.+"
`
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`
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`
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`
`Medical, Surgical, c’rRadiation Oncology
`
`Editedby
`
`Richard Pazdur, MD
`US Food and Drug Administration
`
`Lawrence R. Coia, MD
`Saint Barnabas Health Care System
`
`Cancer
`Management:
`A Multidisciplinary
`* Approach
`
`MELVILLE,NY
`
`William 1. Hosldns, MD
`Memorial Sloan-Kettering Cancer Center
`
`Lawrence D. Wagman, MD
`City of Hope National Medical Center
`
`And the editors of the journal ONCOLOGY
`
`,'
`
`a
`
`PBB:
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`

`

`FOURTH EDITION
`
`Cancer
`
`Management:
`A Multidisciplinary
`Approach
`
`Medical, Surgical, 6'?“ Radiation Oncology
`
`Edited by
`
`Richard Pazdur, MD
`Director, Division of Oncology Drug Products
`Center for Drug Evaluation and Research
`US Food and Drug Administration
`
`Lawrence R. Coia, MD
`Chairman, Department of Radiation Oncology
`Community Medical Center, Toms River, NewJersey
`An affiliate of Saint Barnabas Health Care System
`
`William]. Hoskins, MD
`Deputy Physician in Chief, Disease Management Team
`Chief, Gynecology Service
`Memorial Sloan-Kettering Cancer Center
`
`Lawrence'D. Wagman, MD
`Chairman, Division of Surgery
`City of Hope National Medical Center
`
`And the editors of the journal ONCOLOGY
`
`PERMELVILLE,NY
`
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`

`

`
`
`aUn E 2
`
`.U)
`
`zozI
`
`:I:
`
`
`
`CHAPTER 30
`
`Non-Hodgkin’s
`lymphoma
`
`Arturo Molina, MD, and Richard D. Pezner, MD
`
`BetWeen 1973 and 1996, the incidence of non—Hodgkin’s lymphoma (NHL)
`rose by 81%in the United States, representing one of the largest"1ncreases of
`any cancer. Although some of thisIncrease may be artifactual, resulting from
`improved diagnostic techniques and access to medical care, or may be directly
`related to the development of NHL in 20— to 40-year—old men with human
`immunodeficiency virus (HIV) infection, an unexpected increase in frequency
`of NHL has been observed throughout the United States.
`
`The incidence of NHL per 100,000 persons has risen from 9.8 in 1972—1974 to
`13.6 in 1992—1996. The increases have been relatively higher in whites, males,
`and the elderly, and rates have risen more rapidly in rural than urban areas.
`Similar findings have been reported in other developed countries.
`
`Currently, NHL represents approximately 4.0% of all cancer diagnoses (4.3% in
`males and 3.7% in females). Estimates from the American Cancer Society indi—
`cate that in the year 2000, some 56,800 new cases of NHL will be diagnosed in
`the United States and approximately 25,700 people will die of this disease.
`
`Epidemiology
`
`Gender The overall incidence of lymphoma is slightly higher in men than
`women. The incidence rate (per 100,000 population) in 1989 was 56% higher
`in white males (17.8) than white females (11.4).
`
`Age Except for highwgrade lymphoblastic and small noncleaved cell lymphomas,
`which are the most common types of NHL seen in children and young adults,
`the median age at presentation for all subtypes of NHL is over 50 years. Low-
`grade lymphomas account for 37% of NHLs in patients between the ages of 35
`and 64 years at diagnosis but for only 16% of cases in those below the age of 35
`and are extremely rare in children.
`
`Race Incidence varies by race, with whites at higher risk than blacks and Asian-
`Americans. Most histologies, particularly low--grade small lymphocytic and
`follicular lymphomas, are more common in whites than blacks. The incidence
`0f mycosis fungoidesis highestin black males and lowestin white females.
`
`Geography Certain endemic geographical factors appear to influence the de-
`velopment of NHL in specific areas.
`.xm—_—'—_—u
`
`NON-HODGKIN’S LYMPHOMA
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`HTLV— 7-anooiated NHL Human T—cell lymphotrophic virus—1 (HTLV—1)—associ.
`ated T-cell lymphoma/leukemia occurs more frequently inJapan (KyuShu) and
`the Caribbean.
