2 IFN-a 3 million units SC daily achieves a partial response in up to 80% but CR in <5%; co ntinue to maximum response then cut to three times weekly for 6 \200\22324 months or indefi nitely; normalization of blood 04-leukemia.qxd 10.12.2003 04.12 PM Page 180 counts generally occurs within 6 months and responses persist 12 \200\22315 months after di scontinuation. \200\223 IFN-a may be useful as initial therapy (tiw) for 2 \200\2234 month s before a purine analog in patients with profound cytopenias and for HCL refractory to pur ine analog therapy. Side effects cause intol- erance in some patients. 2 G-CSF may be useful in patients with severe neutropenia. 2 Monitor response by trephine b iopsy stained for CD20/DBA-44 and TRAP. Natural history Hairy cell leukemia is associated with prolonged survival (95% at 5 years), with newer agents capable of producing remissions; some patients may achieve long term cur e. For others careful application of available treat- ments at points of disease relapse/pr ogression will still allow prolonged, good quality survival. If a remission of >5 years has been achieved then a further remission with the same agent is likely. Hairy cell variant D escribes a very rare variant of HCL where the presenting WBC count is high due to circulati ng leukaemic cells (40 \200\22360 109/L) and monocy- topenia is absent. Cells are villou s but have a central round nucleus and a distinct nucleolus like PLL. Marrow is aspirated e asily due to low reticulin but the trephine appearance is similar to HCL and associated neu tropenia. Immunophenotype differs from typical HCL: CD11c+, CD25 & HC2 \200\223ve, CD103 u sually \200\223ve. Response to deoxycoformycin or IFN-a is poor but chlorambucil appears a ctive in this form, and the variant generally follows an indolent course. 180 04-leukemia.qxd 10.12.2003 04.12 PM Page 181 Leukemia 181 04-leukemia.qxd 10.12.2003 04.12 PM Page 182 Splenic lymphoma with villous lymphocytes (SLVL) Rare B-cell lymphoproliferative disorder in which marked splenomegaly and moderate lymphocy tosis represent the main clinical findings. May cor- respond histologically to splenic marg inal zone lymphoma. Clinical and laboratory features 2 Non-specific symptoms, e.g. fatigue. 2 Affects older pat ients, mean age at diagnosis 72 years. 2 Moderate to massive splenomegaly. 2 Hepatomegaly i n 50%. 2 Lymphadenopathy rare. 2 Anemia and thrombocytopenia in 25 \200\22330% usually due to hyper- 182 splenism. Neutropenia not marked. 2 Total WBC not grossly elevated (usually <40 109/L; cf. PLL). 2 Monocytopenia not a fea ture (cf. HCL) 2 Cell morphology: larger than typical CLL cells, round/oval nuclei, villous cytoplasmic projections at one/both poles of the cells. 2 Immunophenotype: CD19+, FMC7+, CD23 \200\223 usually negative for CD5 & CD25: 20% +ve but fail to co-express CD11c and CD103 differenti- ating SLVL from HCL; (cid:9)table p174. 2 Monoclonal IgM or IgG paraprotein; free urinary light chains in 66%. 2 BM aspirate may sh ow lymphocytosis (some plasmacytoid) with typical immunophenotype; biopsy may be normal but usually shows patchy/nodular lymphoid infiltratio n. 2 Spleen histology: characteristic with nodular infiltration involving the white pulp (cf. HCL). Differential diagnosis Main differentials are mantle cell lymphoma (especially 20% CD5+ SLV L) CLL, PLL, HCL and hairy cell variant. Diagnosis requires careful morpho- logical and imm unophenotypic assessment ((cid:9)p174). Prognosis and treatment Generally follows an indolent course. \211 10% may require no trea tment. Splenectomy recommended for bulky organ enlargement or hyper- splenism (and/or to co nfirm diagnosis in some cases) and can control most symptoms. Progression after splenectomy may respond to chloram- bucil or fludarabine given as for CLL. Toxic effects may be marked with purine analogs in this elderly group of patients. Median survival over 6 years. 04-leukemia.qxd 10.12.2003 04.12 PM Page 183 Leukemia 183 04-leukemia.qxd 10.12.2003 04.12 PM Page 184 Mantle cell lymphoma (MCL) B-cell derived lymphoid neoplasm defined in the WHO/REAL classifica- tion (p195) by clinica l, morphological, immunophenotypic, cytogenetic and molecular criteria. Incidence and etiology 4 \200\2238% of cases of adult NHL. Etiology unknown. t(11;14) cause s dysregu- lation of BCL-1 and overexpression of cyclin D1, a protein involved in cell prol iferation. Clinical features and presentation 2 Most common in 9 >50 years (median age 63). 2 36% have lymphocytosis in peripheral blood which may cause presen- 184 tation as ?CLL. 2 Commonly advanced disease at presentation (87%) with generalized lymphadenopathy (57%); s plenomegaly (47%); hepatomegaly (18%). 2 Extranodal involvement, particularly in GI tract is common (18%). Diagnosis and investigation 2 FBC: lymphocytosis in 36%; anemia and mild thrombocytopenia o nly in very advanced disease. 