Most patients with primary melanoma currently have the defect resulting from excision of th e lesion closed directly, but a small num- ber may require either a \202ap or a graft to achieve closure. Patients with Stage 3 disease should have dissection of the regional lymph nodes. At presen t there is one study suggesting that adjuvant alpha interferon, given subcutaneously for on e year after lymph node dissection, statistically improves survival for this group of patie nts. Con \201rmatory trials are in progress. For patients with Stage 4 disease there is no current accepted proven chemotherapy or immun otherapy. All patients should be accurately staged with CT or MRI as appropriate. Limited a dditional surgical procedures to debulk the tumor will often improve the patient \200\231s quality of life. Chemotherapy regimes include DTIC and/or vindesine and produce around 30% response rate, but responses are short-lived and do not sign \201ciantly increase survival time. A recent study suggest- ing that the addition of tamoxifen to combination chemothera py for OHO-26(481-488) 11/18/02 8:37 AM Page 484 SKIN CANCER 484 melanoma improved response rates has not been con \201rmed. Trials are concentrating on th e use of biotherapy that includes the use of inter- leukin 2, often combined with melanoma- directed vaccines. Melanoma is in general not responsive to radiotherapy, but good palliation can be achieved in the case of pain from skeletal metastases. Cerebral metastases are relatively common in long-term survivors from melanoma. If these are asymptomatic there is controversy as to whe ther or not they should be treated. In some centers neurosurgery to one or two isolated met astases is practiced. If cerebral metastases are symptomatic, systemic corticosteroid thera py, with or without additional radiotherapy, may bring symptomatic relief. Experimental surgical approaches (cid:2) Adjuvant limb perfusion \200\224melphalan alone \200\224melphalan + tumor necrosis factor \200\224good palliation for recurrent melanoma \200\224no survival advantage for primary melanoma (cid:2) Sentinel node biopsy \200\224radio-labeled colloid \200\224methylene Blue \200\224if this node is clear then block dissection is not required OHO-26(481-488) 11/18/02 8:37 AM Page 485 PRIMARY CUTANEOUS MALIGNANT MELANOMA 485 OHO-26(481-488) 11/18/02 8:37 AM Page 486 SKIN CANCER 486 Non-melanoma skin cancers Epidemiology These cancers are the commonest malignancies in Western popula- tions, occurri ng particularly in fair-skinned Caucasians exposed to ultraviolet radiation (e.g. farmers, \201shermen). The causes are: (cid:2) Ultraviolet radiation Ionizing radiation (cid:2) Ch ronic in \202ammation (cid:2) Human papillomavirus Immunosuppression (cid:2) (cid:2) (cid:2) Hereditary conditions (Xeroderma pigmentosum, basal cell naevus syndrome) As well as these primary lesions, metastases to skin are fairly common from carcinomas of t he breast, lung, and GI tract. Pathology Basal cell carcinomas (75% of non-melanoma skin cancers) are lesions which arise on sun-exposed areas \200\224face, neck, ears, scalp, and arms. They are normally con \201 ned to hair-bearing skin. They present as a slow- growing, pink papule with telangiectasia. Variant lesions include: (cid:2) Nodular (cid:2) Ulcerative (cid:2) Pigmented (cid:2) Supe r \201cial (cid:2) Cystic (cid:2) Morphoeic (cid:2) Multicentric Metastases are rare and t hey are usually curable by either surgical exci- sion or radiotherapy. The latter is prefer red around the eyelids, nose, lips, and ears. Other treatment strategies are cryosurgery an d topical 5- \202uorouracil. Squamous cell carcinoma (20%): this malignant lesion also ari ses on sun-exposed sites, but appears as a faster-growing, red papule which may erupt on a background of actinic keratosis. Ulceration, bleeding, and metastases to regional nodes may occur. Treatment is either surgery or radiotherapy; chemotherapy has been used for dissemi nat- ed disease (cisplatin, methotrexate, 5- \202uorouracil, bleomycin are active agents). OHO-26(481-488) 11/18/02 8:37 AM Page 487 NON-MELANOMA SKIN CANCERS 487 Merkel cell carcinoma is a rare but highly malignant neuroendocrine tumor of the skin. It p resents as a dermal nodule on the head or neck of an elderly patient, rarely ulcerates, but commonly spreads to adja- cent skin and regional nodes. Treatment is surgical but palliati ve radiotherapy is useful in controlling metastatic disease. Less than 50% survive three ye ars. Apocrine and eccrine gland cancers: a variety of these are described but all are rare and most are only locally invasive. Other uncommon malignancies are: (cid:2) Cutaneous angiosarcoma (cid:2) Kaposi \200\231s sarcoma (HIV-associated or endemic) (cid:2) Other soft tissue malignancies OHO-26(481-488) 11/18/02 8:37 AM Page 488 SKIN CANCER 488 Further reading Kirkwood, J.M., et al. (1996) Interferon alfa-2b adjuvant therapy of high risk resected cut aneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin. Oncol. 