`
`Burkitt’s bimphoma in Africa The incidence (per 100,000 population) of Burkitt’s
`NHL in Africa (Nigeria and Tanzania) is 5.7-7. 6, as compared with 0.1 in the United
`States. The clinical features of Burkitt’s lymphoma in Africa differ from those of
`cases reported to the American Burkitt’s Lymphoma Registry. Etiologic endemic
`factors include malaria as a source ofchronic B—cell antigenic stimulation and Epstem_
`Barr virus (EBV)—induced immortalization of B—lymphocytes.
`
`Middle East lymphoma or (Dc—chain disease on Heavy-chain disease is a disorder of
`B-lymphoid cells characterized by diffuse thickening of the small intestine €er
`to a lymphoplasmacytic infiltrate with secretion of incomplete IgA heavy chains
`This clinicopathologic entity is rarely encountered in individuals other than
`those of Mediterranean ethnic origin.
`
`Follicular lymphomas are more common in North America and Europe but are
`rare in the Caribbean, Africa, China,]apan, and the Middle East.
`
`Peripheral T-cell lymphomas are more common in Europe and China than in
`North America.
`
`Disease site Malignant lymphomas are a heterogeneous group of neoplasms
`that usually arise or present in lymphoid tissues, such as lymph nodes, spleen,
`and bone marrow, but that may arise in almost any tissue. The most frequent
`sites for extranodal lymphomas, which constitute about 26% of all lympho—
`mas, are the stomach, skin, oral cavity and pharynx, small intestine, and CNS.
`Although primary CNS lymphoma is rare, there has been a 3—fold increase in
`incidence, even if patients with HIV infection and other types of immunosup-
`pression are excluded.
`
`Survival The 5—year relative survival rate of patients with NHL increased from
`28% between 1950 and 1954 to 49% between 1979 and 1985. These improve-
`ments in survival occurred mainly in young adults and children. The potential
`for cure varies among the different histologic subtypes and is directly related to
`stage at presentation and response to initial therapy.
`
`Ho1I IoI
`
`2"
`EI
`'3
`
`Etiology and risk factors
`
`1
`
`Chromosomal translocations and molecular rearrangements Nonrandom
`Chromosomal and molecular rearrangements play an important role in the
`pathogenesis of many lymphomas and correlate with histology and
`immunophenotype (Table 1). The most commonly associated chromosomal
`abnormality in NHL is the t(14;18)(q32;q21) translocation, which is found in
`85% of follicular lymphomas and 28% of higher—grade NHLs. This transloca-
`tion results in the juxtaposition of the hol—Z apoptotic inhibitor “oncogene” at
`chromosome band 18q21 to the heavy—chain region of the immunoglobulin
`locus within chromosome band 14q32.
`
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`‘—
`
`TABLE I: Correlation of chromosomal abnormalities
`in NHL with histology, antigen rearrangements,
`and oncogene expression
`
`# c
`
`Oncogene
`Antigen
`yrogenetic
`
`abnormality
`rearrangement
`expression
`Histology
`f.-
`
`B.cell lymphoma
`
`t(|4;|8)(q32;q2|)
`
`Follicular (small
`cleaved. mixed,
`
`large cell), diffuse
`large cell
`
`t(l |;|4)(q | 3;q32)
`
`Mantle cell
`
`t( I; l4)(p22;q32)
`
`MALT lymphoma
`
`t(l I; |8)(q2|;q2|)
`
`MALT lymphoma
`
`lgH
`
`lgH
`
`IgH
`
`lgH
`
`t(9;|4)(pl 3;q32)
`
`Lymphoplasmacytic lgH
`lymphoma
`
`t(|4; I9)(q32;ql 3. l)
`
`B-CLL
`
`8q24 translocations
`t(8; l 4)(q24;q32)
`t(2;8)(pl !- |2;q24)
`t(8;22)(q24;q | l)
`
`Small noncleaved
`(Burkitt’s and
`non-Burkitt’s
`types)
`
`(3;22)(q27;q| l)
`
`Trisomy l2
`
`Diffuse (large cell,
`small cleaved cell)
