plus involved field radiation therapy compared to eight cycles of CHOP chemotherapy alone.239 The 5-year estimates of overall survival for patients receiving CHOP plus radiation therapy was 82 percent. Patients with localized disease who have larger tumor bulks have also been studied in a prospective randomized trial.240 They demonstrated that patients treated with eight cycles of CHOP plus low-dose radiation had a superior result compared to those patients receiving eight cycles of CHOP alone. Six-year overall survival was approximately 64 percent. Therefore, it appears from these two large, prospective randomized clinical trials, that combined modality treatment with CHOP plus radiotherapy is superior to CHOP chemotherapy alone for patients with localized diffuse large B-cell lymphoma. The number of cycles of chemotherapy should be determined by the stage of disease (I versus II) and the tumor bulk.
Advanced-Stage Disease Combination chemotherapy may be curative for patients with advanced-stage high-grade lymphomas. The most active chemotherapeutic agents for treating the aggressive lymphomas are cyclophosphamide and doxorubicin. Initial studies using the “first-generation” chemotherapeutic regimens, such as C-MOPP (cyclophosphamide, vincristine, procarbazine and prednisone) or CHOP, produced complete response rates of 40 to 55 percent, with 30 to 35 percent long-term survivors (Table 103-7).236 A 10- to 15-year follow-up revealed that only a few successfully treated patients experienced a late-disease relapse. Assuming that higher cure rates could be achieved using a larger number of chemotherapeutic agents, several complex treatment regimens were developed. These regimens often included drugs that, by themselves, had little activity in patients with such lymphomas. The most commonly used regimens included m-BACOD (methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone),241 ProMACE/CytaBOM (prednisone, doxorubicin, cyclophosphamide, and etoposide followed by cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue),242 and MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin).243 Single-institution pilot studies reported that 55 to 65 percent of the patients treated with any one of these complex regimens achieved a complete remission. However, longer follow-up of these patients and multicenter clinical trials failed to substantiate that these complex and costly regimens yielded a significant improvement in survival over that achieved by CHOP.244 Thus the ultimate conclusions concerning the efficacy of these new regimens awaited the results of prospective randomized trials. The Southwest Oncology Group (SWOG) conducted a randomized trial comparing standard therapy, CHOP, to the third generation chemotherapy regimens, m-BACOD, ProMACE-CytaBOM, or MACOP-B.245 Fatal toxicity was 1 percent for CHOP, 3 percent for ProMACE/CytaBOM, 5 percent for m-BACOD, and 6 percent for MACOP-B. After over 6 years, there is still no difference in response rate, time to treatment failure, or overall survival between CHOP and the third-generation regimens. Other randomized trials comparing CHOP with each of the previously mentioned third-generation chemotherapy regimens gave similar results.246 Thus CHOP remains the best available standard of care; the recognition of this fact has resulted in significant cost savings and the avoidance of unnecessary toxicity. However, based on the fact that fewer than 50 percent of all patients are cured and, as noted subsequently, that we can now identify subsets of patients with even lower cure rates, it is absolutely essential that oncologists develop new and improved therapeutic approaches for patients with advanced stage, aggressive histology lymphoma. The IPI described above68 reported that patients in the high-risk IPI group had a CR rate of 44 percent and a 5-year survival rate of only 26 percent as compared to a CR rate of 87 percent and a 5-year survival of 73 percent in patients in the low-risk IPI group. Therefore, those patients with a low IPI, whose outcome is predicted to be favorable with conventional therapy, should be spared the added toxicity that often is associated with more aggressive experimental therapy. On the other hand, those with a high-intermediate or high-risk IPI, in whom a CR is unlikely with conventional therapy, should be identified as candidates for more aggressive treatment. When patients on the National High Priority Lymphoma Study are divided into these four risk groups and each risk group is analyzed for time to treatment failure and overall survival, there is no significant difference between the curves for any of the combination chemotherapy regimens in any of the risk groups.


Seventy-five patients with poor risk aggressive lymphoma were randomized to treatment with MACOP-B or with a novel high-dose chemotherapy regimen requiring hematopoietic progenitor cell autotransplantation.247 The toxic death rate on the high-dose arm of the study was initially high (16 percent) but has decreased with modification of the treatment regimen. Thirty-eight patients were randomized to the high-dose therapy, and 37 patients were randomized to MACOP-B. After a median follow-up of 43 months there is a statistically significant improvement in relapse-free survival (93 percent versus 68 percent, P = 0.05) and freedom from progression (88 percent versus 41 percent, P = 0.0001) in favor of the high-dose therapy arm. Overall survival was not statistically improved, however, with 73 percent on the high-dose arm versus 62 percent on the MACOP-B arm.