2 Blood movie: intermediate size lymphocytes; nucleus often has clefts and indentations; smear cells unusual (cf. CLL). 2 Immunophenotype: critical to diagnosis ((cid:9)p174); SmIg strongly+ CD5+, CD10 \200\223, CD19+, CD23 \200\223, CD79b+, cyclin D1+. 2 Cytogenetics: t(11;14) in 50 \200\22390% by FISH techniques. 2 Bone marrow: trephine biop sy demonstrates involvement in >70% with nodular, interstitial or diffuse patterns similar to CLL. 2 Lymph node biopsy: mantle zone expansion or diffuse effacement of nodal architecture by u niform \200\230centrocytes \200\231; characteristic immuno- chemistry pattern: CD5+, CD10 \200\223, CD79b+, cyclin-D1+. 2 Up to 30% have detectable paraprotein band, usually IgM. Differential diagnosis In patients with lymphocytosis differentiation from CLL by immunophe no- type, notably strong SmIg+, CD23 \200\223 and cyclin-D1+; from PLL when CD5+ by morphol ogy; from follicular lymphoma by CD5+, CD10 \200\223 and cyclin D1. Prognostic factors Stage using Ann Arbor system (p210). Use International Prognostic Index (p200) to assess prognosis. Age >70, HB <12g/dL, poor performance status and blood involvem ent are unfavorable features. Management and prognosis There is no evidence that MCL has been cured by either conventiona l chemotherapy or autologous SCT. Response rates of 50 \200\22390% have been achieved with COP or CHOP including CR rates of 30 \200\22350%. Median freedom from progression is <1 yea r. There is no survival advantage for anthracycline containing regimens. 2 Fludarabine \200 \223cyclophosphamide regimens ((cid:9)p616) appear to have a high response rate in previously treated patients. 04-leukemia.qxd 10.12.2003 04.12 PM Page 185 Leukemia 2 Rituximab, the anti-CD20 monoclonal antibody produces responses as a single agent and is under examination in combination with fludara- bine \200\223cyclophosphamide. 2 MCL is generally an aggressive disease with a median survival of 3 years. Most patients develop progressive refractory disease. A small number follow a more i ndolent course. 185 04-leukemia.qxd 10.12.2003 04.12 PM Page 186 Large granular lymphocyte leukemia (LGLL) Uncommon lymphoproliferative disorder, characterized by an increase in LGLs in blood. Heter ogeneous \200\224may be T-cell or NK-cell phenotype; not all cases are clonal. Clinical features 2 Any age group; median age at diagnosis 55 years. 2 Asymptomatic, modest lymphocytosis with large granular lymphocytes on routine FBC. 186 2 Occasional presentation with fatigue or recurrent bacterial infections. 2 Arthralgia, itc hing, rash (25%), mouth ulcers; association with seroposi- tive rheumatoid arthritis in 20% and Felty \200\231s syndrome (neutropenia + splenomegaly + rheumatoid arthritis). 2 Splenomegaly recorded in 50 \200\22380% cases. Lymphadenopathy rare. Laboratory findings 2 Hb and platelets usually normal; chronic neutropenia and mild anemia may be present. 2 Mild/moderate lymphocytosis (usually <10 109/L); large cells with abundant cytoplasm and distinct granules. 2 Most type as \200\230cytotoxic \200\231 T cells (CD3+ CD8+ CD16+ CD56 \200\223 CD57+); others as NK cells (CD3 \200\223 CD8 \200\223 CD16+ CD56+ CD57+/-). 2 Clonal rearrangement of T-cell receptor genes in T-LGLL. 2 Polyclonal hypergammaglobulina emia, rheumatoid factor and antinu- clear antibodies occur in 50% even without joint disease. 2 Bone marrow involvement is often subtle; may be diffuse or nodular pattern usually non-paratrabecular. 2 No characteristic cytogenetic pattern. Differential diagnosis Reactive lymphocytosis (screen for infection especially EBV); other T-cell lymphoproliferative disorders (immunophenotype; (cid:9)p174). Prognosis and management 2 Incurable but generally stable benign disease. Patients with NK pheno- type (more common in Japan) or a CD3+ CD56+ clonal disorder established by TCR rearr angements, i.e. a true leukemia, may have a more aggressive course. Patients with polyclona l disease associated with rheumatoid factor and modest neutropenia may run a more benign co urse. 2 Care is essentially supportive with prompt treatment of infection with appropriate broad spectrum antibiotics. 2 G-CSF may be of value in symptomatic chronic neutropenia. Corticosteroids in modest dosage may improve neutropenia but can predispose to infection, i ncluding fungal infections. 2 Immunosuppression with low dose methotrexate (10mg/m2 PO weekly), cyclosporin (2mg/kg PO bd) or cyclophosphamide (100mg PO od) has been effective in 50% of patients with persistent severe neutropenia. 04-leukemia.qxd 10.12.2003 04.12 PM Page 187 Leukemia 2 The rare patient with an aggressive course has a poor prognosis and lymphoma-type regimens show little benefit. 187 Blood movie showing large granular lymphocytes in LGL leukemia. 