`
`Small lymphocytic,
`B-CLL
`
`lgH
`
`lgH
`lg-k
`lg-K
`
`lg-K
`
`T-cell lymphoma
`
`|4q|| abnormalities
`inv |4(ql |;q32)
`t(| l;|4)(p|3;ql I)
`t(|0;|4)(q24;q| l)
`t(|;|4)(p32;ql I)
`
`7q35 abnormalities
`t(7;9)(q34-36;q32)
`
`Variable
`T-ALL
`Variable
`T-ALL
`
`T-ALL or
`lymphoblastic
`lymphoma
`
`TCR-S
`TCR-E‘)
`TCR-5
`TCR-B
`
`TCR-B
`
`t(7;|4)(q34-36;q| I) Variable
`t(7;|9)(q34-36;q|3) T-ALL
`
`J
`
`TCR-B
`TCR~B
`
`t(2;5)(p23;q35)
`
`Anaplastic
`large cell
`(Ki- | positive)
`
`bcl—Z
`
`bcl-l
`
`bcl—I 0
`
`Unknown
`
`FAX-5
`
`bcl—3
`
`c-myc
`
`bcl-6 (LAZ-3)
`
`tcl-I
`tcl-Z
`hox-I l (id-3)
`tcl (tall,tcl-5)
`
`tcl-4
`
`lyl-l
`
`npm, alk
`
`— a
`
`lk = anaplastic lymphoma kinase gene; B-CLL = B-cell chronic lymphocytic leukemia; lgH = immuno-
`globulin heavy chain; lg-K = immunoglobulin kappa light chain; lg-7l, = Immunoglobulin lambda light
`chain; LAZ-3 = LAZ-3 transcription factor gene; MALT = mucosa-associated lymphoid tissuempm =
`nucleophosmin gene;T—ALL = T-cell acute lymphocytic leukemia;TCR = T-cell antigen receptor
`
`
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`NON-HODGKIN’S LYMPHOMA
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`fl:-
`
`The t(11;14)(q13;q32) translocation results in overexpression of [Ml-7 (CYCIin
`D1/PRAD 1), a cell-cycle—control gene on chromosome 11q13, and has a di-
`agnostic, nonrandom association with mantle cell lymphoma.
`Chromosomal translocations involving 8q24 lead to c~myc deregulation and
`are frequently seen in high-grade small noncleaved lymphomas (Burkitt’s and
`non-Burkitt’s types), including those associated with HIV infection.
`Environmental factors also may play a role in the development of NHL,
`
`Occupations Certain workers have a slightly increased risk of developing NHL
`including farmers, pesticide applicators, grain (flour) millers, meat workerS, Wood
`and forestry workers, chemists, painters, mechanics, machinists, printers, and Work.
`ers in the petroleum, rubber, plastics, and synthetics industries.
`Chemicals that have been linked to the development of NHL include a variety
`of pesticides and herbicides (2,4-D-organophosphates, chlorophenols), solvents
`and organic chemicals (benzene, carbon tetrachloride), wood preservatives,
`dusts (wood, cotton), and some components in hair dye.
`Chemotherapy and radiotherapy Patients who receive cancer chemotherapy
`and/or radiation therapy are also at increased risk of developing NHL.
`Viruses Several viruses have been implicated in the pathogenesis of NHL, in-
`cluding EBV, HTLV-l, Kaposi’s sarcoma—associated herpesvirus (KSHV; 21130
`known as human herpesvirus 8, or HHV-8), and hepatitis C virus (HCV).
`EBVis a DNA virus that has been associated with Burkitt’s lymphoma, par-
`ticularly in endemic areas of Africa; Hodgkin’s disease; lymphomas in im—
`munocompromised patients (ie, organ transplantation and HIV infection);
`sinonasal lymphoma (Asia and South America); and sporadically in other
`B— and T—cell lymphomas. EBV can transform lymphocytes in culture. B—lym-
`phocytes from normal EBV-positive subjects grow as tumors in mice with se-
`vere combined immunodeficiency.
`
`HTLV- 7 is a human retrovirus that is endemic in certain areas ofjapan and the
`Caribbean. HTLV—l establishes a latent infection via reverse transcription
`in activated T—helper cells. A minority (5%) of carriers develop adult T—cell
`leukemia/lymphoma. An HTLV—l-like deleted provirus has been detected in
`some patients with mycosis fungoides, although conflicting findings have been
`reported.