The Groupe d’Etudes des Lymphomes des l’Adulte (GELA) randomized 464 patients who were induced with anthracycline-containing regimens to autotransplant versus sequential chemotherapy. With a median follow-up of 28 months, the 3-year disease-free survival rate was 52 percent in the autotransplant arm (P = 0.46). The 3-year survival did not differ between the two arms. This trial was instituted before the publication of the IPI. Therefore, patients were not stratified by IPI as important prognostic factors. A subsequent retrospective analysis did reveal a relapse-free and overall survival benefit for the patients who were reclassified as having the high-intermediate and high-risk characteristics according to the IPI.249 Prospective randomized trials will be required to determine whether this subset of patients truly benefits from high-dose therapy.
Support for the concept that high-dose therapy after standard induction chemotherapy may be beneficial only for the high-intermediate and high-risk IPI groups has been provided.250 Patients were randomized to receive either standard VACOP-B chemotherapy or VACOP-B followed by autologous marrow transplantation. While there was no difference in the disease-free survival (DFS) or progression-free survival (PFS) for the entire group of 124 patients, there was a statistical improvement in DFS (P = 0.008) and a favorable trend in PFS (P = 0.08) for the high-intermediate and high-risk IPI groups assigned to high-dose therapy.
Based on the previously described data, the lymphoma committees and the marrow transplant committees of SWOG, ECOG, and CALGB (Cancer and Acute Leukemia Group B) have agreed to jointly conduct a randomized clinical trial of early versus delayed high-dose therapy for patients with high-intermediate and high-risk large-cell lymphoma. Patients under the age of 65 years will each receive five cycles of CHOP; responding patients will then be randomized to receive either three more cycles of CHOP, or one additional cycle of CHOP followed by high-dose therapy with autologous stem-cell rescue. Patients on the standard CHOP treatment who relapse will then receive the same high-dose therapy. If this study confirms the benefit of high-dose therapy in this patient group, subsequent trials will attempt to increase the number of responding patients who become eligible for high-dose therapy.
Relapsed or Refractory Aggressive Lymphomas Patients who develop progressive disease during initial therapy or who relapse following the completion of therapy have historically had a very poor prognosis. Retreatment with any of the front-line chemotherapy programs is not associated with a long-term benefit. Salvage regimens such as ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin), DHAP (dexamethasone, high-dose cytarabine and cisplatin), and MIME (methyl-GAG, ifosfamide, methotrexate and etoposide) may provide long-term disease-free survival in approximately 20 to 40 percent of patients who are eligible for transplantation.251,252 The role of high-dose therapy with stem-cell rescue has been provided by the results of the Parma trial.253 Relapsed patients under the age of 60 years were first treated with two courses of conventional salvage chemotherapy; patients responding with a CR or PR were considered to be chemosensitive and were then randomized to receive involved-field radiotherapy and high-dose BEAC chemotherapy versus DHAP chemotherapy for 6 additional months followed by involved-field radiotherapy. The event-free survival (EFS) of patients randomized to high-dose therapy was 46 percent compared to 12 percent for patients continuing to receive salvage chemotherapy (P = 0.001) OS also was superior in the high-dose therapy group (P = 0.038). Thus all relapsed patients with aggressive lymphoma should be evaluated for eligibility for high-dose therapy. Patients not eligible because of age or medical factors should receive one of the previously described salvage regimens.
Treatment of the Elderly Patient As noted, age is an important prognostic factor. The poorer survival of aged patients is secondary, in part, to their increased tendency to experience treatment-related toxicity. Efforts to reduce the amount of chemotherapy given to elderly patients to avoid such toxicities have resulted in fewer initial responses and poorer survival. Because of this, treatment regimens designed specifically for the elderly have been developed. In any case, the ability of elderly patients to tolerate combination chemotherapy is based on their physiologic and not chronologic age.254 Palliative therapy should be considered for appropriate patients who cannot tolerate combination drug chemotherapy.