14, 7 \200\22317. OHO-27(489-514) 11/18/02 8:38 AM Page 489 Chapter 27 Hematological malignancies Acute leukemia 490 Chronic lymphoid leukaemias 494 Hodgkin \200\231s disease 498 Non-Hodgki n \200\231s lymphomas 502 Myeloma 508 Further reading 513 OHO-27(489-514) 11/18/02 8:38 AM Page 490 hematological MALIGNANCIES 490 Acute leukemia Epidemiology The incidence of acute leukemia is 4 \200\2237 cases per 100 000. The peak inc idence of acute lymphoblastic leukemia (ALL) is 3 \200\2234 years and of acute myeloid leuk emia (AML) is over 60 years. Etiology The cause of most cases is unknown. Some inherited diseases carry an increased ris k: (cid:2) Fanconi \200\231s anemia (cid:2) Bloom \200\231s syndrome (cid:2) Klinefelter \200\231s syndrome (cid:2) Ataxia telangiectasia There is a 3 \200\2235 times increased ris k in identical twins. Environmental factors such as ionizing radiation, chemical carcino- gens, or chemotherapeut ic drugs, and infectious agents (e.g. T-cell leukemia virus 1 in the Caribbean or Japan) or more subtle mecha- nisms such as exposure in the very young of naive immune systems to inf ections, have all been implicated as rare causes. Diagnosis and classi \201cation Peripheral blood pancytopenia is the commonest \201nding , but a minority have an elevated white blood cell count (WBC) which may be a clinical mani festation of anemia, bleeding, or infection. There may be associated adenopathy or hepatosp lenomegaly, which is more likely in lymphoid disease. A marrow examination using morphology, immunophenotyping, and cytogenetics will allow class i \201cation into myeloid or lymphoid leukemia, with morphological subtypes related to cel l maturity (desig- nated FAB 0 \200\2237 for myeloid and L1 \200\2233 for lymphoid disease) . CNS in \201ltration can be a feature of ALL and requires a diagnostic lumbar puncture. Acute lymphoblastic leukemia (ALL) ALL is the commonest cancer in children but is responsiv e to effective treatment, with a 70% cure rate. Adult disease responds less well, with only 30% long-term survivors. Chemotherapy Induction of remission is routinely achieved by combining vincri- stine, predn isolone, and L-asparaginase. Additional anthracycline is OHO-27(489-514) 11/18/02 8:38 AM Page 491 ACUTE leukemia 491 used in adults. Remission rates are 90 \200\22395% in children and a little less in adults. Initial response to treatment can predict outcome e.g. remission within two weeks has a fa vorable outlook whereas failure to gain remis- sion by four weeks of chemotherapy predicts a poor prognosis. Such \201ndings re \202ect the use of more sophisticated molecular met hods. Consolidation is a crucial phase during which exposure to new drugs (e.g. cyclophosphamide, thioguanine, cytosine arabinoside) is a key strategy as is clearance of the CNS as a sanct uary site. This may be achieved by CNS irradiation or MTX intra-thecally or in high-dose IV . In high-risk cases there remains a 10% risk of CNS relapse and there are concerns about t he long-term effects of different treatment modalities. Maintenance For about two years patients in remission continue on a cyclical sched- ule of methotrexate, 6 thioguanine, vincristine, and prednisolone. Prognostic factors (cid:2) Adverse factors \200\224male sex \200\224older age \200\224age <1 year \200\224h igh blast count \200\224hypodiploidy \200\224Philadelphia chromosome positive (cid:2) Good prognostic factors \200\224cure rate 50% (cid:2) Bad prognostic factors \200 \224cure rate 20% Treatment of high-risk disease Various approaches are in use for high-risk disease. Intensi \201cation in consolidation with cyclophosphamide or methotrexate in higher dosage has br ought some success. Stem cell transplantation in \201rst remission will cure 50% (allogra ft) or 30% (autograft) \200\224but insuf \201- cient prospective comparisons with intensi \201ed conventional chemotherapy have been undertaken. When treatment fails, outcome