`'
`KSHV KSHV—like DNA sequences are frequently detected in body cavity-
`based lymphomas in patients with HIV infection and in those with multicen—
`tric Castleman’s disease.
`
`HCVinfection is associated with the development of clonal B-cell expansions
`and certain subtypes of NHL, particularly in the setting of essential (type 11)
`mixed cryoglobulinemia. HCV may predispose B-cells to malignant transfor-
`mation by enhancing signal transduction upon binding to the CD81 (TAPA-I)
`molecule.
`
`Immunodeficiency Patients with congenital and acquired states of immu'
`nosuppression are at increased risk for NHL.
`_—’_—___—_—_______/
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`Fr
`
`fl
`
`Gangenital immunodeficiency states that are associated with an increased risk in-
`clude ataxia-telangiectasia, Wiskott—Aldrich syndrome, common variable hypo-
`gammaglobulinemia, X—linked lymphoproliferative syndrome, and severe com—
`bined immunodeficiency.
`Acquired immunodeficiency states, such as HIV infection, iatrogenic immuno—
`Suppression (ie, organ or bone marrow transplant [BMT] recipients, long—term
`survivors of Hodgkin’s disease), and a variety of collagen vascular and autoim—
`Inufle diseases (eg, Sjogren’s syndrome, rheumatoid vasculitis and Felty’s syn-
`drome, systemic lupus erythematosus, chronic lymphocytic thyroiditis, and
`angioimmunoblastic lymphadenopathy) also pose an increased risk of de—
`veloping NHL.
`
`GE lymphomas An increased incidence of GI lymphomas is seen in patients
`with celiac (nontropical) sprue and inflammatory bowel disease, particularly
`Crohn’s disease. Gastric mucosa—associated lymphoid tissue (MALT) lymphoma
`is seen most frequently, but not exclusively, in association with Helicobaeter
`pylori infection. In contrast to studies performed in European patients, Mexi-
`can patients with intestinal lymphomas show a very high frequency of EBV—
`positivity; this finding is not limited to T—cell NHLs, but rather, includes a
`significant portion of B—cell NHLs.
`
`Signs and symptoms
`__________—_____————
`
`Fever, weight loss, and night sweats, referred to as systemic B symptoms, as
`well as fatigue and weakness, are more common in advanced or aggressive
`NHL but may be present in all stages and histologic subtypes.
`
`Low-grade lymphomas Painless, slowly progressive peripheral adenopathy
`is the most common clinical presentation in patients with low-grade lymphomas.
`Patients sometimes report a history of waxing and waning adenopathy before
`seeking medical attention. Spontaneous regression of enlarged lymph nodes
`can occur and can cause a low—grade lymphoma to be confused with an infec—
`tious condition.
`
`Primary extranodal involvement and B symptoms are uncommon at presen-
`tation; however, both are common in advanced or end—stage disease. Bone
`marrow is frequently involved, sometimes in association with cytopenias.
`Splenomegaly is seen in about 40% of patients, but the spleen is rarely the
`only involved site at presentaticm.
`
`Intermediate- and high-grade lymphomas The clinical presentation of in—
`termediate— and high-grade lymphomas is more varied. Although the majority
`of patients present with adenopathy, more than one—third present with
`extranodal involvement, the most common sites being the GI tract (including
`Waldeyer’s ring), skin, bone marrow, sinuses, GU tract, thyroid, and CNS.
`B symptoms are more common, occurring in about 300/0-400/0 of patients.
`Lymphoblastic lymphoma often presents with an anterior superior mediastinal
`mass, superior vena cava syndrome, and leptomeningeal disease with cranial
`nerve palsies.
`
`NON-HODGKIN'S LYMFHOMA
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`# U
`
`S patients with Burkitt’s lymphoma often present with a large abdominal
`mass and symptoms of bowel obstruction.
`
`Screening and diagnosis
`________________—_—————-———-
`N0 effective methods are available for screening or identifying populations at
`high risk for the development of NHL. A definitive diagnosis can be made
`only by biopsy of pathologic lymph nodes or tumor tissue. A formal review by
`an expert hematopathologist for additional studies, such as immunophenotyping
`and genotyping, should be considered.