04-leukemia.qxd 10.12.2003 04.12 PM Page 188 Adult T-cell leukemia-lymphoma (ATLL) Aggressive lymphoid neoplasm with viral pathogenesis and distinct geo- graphical distributi on. Incidence Highest incidence among populations where HTLV-I infection endemic: Kyushi distri ct of SW Japan, Caribbean, parts of Central and South America, Central and West Africa. Inc idence 2/1000 males and 0.5 \200\2231/1000 females seropositive for HTLV-I (37% males >40) in SW Japan. Risk 2.5% at 70 years. Non-endemic cases generally originate from these areas. 188 Etiology HTLV-I provirus demonstrated in ATLL cells and all patients with ATLL are seroposi tive for previous HTLV-I infection. HTLV-I clearly involved in pathogenesis. Not all infect ed patients develop ATLL and long latent period suggests that further event(s) are necessar y for neoplastic transformation. Clinical features and presentation 2 Median age at diagnosis 58 (range 20 \200\22390); 9 : 3 ratio 1:4. 2 Usually short history of rapidly increasing ill health. 2 Abdominal pain, di arrhea, pleural effusion, ascites and respiratory symptoms (often due to leukaemic infiltration of lungs). 2 History of residence or origin in HTLV-I endemic area usual. 2 Lymphadenopathy 60%; hepat omegaly 26%, splenomegaly 22%; skin lesions 39%. Diagnosis and investigation 2 FBC: WBC usually markedly 4 (up to 500 109/L) but may be n ormal; anemia and thrombocytopenia common. 2 Blood movie: large numbers of lymphoid cells with marked nuclear irregu- larity occasiona lly multilobulated with \200\230floral \200\231 or \200\230clover leaf \200\231 appearanc e. 2 Immunophenotyping: generally CD4+, CD8 \200\223, CD25+, HLA-DR+ T cells ((cid:9)p174). 2 Cytogenetics: multiple abnormalities described; no consistent pattern. 2 Serum chemistry: hypercalcaemia in 33 \200\22350% of patients at diagnosis. 2 Bone marrow: diffuse infiltra tion by ATLL cells. 2 Serology: positive for HTLV-I. Blood movie in ATLL: note clover-leaf cell (center). From Oxford Textbook of Oncology, 2E, with permission. 04-leukemia.qxd 10.12.2003 04.12 PM Page 189 Leukemia Prognostic factors and staging Poor prognostic features are 2 4 LDH. 2 Hypercalcaemia. 2 Hy perbilirubinaemia. 2 4 WBC. 189 Four clinical subtypes are described: acute, chronic, smoldering and lymphomatous forms. Ac ute subtype most common (66%), median survival 6 months despite therapy. Other forms have l onger survival but often progress to the acute form after several months. The smoldering fo rm is most indolent and is associated with few circulating cells, skin lesions and occasion al pulmonary involvement and survival >24 months. Management and prognosis Treatment of ATLL is unsatisfactory. Short responses including CRs (6 \200\22312 months) have been achieved with combination chemotherapy (e.g. CHOP) for acu te and lymphomatous forms. Infectious complications are frequent with this and more intensi ve therapy. Single agent deoxyco- formycin has produced responses in relapsed or refractory patients. Patients with acute ATLL or lymphomatous ATLL have median survivals of 6 and 10 months respectively. Death is usually due to opportunistic infection. 04-leukemia.qxd 10.12.2003 04.12 PM Page 190 S zary syndrome (SS) Leukaemic phase of a low grade cutaneous mature T-cell lymphoma (mycosis fungoides; MF). Incidence Occurs in up to 20% of cases of cutaneous T-cell lymphoma; median age 52; 9 : 3 r atio 2:1. Clinical features 2 Generally diagnosed as a result of blood movie report in a patient with exfoliative erythroderma; but not necessarily end-stage and may present de novo. 190 2 MF classically progresses through eczematoid plaque stage, infiltrative plaque stage and overt tumor stage and has characteristic histology on skin biopsy (epidermotropism and Paut rier microabscesses). Investigations and diagnosis 2 FBC: generally moderate leucocytosis (WBC rarely >20 109/ L); Hb and platelets usually normal. 2 Blood movie: typically reveals large numbers of large lymphoid cells with characteristic \200\230cerebriform \200\231 folded nucleus. 2 Immunophenotyping: CD3+, CD4+, CD7 \200\223, CD8 \200\223, CD25 \200\223 T cells. 2 Cytog enetics: no typical pattern. Blood movie in S zary syndrome showing typical cerebriform nuclei. Image on right is from The Oxford Textbook of Oncology, 2E, with permission. Management and prognosis Patients with SS have a poor prognosis. There is no evidence that single agent or combination chemotherapy improves survival. Median survival 6 \200\2238 mon ths. 04-leukemia.qxd 10.12.2003 04.12 PM Page 191 Leukemia 191 04-leukemia.qxd 10.12.2003 04.12 PM Page 192 This page intentionally left blank 192 05-lymphoma.qxd 10.12.2003 04.13 PM Page 193 Lymphoma 5 Non-Hodgkin \200\231s lymphoma (NHL) 194 CNS lymphoma 206 Hodgkin \200\231s lymphoma (Hodgkin \200\231s disease) 208 05-lymphoma.qxd 10.12.2003 04.13 PM Page 194 Non-Hodgkin \200\231s lymphoma (NHL) NHL is a diagnosis applied to a group of histologically and biologically het- erogeneous cl onal malignant diseases arising from the lymphoid system. Epidemiology The annual incidence in Western countries is 14 \200\22319 cases per 100,000 ( i.e. 4% of all cancers) and has increased at a rate of 3 \200\2234% per annum since the 197 0s. Incidence increases with age. 9 : 3 ratio 3:2. The increased incidence is only in part due to increased mean age of the population, improvements in diagnosis, the HIV pandemic an d immunosuppressive therapy. 