Under the Working Formulation this was diffuse large cell cleaved, noncleaved, immunoblastic, or diffuse mixed small and large cell. The predominant cell represents either a large noncleaved cell or an immunoblast, or a mixture of both cell types.10 Other cell types include large cleaved or multilobated cells and anaplastic large cells. In some cases there may be a predominance of small T lymphocytes or histiocytes resembling either a T-cell lymphoma or Hodgkin disease of the lymphocyte predominant variety.10,227,228 and 229 The REAL classification suggests that with current technology, this tumor should not be subclassified but rather designated large B-cell lymphoma, and future studies should focus on identifying clinically relevant subtypes.10 All cases express classic B-cell-associated antigens CD19, CD20, and CD22, with or without surface immunoglobulin, and typically do not express CD5 or CD10. BCL-2 is rearranged in approximately 30 percent of cases, and C-MYC is rearranged in a minority of cases.
Large B-cell lymphomas represent approximately 40 percent of adult lymphomas with a median age of 60 years. Patients typically present with an enlarging mass at a single nodal or extranodal site, and 40 percent of the cases present with extranodal involvement. It is a very aggressive disease, but is potentially curable with anthracycline-based therapy. Chemotherapeutic regimens routinely used for diffuse large-cell lymphoma are not adequate. Effective regimens include prophylactic therapy of the CNS and are similar to those developed to treat patients with acute lymphoblastic leukemia.
The treatment goal for all patients with diffuse large B-cell lymphoma is cure, which can be accomplished for approximately half of all patients. While it was previously thought that the complete remission rate would invariably reflect the number of cured patients, recent studies in advanced stage patients have demonstrated that this is not universally correct.236,237 Thus failure-free survival and overall survival have become the most meaningful endpoints in determining the results of new therapies. The selection of a patient’s therapy should be based primarily on the clinical stage, rather than the histologic subtype. As described later, patients with early-stage disease, defined as stage I or II (nonbulky), have a much better prognosis than patients with advanced-stage disease, defined as stage II (bulky), stage III, or stage IV. These conclusions are based on studies of patients with the most common high-grade lymphoma, namely diffuse large-cell lymphoma (malignant lymphoma, diffuse, large-cell, or immunoblastic in the Working Formulation). Since the clinical behavior of most other intermediate- and high-grade lymphomas appears similar to that of diffuse large-cell lymphoma and since these histologic subtypes are difficult to categorize reproducibly, most studies have treated all patients with intermediate- or high-grade lymphomas in a similar manner.
Diffuse large-cell lymphomas have been referred to as the aggressive lymphomas to distinguish them from the indolent or low-grade histologies. The new REAL classification, in fact, groups all of these B-cell aggressive lymphomas into one category, termed diffuse large B-cell lymphoma.10 Patients with lymphoblastic lymphoma or Burkitt lymphoma are exceptions to this and will be discussed separately.
The disease course is aggressive and there is no known curative therapies. Median survival is 3 to 5 years. The blastoid variant is more aggressive. The overall response rate of 524 patients with mantle zone cell lymphoma treated on 12 trials with conventional chemotherapy was 84 percent, with 46 percent achieving objective complete responses.269 The median progression-free survival was 20 months in these patients, and the median overall survival was 36 months. There has been no convincing evidence from any of these studies to suggest that any conventional chemotherapy regimen is curative. Hence, consideration of innovative treatment protocols appear warranted. Since prospective, randomized clinical trials will be necessary to define optimal treatment strategies for mantle zone cell lymphoma, patients should be encouraged to participate in cooperative group protocols whenever possible. Off protocol, it seems reasonable to individualize therapy. Patients presenting with slowly progressive disease (especially those with the mantle zone variant) might be managed using oral chlorambucil, cyclophosphamide, or CVP. Patients who are markedly symptomatic or who have rapidly progressive disease are probably best treated with CHOP, if they are not eligible for cooperative group protocols.
The small noncleaved cell malignant lymphomas include Burkitt and non-Burkitt lymphoma. Even though these two entities cannot be easily separated by expert hematopathologists, patients with non-Burkitt lymphomas traditionally have been treated with chemotherapy similar to that used for patients with the diffuse large-cell lymphomas. Burkitt lymphoma is an aggressive, rapidly dividing malignant lymphoma, most commonly seen in children. The tumor is highly aggressive but potentially curable. Prognosis, particularly in children, correlates inversely with bulky disease at the time of diagnosis.278 The staging evaluation should be considered a medical emergency, and the patient should receive chemotherapy within 48 to 72 h after establishing the diagnosis. These lymphomas are exquisitely sensitive to chemotherapy.279,280 Therefore, treated patients are at high risk for developing the rapid-tumor-lysis syndrome unless they are concomitantly treated with allopurinol and forced alkaline diuresis. Frequent monitoring of electrolytes and renal function are recommended during therapy. Successful treatment regimens use high dose of cyclophosphamide, moderate to high doses of methotrexate, and CNS prophylaxis.