`Initial diagnostic evaluation of patients with lymphoproliferative malignancy
`should include:
`I Careful history (night sweats, weight loss, fever; neurologic, musculo-
`skeletal, or G1 symptoms)
`I Physical examination (lymph nodes, including submental, infraclavi—
`cular, epitrochlear, iliac, femoral, and popliteal nodes; pericardial rub,
`pleural effusion, distended neck and/or upper extremity veins in
`superior vena cava syndrome; breast masses; hepatosplenomegaly,
`bowel obstruction, renal mass, and testicular or ovarian mass; focal
`neurologic signs, such as plexopathy, spinal cord compression, nerve
`root infiltration, and meningeal involvement; skin lesions)
`
`I Biopsy of peripheral lymphadenopathy
`I Chest x—ray (mediastinal or hilar adenopathy, pleural effusions,
`parenchymal lesions)
`I CT scan of the chest (mediastinal, hilar, or parenchymal pulmonary
`disease)
`I CT scan of the abdomen and pelvis (enlarged lymph nodes, spleno-
`megaly, filling defects in liver and spleen)
`
`I Bilateral bone marrow biopsy
`
`I Gallium scan (optional/selected cases)
`I Bone scan (selected cases) if musculoskeletal symptoms are present or
`alkaline phosphatase is elevated
`I CBC with differential and platelet count (peripheral blood lymphocy—
`tosis with circulating malignant cells is common in low-grade lym—
`phomas). Bone marrow and peripheral blood involvement may be
`present, and the distinction between leukemia and lymphoma is diffi-
`cult to make in some cases.
`I General chemistry panel, BQ-microglobulin are recommended
`I HIV serology in patients with diffuse large cell, immunoblastic, and
`small noncleaved histologies; HTLV—l serology in patients with cuta-
`neous T—cell lymphoma, especially if they have hypercalcemia
`
`/ 5
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`I Cytogenetic and molecular analyses of lymph node, bone marrow, and
`peripheral blood (selected cases)
`
`I Perform examination of CSF and strongly consider CNS prophylaxis
`in patients with (1) diffuse aggressive NHL with bone marrow, epidu—
`ral, testicular, paranasal sinus, or nasopharyngeal involvement; (2) high—
`grade lymphoblastic lymphoma and small noncleaved cell lymphomas
`(Burkitt’s and non-Burkitt’s types); (3) HIV-related lymphoma; and
`(4) primary CNS lymphoma
`
`I Upper GI series with small bowel follow-through in patients with head
`and neck involvement (tonsil, base of tongue, nasopharynx) and those
`with a GI primary
`
`I Ultrasound of opposite testis in patients with a testicular primary
`
`I Spinal MRI scan for epidural disease when clinically indicated (useful
`in the evaluation of suspected spinal cord compression)
`
`I PET (FD G—glucose) scanning is gaining wider acceptance as a poten-
`tial diagnostic approach for staging at diagnosis and relapse.
`
`PCR and Southern blot studies Circulating monoclonal lymphoid cells can
`be detected by polymerase chain reaction (PCR) or Southern blot techniques,
`but the clinical utility of these studies is not well defined. Several studies have
`demonstrated the presence of circulating t(l4;18)-positive cells in patients with
`durable remissions of follicular lymphoma, but whether this is a harbinger of re-
`lapse remains controversial. The t(l4;18) translocation has been found in B—cells
`from blood of normal individuals, indicating that additional oncogenic events are
`necessary to establish the neoplastic phenotype.
`
`’athology
`
`Despite an improvement in immunologic, cytogenetic, and molecular tech-
`niques used by hematopathologists for diagnosing and classifying lymphoma,
`many problems and areas of confusion remain.
`
`Working Formulation
`
`Proposed in 1982 as a modification of the Rappaport classification of NHL,
`the Working Formulation established a uniform language that is clinically rel-
`evant and useful in predicting survival and curability (Table 2). This classi-
`fication is based on two criteria: (1) morphology (growth pattern in lymph
`nodes and cytologic features of neoplastic cells) and (2) biological aggressive-
`ness (low, intermediate, and high grade).