depen ds on age and length of \201rst remission. In children with long remissions, further chem otherapy may achieve salvage, for others stem cell transplant is indicated. Acute myeloid leukemia (AML) In clinical practice, three factors will be taken into account in estab- lishing the diagnosis: (cid:2) Acute promyelocytic leukemia must be identi \201 ed at diagnosis to ensure that retinoic acid is included in the treatment schedule. (cid:2) The patient \200\231s age. (cid:2) The clinical condition or performance score. It is now usual that patients under 60 years are given intensive treatment that may OHO-27(489-514) 11/18/02 8:38 AM Page 492 hematological MALIGNANCIES 492 include stem cell transplantation. Older patients constitute the majority, and some patient s are not considered suitable for intensive treatment and are offered a palliative approach . Chemotherapy Anthracycline and cytosine arabinoside, given over 7 \200\22310 days, has been the backbone of treatment for 30 years. The addition of a third drug (thioguanine or etopo side) is widely used, but there is little evidence that one or other is superior. There is recent interest in giving higher ara-C doses in induction but without de \201nite evidence of bene \201t. Successful induction depends on patient age (90% in children, 75% 50 \200\22360 years, 65% 60 \200\22370 years) \200\22470 \200\22380% of all patients achieve com- plete response wit h the \201rst course. Three or four further intensive courses incorporating other drugs ( e.g. amsacrine, etoposide, idaru- bicin, mitoxantrone, and araC at higher doses) are usuall y given. It is not at present clear how many courses of consolidation is optimum. Older pat ients seldom tolerate more than two. Maintenance treatment has become unfashionable \200\224but may become of renewed interest for the elderly. Prognostic factors A number of characteristics can identify different risks of relapse and therefore survival. Most powerful of these are cytogenetics, patient age, and initial respo nse of marrow blasts to treatment. Other factors are also important: (cid:2) Male sex (cid: 2) High WBC on presentation (cid:2) Greater age (cid:2) Less cellular differentiation (cid: 2) Leukemia secondary to prior chemotherapy (cid:2) Myelodysplasia Favorable cytogenetics a re t(8:21), t(15:17), inv(16) that tend to be associated with young age and comprise about 25% of patients under 60 years. Adverse cytogenetics are abnormalities of chs 5 or 7 3q- or more complex abnormalities that tend to be more frequent in older patients and are associa ted with therapy-related leukemia and prior MDS. A chemoresistance phenotype of P-glycoprot ein overexpression occurs particularly in the elderly and is associated with a lower rate o f remission and higher relapse risk. Stem cell transplantation If the patient is under 45 years and has an HLA-matched sibling, allo- geneic transplantation of blood or bone marrow stem cells will be considered. In good -risk patients this is only used when patients fail \201rst-line treatment, but is given as consolidation in other groups. OHO-27(489-514) 11/18/02 8:38 AM Page 493 ACUTE leukemia 493 Acute promyelocytic leukemia This is a separate entity having FAB-M3 morphology, the t(15:1 7) rearrangement creating the PML-RAR fusion gene. All-transretinoic acid (ATRA) used alone can induce remission by differentiation with- out hypoplasia but is not curative. Addition al chemotherapy, either given with or subsequent to chemotherapy, remains essential. The le vel of the WBC at diagnosis is of key importance. Low count patients given ATRA and chemoth erapy will have 80% survival. The 25% of patients who present with higher WBC have a high r isk of early death and only 60% survival. Autologous transplantation has been widely used to consolidate \201rst remissions with re sults almost equivalent to allogeneic BMT. It is available to older patients (up to 60 year s) and those without donors. It appears to be superior to chemotherapy, except in children, where it adds little. Treatment outcome Remission is achieved in 80% of patients under 60 years, and 60 \200\2236 5% of patients over 60 years. Survival is age-related and will depend on prognostic factors . Most patients will relapse, but the patient \200\231s age, length of \201rst CR, and in itial cytogenetic risk group will dictate out- come. If \201rst remission is short and cy togenetics are not favorable in older patients, the outlook is grave. Future