Four therapeutic modalities produce remissions in most patients with cutaneous T-cell lymphoma: topical nitrogen mustard, photochemotherapy with psoralen and ultraviolet A light (PUVA), systemic chemotherapy, and radiation therapy (particularly total-body electron beam therapy). Each induces remission, but cure is uncommon and possible only in early disease.
Topical Nitrogen Mustard Topical nitrogen mustard is used predominantly in patients with early cutaneous stages of disease. In more advanced stages, this approach is used to supplement other therapies. The major advantage of topical therapy is that it is relatively nontoxic. Disadvantages include the inconvenience of daily application to large areas of skin, the allergic reactions in up to half of cases,313 the potential for development of skin cancer,314 and the inability to cure the disease. Nitrogen mustard (10 mg diluted to 60 ml of tap water or 60 g of a water-miscible cream or an anhydrous ointment, which may have less allergic sensitization) is administered daily using a cotton swab or small pain brush. Therapy is continued for up to 12 months in responders. Frequency is then reduced to every other day for an additional 1 to 2 years. Therapy is discontinued after 3 years or when cutaneous lesions disappear completely.
Psoralen Psoralen is a phototoxic furocoumarin activated by ultraviolet A light. In its active form, it bonds covalently and irreversibly to DNA. Ultraviolet A light penetrates only the upper part of the dermis. Therefore, psoralen activated by ultraviolet A light affects cells primarily in the epidermis and papillary dermis. A 60 percent complete remission rate has been reported with psoralen; patients with generalized erythroderma and tumors have lower response rates than those with plagues.315,316 and 317 Psoralen is usually given at a dose of 0.6 mg/kg orally, 2 h before the ultraviolet A light therapy. Treatments are initially given three times weekly. Maintenance therapy may be given every 2 to 4 weeks indefinitely. Adverse effects of PUVA therapy include mild nausea, pruritus, and sunburnlike changes with atrophy and dry skin. PUVA is not cross-resistant with other treatment modalities. Disadvantages of this therapy are its inability to cure and its expense. Long-term side effects are not yet reported.
Chemotherapy The largest experience with single-agent chemotherapy is with alkylating agents, including nitrogen mustard, 0.4 mg/kg intravenously every 4 to 6 weeks; cyclophosphamide; and chlorambucil. Response rates of 60 percent, with 15 percent complete remissions, have been reported.292,321,322,323 and 324 Similar results occur with methotrexate, 2.5 to 10 mg/day by mouth; bleomycin, 7.5 to 15 mg intramuscularly twice weekly; and doxorubicin, 60 mg/m2 once monthly.292,325,326,327,328,329,330 and 331 Single-agent therapy does not cure cutaneous T-cell lymphoma. Combination therapy with these and other drugs produces objective responses in more than 80 percent of patients and complete responses in about one-fourth of cases.292,332,333 Duration of remission varies, with a median of about 1 year; no long-term disease-free survival has been reported.
Electron Beam Therapy Electron beam therapy penetrates only into the upper dermis, and there are minimal systemic effects and an 80 percent complete remission rate.318,319 and 320 Twenty percent of patients remain relapse-free at 3 years. Typically, treatment is 4 Gy per week to a total dose of 36 Gy in 8 to 9 weeks. The advantage of electron beam therapy is a high frequency of durable complete responses without systemic toxicity. Disadvantages are alopecia, atrophy, edema, dermatitis, and high cost.