`
`The terminology is based primarily on the Lukes—Collins and Kiel (Lennert)
`systems, which recognize the immunologic origin of NHL. Thus, the nodular
`(follicular) growth pattern represents lymphomas arising from follicular center
`cells (B-cells) of normal lymphoid follicles, whereas large cell lymphomas are
`derived from transformed B- or T—cells. The advantages of this classification
`system include a good correlation between histologic subtype and clinical course,
`
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`NON-HODGKIN'S LYMPHOMA
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`TABLE 2: Working Formulation and Rappaport classification
`equivalents for NHL
`m_
`
`
`
` Working Formulation Rappaport equivalent
`
`Low-grade
`A. Small lymphocytic
`B. Follicular. small cleaved cell
`C. Follicular, mixed, small cleaved
`and large cell
`
`Intermediate-grade
`D. Follicular, large cell
`E. Diffuse, small cleaved cell
`F. Diffuse, mixed small and large cell
`G. Diffuse, large cell
`
`Diffuse, well-differentiated, lymphocytic
`Nodular, poorly differentiated, lymphocytic
`Nodular, mixed
`
`Nodular, histiocytic
`Diffuse, poorly differentiated, lymphocytic
`Diffuse, mixed
`Diffuse, histiocytic
`
`High-grade
`H. Immunoblastic
`|. Lymphoblastic
`J. Diffuse, small noncleaved cell
`
`Diffuse, histiocytic
`Lymphoblastic
`Diffuse, undifferentiated
`(Burkitt’s and non-Burkitt’s types)
`
`
`and the potential for widespread application among different institutions be—
`cause determination of immune surface markers is not required.
`
`Unfortunately, the Working Formulation does not distinguish between neo-
`plasms of B— and T—cell lineage or recognize other subtypes of lymphoma that
`are defined by immunophenotypic and genetic techniques and/or character—
`ized by unique clinical and biological features (Table 3). In addition, the Work
`ing Formulation classifies immunoblastic lymphoma, a morphologic variant of
`diffuse large cell lymphoma, as a high grade NHL, and yet its clinical course
`and survival do not differ from those of intermediate-grade diffuse large cell
`lymphoma.
`
`REAL classification A revised European-American classification of lymphoid
`neoplasms (REAL classification) has been proposed by the International Lym-
`phoma Study Group (ILSG). This approach to lymphoma categorization at-
`tempts to define the diseases recognized with currently available morphologic,
`immunologic, and genetic techniques. This system incorporates new
`lymphoproliferative disorders that were not recognized by the Working For-
`mulation (Table 3) and omits the general grading of lymphomas into low—,
`intermediate-, and high-grade categories.
`
`The list of lymphoid neoplasms recognized by the ILSG includes 12 different
`types of B-cell neoplasms and 11 types of T—cell malignancies, including pre-
`cursor B-cell and T—cell acute leukemia. The subtypes of Hodgkin’s disease are
`also included. The clinical relevance of the REAL classification is under study.
`
`The 13 most frequently occurring clinical entities that are recognized by the
`REAL classification are diffuse large B-cell lymphoma (31%), follicular lym-
`phoma (22%), small lymphocytic lymphoma (6%), mantle cell lymphoma (6%),
`
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`.—
`
`TABLE 3: Lymphomas and atypical lymphoproliferative
`disorders not recognized by the Working Formulation
`fl
`Mantle cell lymphomaa
`Resembles follicular small cleaved cell NHL but derived from a different type of B-cell
`found in mantle zone surrounding B-cell follicles; frequent detection of a t(| I; I4)
`translocation involving bcl-l rearrangement; comprises ~ 5% of NHLs in Europe and the
`us; propensity for extranodal involvement and aggressive behavior; low potential for cure
`with standard therapies; bone marrow involved in > 75% of cases, peripheral blood
`involved in ~ 30%
`
`Monocytoid B-cell lymphomalmarginal zone lymphoma of nodal type
`Low—grade NHL; extremely indolent course; predominant lymph node involvement
`
`Lymphoma of mucosa-associated lymphoid tissue (MALT)
`Tends to have an indolent natural history; primarily affects organs containing epithelial cells,
`such as the GI tract, lung, breast, thyroid, and salivary glands; 80% 5-year survival