194 Etiology The rearrangement and mutation of immunoglobulin genes that occur in B-cell differ entiation and the response to antigen offers an opportunity for involving genetic accidents such as immunoglobulin gene loci that have been characterized in many lym- phomas. Most tr anslocations involve genes associated with either prolifer- ation (e.g. c-MYC) or apoptosis (e.g. BCL-2). Factors associated with NHL are: 2 Congenital immunodeficiency: ataxia telan giectasia, Wiskott \200\223Aldrich syndrome, X-linked combined immunodeficiency (?EBV infec tion important). translocations or mutations 2 Acquired immunodeficiency: immunosuppressive drugs, transplantation, HIV infection (typic ally high grade and often occur in extranodal sites e.g. brain). 2 Infection: HTLV-I (ATLL); EBV (Burkitt lymphoma and immunodefi- ciency related high grade lymphomas); Helicobacter pylori (gastric MALT lymphomas). 2 Environmental toxins: association with exposure to agricultural pesti- cides, herbicides and fertilizers, solvents and hair dyes. 2 Familial: risk increased 2 \200\2233 fold in close relatives (?genetic or environ- mental). Classification The World Health Organization (WHO) classification of lymphoid neo- plasms ( p195) has refined the Revised European American Lymphoma (REAL) classification producing a list of clinico-pathologically well charac- terised lymphomas using morphology, immunopheno type, genotype, the normal cell counterpart and clinical behavior. Inter- and intraobserver reproducibility is 85 \200\22395%. In Europe and the USA 85% of lymphomas are B-cell type. The clinical behavior of lymphomas informs management strategies in clinical practice and c urrent treatment protocols are still based on classifi- cation systems that group histologi cal diagnoses into indolent (low grade) and aggressive (intermediate and high grade or simp ly high grade) NHL. More biologically relevant classification of lymphoma diagnosis using t he WHO system and emerging therapeutic options based on immunological and molecular charact eristics may increase the diagnosis-specific nature of therapy in the future. 05-lymphoma.qxd 10.12.2003 04.13 PM Page 195 Lymphoma WHO classification of lymphoid neoplasms B-cell neoplasms Precursor B-cell neoplasms 2 Precursor B-lymphoblastic leukemia/lymphoma ( precursor B-cell acute lymphoblastic leukemia) Mature (peripheral B-cell) neoplasms 2 Chronic lymphocytic leukemia/B-cell small lymphocyti c lymphoma 2 B-cell prolymphocytic leukemia 2 Lymphoplasmacytic lymphoma 2 Splenic marginal zone B-cell lymphoma (splenic lymphoma with villous lymphocytes) 2 Hairy cell leukemia 2 P lasma cell myeloma/plasmacytoma 2 Extranodal marginal zone B-cell lymphoma (MALT lymphoma) 2 Nodal marginal zone B-cell lymphoma 2 Follicular lymphoma 2 Mantle cell lymphoma 2 Diffus e large B-cell lymphomas 2 Burkitt lymphoma/leukemia 195 T-cell neoplasms Precursor T-cell neoplasms 2 Precursor T-lymphoblastic leukemia/lymphoma ( precursor T-cell acute lymphoblastic leukemia) 2 Blastoid NK-cell lymphoma Mature (peripheral) T-cell neoplasms 2 T-cell prolymphocytic le ukemia 2 T-cell large granular lymphocytic leukemia 2 Aggressive NK-cell leukemia 2 Adult T -cell leukemia/lymphoma 2 Extranodal NK/T-cell lymphoma (nasal type) 2 Enteropathy type T-c ell lymphoma 2 Hepatosplenic T-cell lymphoma 2 Subcutaneous panniculitis-like T-cell lympho ma 2 Mycosis fungoides/S zary syndrome 2 Primary cutaneous anaplastic large cell lymphoma 2 Peripheral T-cell lymphoma (not otherwise specified) 2 Angioimmunoblastic T-cell lymphoma 2 Primary systemic anaplastic large cell lymphoma Hodgkin lymphoma 2 Nodular lymphocyte predominant Hodgkin lymphoma 2 Classical Hodgkin lymp homa \200\223 Nodular sclerosis Hodgkin lymphoma (Grades 1 & 2) \200\223 Lymphocyte-rich class ical Hodgkin lymphoma \200\223 Mixed cellularity Hodgkin lymphoma \200\223 Lymphocyte dep leted Hodgkin lymphoma Harris, N.L. et al. (1994) A revised European-American classification of lymphoid neoplasms : a proposal from the International Lymphoma Study Group. Blood, 84, 1361 \200\2231392; Jaf fe ES et al (2001). In Kleihues P, Sobin L eds. WHO Classification of Tumors. Lyon: ARC Pre ss. 05-lymphoma.qxd 10.12.2003 04.13 PM Page 196 \200\230Clinical grade \200\231 & frequency of lymphomas in the REAL classification Diagnosis % of all cases Indolent lymphomas (low risk) Follicular lymphoma (Note: grade I & II; grade III intermedia te risk) Marginal zone B-cell, MALT lymphoma Chronic lymphocytic leukemia/small