Combined Modality Therapy Randomized trials with whole-body electron beam therapy as a single modality compared with electron beam therapy followed by topical nitrogen mustard suggest a benefit of combined therapy.334 Studies of electron beam therapy combined with chemotherapy suggest no advantage over either alone,335 although combined modality therapy produced disease-free survival in some patients with early-stage disease; those with advanced disease failed to benefit. A report on patients randomized either to early intensive therapy with cyclophosphamide, doxorubicin, vincristine, and etoposide combined with either topical nitrogen mustard or 30 Gy of electron beam radiation therapy or to topical or radiation therapy only showed no difference.336
Investigational Therapy Many therapeutic approaches to cutaneous T-cell lymphoma are being evaluated. One study reported a 50 percent response with high-dose interferon-a.337 In another study, three of four patients receiving 13 cis-retinoic acid improved.338 Some investigators claimed success using leukapheresis to treat patients with cutaneous T-cell lymphoma.339 In other studies,340 subjects received oral psoralen followed by leukapheresis. The lymphocyte-enriched blood fraction was exposed to ultraviolet A light and returned. This approach decreased lymphocyte viability by 90 percent. Twenty-seven of 37 patients with otherwise resistant cutaneous T-cell lymphoma responded to the treatment. Treatment of four patients with advanced cutaneous T-cell lymphoma with pentostatin resulted in two complete and two partial responses.341 A response rate of 30 percent has been reported for cladrabine.342,343 Finally, therapy with monoclonal antibodies was also studied. Unlabeled monoclonal antibodies had only a minimal transient effect,344 while 131I-labeled monoclonal antibody produced more prolonged and consistent responses.345
Prognosis Median survival after histologic diagnosis of cutaneous T-cell lymphoma is about 10 years. However, lymph node involvement is associated with a poorer prognosis than disease limited to the skin.292,293 Patients with cutaneous T-cell lymphoma with visceral involvement that includes liver, spleen, pleura, and lung have the poorest prognosis. Such patients have a median survival of less than 1 year.
Fifty percent of deaths of patients with cutaneous T-cell lymphoma result from infections. These are usually staphylococcus- and pseudomonas-related and develop from cutaneous lesions.292 Septicemia and bacterial pneumonia are common. Herpes infections occur in up to 10 percent of patients with advanced cutaneous T-cell lymphoma. Visceral involvement does not appear until late in the course of the disease. Progressive cutaneous T-cell lymphoma with widespread visceral involvement is the next most common cause of death.
Patients with adult T-cell leukemia/lymphoma treated with combination chemotherapy are usually treated using a regimen that includes doxorubicin, such as CHOP. Complete and partial responses are attained in most patients. However, most patients relapse within 6 to 12 months, and cures are not reported. Encouraging responses have been observed in patients who received passive immunotherapy or radioimmunotherapy using monoclonal antibodies specific for antigens expressed by the neoplastic T cells, such as CD25.413,414 Other biological agents, such as interferon-a, have had modest effects.415,416 Therapy with the nucleoside pentostatin may benefit some patients with this disease.417 Responses to combination therapy with interferon-a and zidovudine have been reported.418,419
Patients with the smoldering type of adult T-cell leukemia/lymphoma have an indolent course, if they do not succumb to opportunistic infections.385,420 They typically have a long survival without therapy and without hypercalcemia. Skin lesions are characteristic and occur as erythema, papules, or nodules. The proportion of adult T-cell leukemia/lymphoma cells in the blood is low (less than 5 percent), with minimal lymphadenopathy, hepatosplenomegaly, and marrow infiltration. One patient developed aggressive adult T-cell leukemia/lymphoma after more than 5 years of illness and another after 13 years. Patients with smoldering adult T-cell leukemia/lymphoma are more likely to have a normal karyotype.
In one study, 28 patients with angioimmunoblastic lymhadenopathy-like lymphoma were treated with either prednisone or prednisone with combination chemotherapy including cyclophosphamide, doxorubicin, bleomycin, vincristine, procarbazine, ifosfamide, methotrexate, etoposide, and mesna.366 Complete remissions were more common in the chemotherapy arm of the protocol, but there was no significant difference in survival. Others have reported responses and long complete remissions in patients treated with combination chemotherapy.367 Based on these results, combination chemotherapy with a CHOP-like regimen would be a reasonable first choice for therapy for patients with angioimmunoblastic lymphadenopathy-like lymphoma. Prednisone may be considered for elderly patients with a more indolent disease. Mean survival is 30 months; infection is the most common cause of death.
There may be a role for surgery in patients with gastric lymphoma.94,95,96 and 97 Patients who present with a major hemorrhage or perforation will require partial gastrectomy in addition to chemotherapy and radiation therapy. Patients with stage I and II diffuse B-cell large-cell lymphoma can be treated with upper abdominal radiation after three cycles of chemotherapy. Those with B symptoms, bulky disease, or stage III or IV disease will require a full course of chemotherapy with radiation reserved for residual disease following chemotherapy.
Definitive therapy of testicular lymphoma depends on the stage of disease. If the patient receives systemic chemotherapy, the risk of relapse in the opposite testicle is 25 percent.98,99 and 100 The addition of 25 Gy of radiation eliminates this risk.84 CNS involvement is unusual as an isolated site of relapse for patients who present with primary disease of the testicle. However, for patients with systemic lymphoma, with the testicle as a site of disease, prophylactic CNS intrathecal chemotherapy is recommended.

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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