`Anaplastic large-cell lymphomab
`Commonly infiltrates the sinusoids of lymph nodes; frequently misdiagnosed as HD,
`malignant histiocytosis, or metastatic carcinoma; skin often involved; most cases are of
`T-cell origin and some are characterized by the detection of a t(2;5) translocation
`
`Nycosis fungoides
`Indolent cutaneous T-cell lymphomas with a CD4+ phenotype; initially involves the skin
`but disseminates into lymph nodes and visceral organs in many patients; more advanced
`form (leukemic peripheral blood involvement and generalized erythroderma) known as
`Sézary syndrome; ulcerated lesion commonly complicated by bacteria; involvement of
`viscera (usually the lung and liver) associated with very poor prognosis
`
`Angiocentric lymphoma
`T—cell neoplasm with propensity to invade and destroy blood vessels
`T-cell— rich B-cell lymphoma
`Previously classified as subset of diffuse lymphocyte-predominant HD; usually aggressive;
`response to multiagent chemotherapy and outcome similar to other large B-cell NHLs
`
`Angiotropic (intravascular) large cell lymphoma
`Usually of B—cell lineage; characterized by diffuse intravascular proliferation of neoplastic
`cells within capillaries, arterioles, and venules
`
`Angio-immunoblastic lymphadenopathy (AILD)
`Lymphoproliferative disorder characterized by diffuse lymphadenopathy, hepatospleno-
`megaly, skin rash, systemic symptoms,cytopenias, and polyclonal hypergammaglobul-
`inemia; often evolves into T-cell lymphoma. but EBV-related B-cell NHLs can also develop
`
`Divergent or discordant lymphoma
`Large cell histology in a lymph node with low-grade small cleaved cell lymphoma in bone
`marrow; histologic transformation of low-grade NHL into a more aggressive lymphoma
`occurs at annual rate of 3%-4% and is associated with increased morbidity and mortality
`
`Composite lymphoma
`Two histologic subtypes in the same lymph node, sometimes with coexistent HD
`Castleman’s disease
`Lymphoproliferative disorder associated with both immunodeficiency (HIV infection) and
`increased rate of malignancy (lymphoma, HD, and KS);associated with HHV-S infection.
`
`Adult'F-cell leukemiallymphoma
`Aggressive T-cell malignancy with unique clinical features, including skin infiltration, lytic
`bone lesions,and hypercalcemia; associated with HTLV-I infection
`fl
`
`3Also known as mantle zone or lymphocytic lymphoma of intermediate differentiation.
`Ki-l
`lymphoma. HD = Hodgkin’s disease; KS = Kaposi's sarcoma
`
`'3 Also known as
`
`
`
`NON-HODGKIN‘S LYMPHOMA
`
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`peripheral T—cell lymphoma (6%), lymphoma of mucosa associated tissue
`(MALT) type (5%), primary mediastinal large B-cell lymphoma (2%), anaplas_
`tic large (T—/null—cell lymphoma (2%), lymphoblastic lymphoma of T— or B-cell
`lineage, Burkitt’s-like lymphoma (2%), marginal zone (monocytoid) B—cell lym-
`phoma (< 1%), lymphoplasmacytic lymphoma (1%), and Burkitt’s lymphoma
`(<1%). When immunotyping is used, the diagnostic accuracy of the REAL
`classification exceeds 85% for most subtypes, with the exception of Burkitt’s-
`like and lymphoplasmacytic lymphomas, for which the classification has diag-
`nostic accuracy rates of 53% and 56%, respectively.
`
`World Health Organization (WHO) classification The proposed WHO
`classification for lymphomas will use the principles of the REAL classification
`and will define each entity according to morphologic features, immunophenotype,
`genetic features, postulated normal counterpart, and clinical features. The WHO
`classification is similar to the REAL classification, with some modifications
`and reassessments based on more current data.
`
`REAL classification vs Working Formulation Several studies have com—
`pared the REAL classification with the Working Formulation. In one study,
`the presence of a T—cell phenotype was associated with a worse prognosis in
`68 out of 560 patients with Working Formulation intermediate-grade, immu—
`noblastic NHL. The poor prognoses of these peripheral T-cell lymphomas were
`independent of the International Prognostic Index (IPI), suggesting that the
`immunophenotypic basis of the REAL classification is clinically relevant.