lymphocytic lymphoma Marginal zone B-cell, nodal Lymphoplasmacytic lymphoma 22% 8% 7% 2% 1% 196 Aggressive lymphomas (intermediate risk) Diffuse large B-cell lymphoma Mature (peripheral) T-cell lymphomas Mantle cell lymphoma Mediastinal large B-cell lymphoma Anaplastic large ce ll lymphoma 31% 8% 7% 2% 2% Very aggressive lymphomas (high risk) Burkitt lymphoma Precursor T-lymphoblastic 2% 2% Other lymphomas 7% A clinical evaluation of the International Lymphoma Study Group classification of non- Hodg kin s lymphoma. The Non-Hodgkin s Lymphoma Classification Project. (1997) Blood, 89, 3909 \200\2233918. Presentation The features at presentation reflect a spectrum from low grade lymphoma (widel y disseminated at diagnosis but with an indolent course; non- destructive growth patterns) to high grade lymphoma (short history of localized rapidly enlarging lymphadenopathy con stitutional upset with drenching night sweats, >10% weight loss and/or fever; destructive g rowth patterns). In Europe and the USA almost 75% of adults present with nodal disease, usually superficial painless lymphadenopathy. 25% are extranodal ( 50% in the Far East) and may present with or opharyngeal involvement (5 \200\22310%), GI involvement (15%), CNS involvement (5 \200\2231 0%, esp. high grade NHL) skin involvement (esp. T-cell lymphomas) or autoimmune cytopenias. Patients with GI involvement have a higher frequency of oropharyngeal and vise versa. ring ) Hepatosplenomegaly is common in advanced disease. involvement (Waldeyer \200\231s Clinical features of indolent lymphomas: Up to 40% of cases; slowly progressive disorders. Follicular lymphoma: most common in middle and old age (median age 55 years); presents with painless lymphadenopathy at \211 1 sites, effects of BM infiltration, constitutional symp toms (15 \200\22320%) or pressure effects of bulky nodes (ureter, spinal cord or orbit); LN may fluctuate in size; at diagnosis, 66% stage III or IV, 70% BM involvement, 15 \200\2232 0% localized stage I or II disease; median survival 8 \200\22310 years; 30% may transform to high grade DLBCL (often resistant to treatment; median survival 12 months). Note: 05-lymphoma.qxd 10.12.2003 04.13 PM Page 197 Lymphoma cases of FL with a high proportion of centroblasts (>50%) on histology follow a more aggres sive clinical course and are treated as aggressive lymphomas. Marginal zone lymphomas take 3 forms: 2 Mucosa-associated lymphoid tissue (MALT) lymphomas \200\224associated with local invasion at site of origin, e.g. stomach, small bowel, saliva ry gland or lung; gastric MALT lymphomas present with long history of abdominal pain; diagn osis by endoscopic biopsy; localized in 80 \200\22390% and respond to antibiotic treatment for H pylori; good prognosis (>80% 5 year survival). 197 2 Nodal marginal zone lymphoma (MZL) or monocytoid B-cell lym- phoma rare; associated with Sj gren \200\231s syndrome \200\224usually localized to head, neck and parotid gland. 2 Spleen MZL related to SLVL (p182); elderly patients with marked splenomegaly hypersplenism, BM involvement villous lymphocy- tosis, lymphadenopathy a bsent. Small lymphocytic lymphoma: nodal form of CLL (p168); generally age >60 years; disseminated peripheral lymphadenopathy and splenomegaly; lymphocyte count <4.5 109/L; BM involvemen t in 80%; constitutional symptoms <20%; serum paraprotein, usually IgM in 30%; median survi val 8 \200\22310 years; some patients evolve into CLL, others to DLBCL. Lymphoplasmacytic lymphoma: occurs in older patients; usually isolated lymphadenopathy s erum paraprotein; usually IgM, symptoms of hyperviscosity if markedly 4 ((cid:9)Waldenstr m \200\231s macroglobulinaemia, p284). Clinical features of aggressive lymphomas 50% of cases; rapidly progressive if untreated. Diffuse large B-cell lymphoma: most common lymphoma diagnosis; occurs at all ages, generall y >40 years; presents with localized stage I or II disease in 50% of patients but dissemina ted extranodal disease is not uncommon; constitutional symptoms in 33%; extranodal sites in 30-40% most commonly GI. Ascites and pleural effusions are common end-stage symptoms. T-cell rich B-cell lymphoma: subtype of DLBCL; occurs in younger patients; more aggressive with early BM involvement. Mature (or peripheral) T-cell lymphomas: a number of different conditions; most common T-ce ll NHL in the West but more common in Far East; median age 56; 9 : 3 ratio 2:1; variable cl inical behavior; nodal form generally more aggressive and less responsive to therapy than D LBCL; heterogeneous group of extranodal forms; 80% stage III \200\223IV at diagnosis; const itutional symptoms, BM and skin involvement common; 41% 5 year survival with combination th erapy. Mycosis fungoides: mature T-cell lymphoma; presents as localized or generalized plaque or e rythroderma; lymphadenopathy in 50%; median 05-lymphoma.qxd 10.12.2003 04.13 PM Page 198 survival 10 years but prognosis poor with lymphadenopathy, blood ((cid:9)S zary syndrome p 190) or visceral involvement . Angio-immunoblastic symptoms, generalized lymphadenopathy, hepatosplenomegaly, skin rash, p olyclonal hypergammaglobulinaemia, DAT+ve haemolytic anemia and eosinophilia; 33% of patien ts progress to immunoblastic lymphoma; poor prognosis. lymphadenopathy: constitutional Mantle cell lymphoma: usually elderly; median 63 years; B symptoms 50%; usually disseminate d at diagnosis: BM involvement 75%, GI involvement 15 \200\22320%; poor therapeutic outcome : partial responses and eventual chemoresistance; median survival 3 \200\2234 years ((cid:9 )p184). 198 Mediastinal large B-cell lymphoma: typically occurs in women <30 years; anterior mediastina l mass sometimes causes superior vena caval obstruction; tendency to disseminate to other e xtranodal sites including CNS; cure rate with therapy similar to LBCL. Anaplastic large cell lymphoma: usually occurs in younger patients and children; typically as lymphadenopathy at a single site; favorable prognosis as curable with chemotherapy; 64% overall 5 year survival. Clinical features of very aggressive lymphomas 10% cases of NHL; require prompt treatment. Burkitt lymphoma 2 Endemic BL: presents in childhood/adolescence in Africa with large extranodal tumors in jaw or abdominal viscera; 90% associated with EBV infection; aggressiv e but curable disease. 2 Sporadic BL: often children, rare in adults (median age 31); presents with rapidly growin g lymphadenopathy, often intra-abdominal mass arising from a Peyer \200\231s patch or mesen teric node; BM, CNS and blood involvement frequent; 30% associated with EBV infection; also associ- ated with HIV infection; aggressive but curable disease in non-HIV- associated cas es. Lymphoblastic lymphomas: 2 Young patients (median age 15 years; >50% of childhood lymphomas ); share features with ALL; T-cell LBL more frequent (85%) and usually associated with thym ic mass; 33-50% present with BM involvement; CNS involvement common; commonly progresses to ALL; aggressive but potentially curable in children. Laboratory features 2 Normochromic normocytic anemia common. 2 Leucoerythroblastic movie if extensive BM infiltration pancytopenia. 2 Hypersplenism (occasionally). 2 PB may show l ymphoma cells in some patients: moderate lymphocy- tosis in MCL; cleaved \200\230buttock \200\231 cells in FL and blasts in high grade disease. 2 LFTs abnormal in hepatic infiltration. 2 Serum LDH and b2-microglobulin are useful progno stic factors ((cid:9)p200). 2 Lymph node biopsy provides the best material for classification and precise diagnosis usi ng morphology, immunophenotype and genetic 05-lymphoma.qxd 10.12.2003 04.13 PM Page 199 Lymphoma features e.g. translocations or immunoglobulin and T-cell receptor gene rearrangement. 2 20% of patients with SLL or FL have a serum paraprotein, usually IgM. Diagnostic immunohistochemical and cytogenetic features Indolent lymphomas Follicular lymphomas: Pan-B markers; CD5 \200\223, CD10+, BCL \200\2232+. t(14;18)(q32;q21) in 90% (cf. reactive lymphoid hyperplasia with normal follicles BCL-2 \200\223). 199 Small lymphocytic lymphoma: Pan-B markers (CD20+, CD79a+); CD5+, weak SmIg, CD23+, cyclin-D 1 \200\223 (cf. MCL). Marginal zone lymphomas: Pan-B markers; CD5 \200\223, CD10 \200\223, BCL-2 \200\223. t(11,1 9)(q21;q21) 50%, t(1;14)(p22;q32) rare, overexpress bcl-10 and poor response to H pylori er adication. Aggressive lymphomas Diffuse large B-cell lymphoma: Pan-B markers (CD20+, CD79a+), generall y Ig+; Ki67 <90% favors DLBCL (cf. Burkitt >99%); probably multiple unrecognized entities; two subgroups delineated by gene expression profiling using DNA microarrays: germinal cente r-B-cell profile (favorable) and activated B-cell profile (unfavorable). Der(3)(q27) involv ing BCL-6 gene mutations 35%; t(14;18) 25%; t(8;14) 15%. Mature T-cell lymphomas: Pan-T markers (CD3+, CD2+); TdT \200\223 (cf. precursor T-lymphobl astic TdT+). Mantle cell lymphoma: Pan-B markers; CD5+, strong SIg, CD23 \200\223, cyclin- D1+. t(11;14) (q13;q32) in 70%. Anaplastic large cell lymphoma: Pan-T markers, TdT \200\223, CD30+, ALK+. t(2;5)(p23;q35) i n 60%. Very aggressive lymphomas Burkitt lymphoma: Pan-B markers, Ig+, Ki67 >99% favors BL (cf. DL BCL <90%). 80% t(8;14)(q24;q32), 15% t(2;8)(q11;q24), 5% t(8;22)(q24;q11) juxtapose c-MYC w ith Ig gene loci and cause MYC overexpression but this is not diagnostically useful as expr essed in normal cells and other lymphomas. Endemic cases have raised antibody titres to EBV antigens and multiple copies of EBV DNA in the tumor (unusual in sporadic cases). Precursor B-lymphoblastic: Pan-B markers, Ig \200\223, CD10+, TdT+. Precursor T-lymphoblastic: Pan-T markers, TdT+. Staging investigations 2 Histological diagn osis by expert haematopathologist: biopsy of lymph node or extranodal mass with immunophenotyping molecular analysis. 