`
`However, in a European study of 670 cases of NHL, only 3.8% of cases had a
`T—cell phenotype, and a statistically significant survival difference could not be
`demonstrated. In this analysis, mantle cell lymphoma and marginal zone
`B-cell lymphoma were seen in 11% and 5% of patients, respectively. These
`histologic subtypes, which are not recognized by the Working Formulation,
`were characterized by a shorter median survival, suggesting that the REAL
`classification may be of value in identifying NHL entities with distinct clinical
`behaviors and prognoses.
`
`Staging and prognosis
`
`Determining the extent of disease in patients with NHL provides prognostic
`information and is useful in treatment planning. However, histologic sub—
`classification (Working Formulation) is the primary determinant of survival
`and potential for cure. Compared to patients with limited disease, those with
`extensive disease usually require different therapy, and certain extranodal
`sites of involvement, such as the CNS and testes, require specific treatment
`modalities.
`
`Ann Arbor system Although initially devised for Hodgkin’s disease, the Ann
`Arbor system has been routinely applied to NHL (Table 4). Because Hodgkin’s
`disease commonly spreads via contiguous lymph node groups, this system is
`based primarily on the distribution of lymphatic involvement with respect to
`the diaphragm and the presence of extralymphatic organ involvement. The
`
`
`592
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`.—
`
`TABLE 4: Ann Arbor staging classification for NHL3
`WF
`
`Area of involvement
`stage
`r'__—_——_—__—————‘—'—‘—
`
`|
`
`IE
`“
`
`”E
`m
`
`|||E
`|||S
`
`mSE
`
`One lymph node region
`
`One extralymphatic organ or site
`Two or more lymph node regions on the same side of the diaphragm
`
`One extralymphatic organ or site (localized) in addition to criteria for stage H
`Lymph node regions on both sides of the diaphragm
`
`One extralymphatic organ or site (localized) in addition to criteria for stage III
`Spleen in addition to criteria for stage III
`Spleen and one extralymphatic organ or site (localized) in addition to criteria
`for stage III
`
`|V
`
`One or more extralymphatic organs with or without associated lymph node
`involvement (diffuse or disseminated); involved organs should be designated by
`subscript letters (P, lung; H, liver; M, bone marrow)
`#-
`*1 ClassA patients experience no symptoms; class B patients experience unexplained fever of 2 l0|.5°F;
`unexplained. drenching night sweats; or loss of > | 0% body weight within the previous 6 months.
`
`Ann Arbor system does not reflect the noncontiguous nature of disease spread
`in NHL, does not discriminate well between stage III and IV intermediate—
`grade disease, and fails to account for tumor bulk or number of extranodal sites.
`
`Prognostic factors Histology and morphol-
`A new prognostic factor model
`
`ogy are the major determinants of treatment
`was recently devised based on a
`retrospective study of 987 cases
`outcome and prognosis. Some patients with
`of follicular lymphoma. Muitivari-
`slow-growing low-grade lymphoma may re—
`ate anaiysis showed that gender.
`main well for many years with minimal or no
`age, number of extranodal sites.
`initial therapy, whereas survival of patients
`LDH, systemic symptoms, and
`with some types of high—grade lymphoma is
`erythrocyte sedimentation rate
`(ESR) were predictors of overall
`measured only in weeks, unless aggressive
`survivaE.The lPl was also useful in
`treatment is initiated promptly. The biologi-
`cal and clinical behavior of these disorders
`varies among the different histologic subtypes.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Several clinical pretreatment characteristics
`
`
`have been identified that are associated with
`(Federico M,Vitoio U, Zinzani P, et al:
`
`
`Proc Am Soc Clin Oncol l8:9a
`improved survival after therapy for aggressive
`
`
`[abstract 30], l 999).
`(intermediate- and high-grade) NHL: age at
`
`diagnosis; performance status; systemic symp-
`toms; serum lactic dehydrogenase (LDH) level; number of nodal and extra-
`nodal sites; tumor bulk; BQ-microglobulin level (BQM); and Ann Arbor stage.
`In general, these clinical characteristics are thought to reflect the following
`host/tumor characteristics:
`
`strat