2 Detailed history and physical examination including Waldeyer \200\231s ring 05-lymphoma.qxd 10.12.2003 04.13 PM Page 200 2 FBC, plasma viscosity/ESR and blood movie. 2 U&E, uric acid, LFTs, LDH, serum b2-microglo bulin. 2 Serum protein electrophoresis 2 Bone marrow trephine biopsy. 2 CXR. 2 CT of chest, abdomen and pelvis to define areas of nodal and extran- odal disease. 2 Others as necessary e.g. LP and CT head/spine for patients with overt CNS symptoms: LP al so for high grade disease with marrow, testicular or paranasal sinus involvement, lymphobla stic or Burkitt histology; MRI spine, bone scan, gallium scan, PET scan etc 200 Staging helps to define prognosis and select appropriate therapy. Also helps assess respons e to therapy. The Ann Arbor staging system devel- oped for Hodgkin s disease is widely used in NHL ((cid:9)Hodgkin \200\231s disease p210). Prognostic factors 2 Histologic grade. 2 Performance status. 2 Constitutional (B) symptoms unfavorable. 2 Age (unfavorable >60 years). 2 Disseminated disease (stage III \200\223IV) u nfavorable. 2 Extranodal disease (poorer \211 2 extranodal sites). 2 Bulky disease (poorer if >10 cm). 2 Raised serum LDH (poorer if 4). 2 Raised serum b2-microglobulin. 2 High prol iferation rate measured by Ki-67 immunochemistry. 2 BCL-2 protein expression. 2 P53 mutatio ns. 2 T-cell phenotype. 2 High grade transformation from low grade NHL. The International Prognostic Index (IPI)was developed for aggressive NHL and validated in a ll clinical grades of NHL as a predictor of response to therapy, relapse and survival. One point is awarded for each of the fol- lowing characteristics: age >60, stage III or IV, \211 2 extranodal sites of disease, performance status \211 2 and raised serum LDH to iden tify 4 risk groups. An age-adjusted IPI has also been developed. Score Risk group %CR 5yr CR-DFS 5yr overall survival 0 or 1 2 3 4 or 5 Low Low/intermediate Intermediate/high High 87% 67% 55% 44% 70% 50% 49% 40% 73% 51% 43% 26% A predictive model for aggressive non-Hodgkin s lymphoma. The International Non- Hodgkin s Lymphoma Prognostic Factors Project. (1993) N Engl J Med, 329, 987 \200\223994. Treatment of indolent lymphomas FL and SLL comprise the majority of patients and are treate d in a similar way. These diseases are usually responsive to chemotherapy and radio- 05-lymphoma.qxd 10.12.2003 04.13 PM Page 201 Lymphoma therapy but unless truly localized, inevitably recur. There is no firm evi- dence of a cura tive therapy for advanced disease. Many patients have few or no symptoms; the decision to i nitiate treatment and choice of treat- ment must take account of individual quality of life issues. At each stage, the pros and cons of treatment options should be shared with the pa tient to reach an agreed treatment decision. 201 Initial treatment of localized FL and SLL Involved field radiotherapy (35 \200\22340Gy) may be curative in the few patients with localized disease. 5-year DFS >50% may be expected. R ecurrence generally outside radiation field. Late relapses occur. Addition of chemotherapy improves DFS but not overall survival. Initial treatment of advanced FL and SLL Three options are available: (1) watch and wait; ( 2) conventional chemotherapy and/or radiotherapy; (3) intensive chemotherapy and/or radioth erapy. Watch-and-wait: therapy may be deferred for many months/years after diagnosis until clinica l symptoms develop. Patients may have better quality of life and avoid exposure to cytotoxi c agents but must be monitored closely to prevent or identify insidious complications promp tly. Overall survival >80% at 5 years. Conventional therapy: generally involves one of the following approaches: 2 Chlorambucil (0 .1 \200\2230.2mg/kg/d x 7 \200\22314 days, q28 or 0.4 \200\2230.6mg/kg every 2 weeks) or cy clophosphamide (50 \200\223150mg/d PO) as single agents or with prednisolone; response rate s of 50 \200\22380% after 12 \200\22318 months \200\231 treatment; most relapse within 5 ye ars; convenient oral regimen; well tolerated. 2 \200\230Simple \200\231 combination chemotherapy e.g. CVP: more rapid response than chlorambucil (useful with bulky disease or symptomatic patients) but otherwise similar : response rates 80 \200\22390%; median response 1.5 \200\2233 years; few durable remission s; IV and oral regimen; causes alopecia. 2 \200\230High grade \200\231 regimens: high \200\230CR \200\231 rates ( 60%) with CHOP-type regi- mens but continuous pattern of relaps e and overall survival not con- vincingly improved in indolent FL (histological grades I an d II). In histological \200\230grade III \200\231 FL CHOP produces results equivalent to t hose in DLBCL (see below). 2 Radiotherapy for treatment of local problems e.g. cord compression. Intensive therapy: patients with high tumor burden and high LDH who achieve CR have signifi cantly longer survival (63% at 10 years). To improve the CR rate high dose chemotherapy TBI followed by autologous SCT (with monoclonal antibody purging of the \200\230graft \200 \231 in some centers) has been utilized in younger patients with advanced FL and/or poor pr ognostic features after initial response to chlorambucil or CHOP. 80% CR rate; 66% overall survival and up to 40% DFS at 8 years. Still largely investigational; continuing risk of r elapse; too early to assess effect 05-lymphoma.qxd 10.12.2003 04.13 PM Page 202 on long term survival. Myelodysplasia develops in up to 15% of heavily pre-treated long-ter m survivors. Relatively few allografts have been undertaken. Most use TBI-containing conditioning. CR ra te >80% and relapse rates are clearly lower than after autograft (12% vs. 55% at 5 years) a nd very few after 2 years. Curative potential requires longer follow-up. The benefit of bet ter disease control is offset by a higher treatment-related mortality (15 \200\22330%). Non -myeloab- lative regimens may reduce toxicity, preserve the GvL effect and widen the availa bility of this treatment. AlloSCT should be considered in appro- priate patients with poor prognosis disease. Total lymphoid (or nodal) irradiation may achieve very high CR rates wit h 5-year DFS rates >60% but is rarely utilized due to toxicity. 202 Further treatment of indolent lymphomas When indolent lymphoma progresses after a partial o r complete response to initial therapy, it is important to rule out transformation to DLBCL (esp. if LDH 4, LN rapidly enlarging, constitutional symptoms, extranodal disease). In rec urrent indolent NHL, further responses can be achieved with the prior therapy in most patie nts who have achieved a durable response (>12 months). However, chemoresistance to alkylati ng agents ultimately develops. Interferon-a maintenance: several large randomized trials demonstrate a beneficial effect o n survival for patients treated with \211 9 million units/week administered with and after intensive chemotherapy for >18 months or until progression; side effects reduce quality of life and the attraction of this therapy. Purine analogs: fludarabine has a response rate of 70% (38% CRs) in untreated patients and 50% (15% CRs) in previously treated patients. Responses to cladribine are similar for prev iously treated patients but less in de novo treatment and responses are less durable. Neith er convincingly improve disease free or overall survival. Fludarabine achieves responses in most patients with FL or SLL refractory to chlorambucil. Combinations of fludarabine with cyclophosphamide or with mitoxantrone (mitozantrone) and dexamethasone (FMD) increase respo nse rates and are widely used. Prophylaxis of P carinii by cotrimoxazole in all patients an d HZV by acyclovir in some is required during and for 6 months after therapy. Cellular bloo d products must be irradiated for 2 years after therapy. Monoclonal antibody therapy: 2 Rituximab (MabThera, Rituxan) is a humanized anti-CD20 monoc lonal antibody. As a single agent 375mg/m2 infusion weekly 4 weeks achieves a response rate 5 0% (6% CRs) in previously treated patients; median duration 13 months1. On relapse 40% will respond again. In newly diagnosed patients 4 further doses given over 9 months as main- te nance therapy enhances EFS (22 vs. 13 months). Toxicity is mild though there is a risk of a naphylaxis with the first course. Combination with chemotherapy enhances the response rate. In newly diagnosed patients: CHOP-R 100% responses, 66% CRs, >50% progression-free surviva l (PFS) with median follow up of 6 years. It has been used for \200\230in vivo purging \200\231 prior to stem cell harvest to improve the prospect of a PCR-negative harvest. In t he UK, NICE recommends its use in chemoresistant disease. 05-lymphoma.qxd 10.12.2003 04.13 PM Page 203 Lymphoma 2 Tositumomab, (Bexaar) a 131I-radiolabelled murine anti-CD20 mono- clonal antibody; beta a nd gamma emission; due to the targeted radia- tion a single infusion achieves higher respon se rates (97% OR and 76% CR in untreated patients; 74% OR & 30% CRs in treated patients) an d a higher response rate and more prolonged responses in advanced disease than the prior ch emotherapy had achieved; transient mild to moderate myelosuppression; antimurine antibodies develop especially in untreated patients. 203 2 Ipritumomab (Zevalin) a 90Yt-labeled murine anti-CD20 monoclonal antibody; beta emission only; also achieves superior response rates (80%) to rituximab in relapsed FL. Treatment of marginal zone lymphomas Gastric MALT lymphoma: eradication of H. pylori by 2 w eek course of clar- ithromycin, amoxicillin with omeprazole achieves CR in up to 80% of pat ients. Local radiotherapy or single agent chlorambucil can achieve CR in non-responders. No n-gastric MALT lymphomas: single agent chlorambucil, simple combination regimens or local r adiotherapy achieve good responses.