prospects AML is a heterogenous disease and it is likely that subtypes require risk- directed therapy. Arsenic compounds may \201nd a role in AML; there will be re \201nemen ts in the techniques of stem cell transplanta- tion; and immunologically based approaches w ill be evaluated. The disease in the elderly remains a major challenge. It must be establis hed which patients bene \201t from an intensive approach and improved non- intensive treat ment is needed. Modulation of molecular resistance is theoretically possible and will be ev aluated in the next few years. OHO-27(489-514) 11/18/02 8:38 AM Page 494 hematological MALIGNANCIES 494 Chronic lymphoid leukaemias Heterogeneous group of conditions associated with accumulation of lymphoid cells in the per ipheral blood. Classi \201ed by morphology, sur- face immunophenotype, cytogenetics, and m olecular biology. Some lymphomas may present with lymphoid cells in the blood and bone marr ow in \201ltration. B-cell chronic lymphocytic leukemia Common leukemia of late middle-age and old age with acc umula- tion of small, mature-looking B lymphocytes in the peripheral blood, bone marrow, an d lymphatic tissues. Accounts for 30 \200\22340% of all leukaemias diagnosed in adults in Europe and North Ameri ca. Annual incidence, 2.5 per 100 000; male to female ratio 2:1; median age at diagnosis 65 \200\22370 years; 79% of patients over 60 years of age at diagnosis; only 6% under 50 year s. Environmental associations: (cid:2) Farming (especially soya bean, cattle, diary, herbicide use) (cid:2) Rubber manufac ture (cid:2) Abestos (cid:2) Tire-repair (cid:2) Carbon tetrachloride exposure Table 27.1 Chronic lymphoid leukaemias (CLL) B-cell B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Hairy-cell leukemia and variants Splenic lymphoma with villous lympocytes Leukaemic phase of mantle cell lymphoma Leukaemic phase of follicle center cell lymphoma Leukaemic phase of lymphoplasmacytoid lymphoma T-cell T-cell chronic lymphocytic leukemia (large granular lymphocytic leukemia) T-cell prolymphocytic leukemia Adult T-cell leukemia/lymphoma Leukaemic phase of mycosis fungoides/S zary syndrome OHO-27(489-514) 11/18/02 8:38 AM Page 495 CHRONIC LYMPHOID LEUKAEMIAS 495 Genetic factors may predominate \200\224compare, for example, the low inci- dence of CLL in Japanese people both in Japan and after emigration. Clone expansion is due to prolonged survival of CLL cells through failure to respond to apo ptotic signals rather than through prolifera- tive advantage; CLL cells constitutively expr ess high levels of Bcl-2 protein, inhibiting apoptosis. Pathology Gradual accumulation of small lymphocytes in the lymph nodes, spleen, bone marrow , and blood causing slowly progressive enlarge- ment of the lymph nodes and spleen and bone marrow in \201ltration with anemia, thrombocytopenia, and neutropenia (important prog- no stic factors at diagnosis). Other features: (cid:2) Sometimes autoimmune haemolytic anemia (cid:2) Evan \200\231s syndrome (cid:2) Hypogammaglobulinaemia (cid:2) Disorders of T-lymph ocyte function are common Clinical presentation Variable but generally indolent clinical course. Now usually diagnose d early, often after routine blood count or presentation with painless lymphadenopathy, ane mia, or infection. Constitutional symptoms restricted to patients with advanced disease. Lymphadenopathy is symmetrical, often generalized. Splenomegaly at presentation in 66%; hep atomegaly much less frequent at presenta- tion but common in advanced disease; involvement of other organs infrequent at diagnosis. Diagnosis Clear criteria for the diagnosis of CLL. Surface antigen immuno- phenotyping is e ssential to exclude reactive causes (usually T-lympho- cytosis) and lymphocytosis due to ot her lymphoid neoplasms. Management No evidence that treatment prolongs survival of patients with lymphocytosis or u ncomplicated lymphadenopathy. Systemic therapy is indicated for advanced disease and those with diffuse in \201ltration on the trephine biopsy or a low lymphocyte doubling time (<12 months), irrespective of stage. NCI Working Party guidelines are to initiate treatment if: (cid:2) Constitutional symptoms referable to CLL (weight loss >10% in 6 months, fatigue or performance score 2 or worse, fever without overt infection, night sweats) (cid:2) Symptomatic lymphadenopathy; symptomatic hepatosplenomegaly (cid:2) Progressive ane mia with hemoglobin <10 g/dl OHO-27(489-514) 11/18/02 8:38 AM Page 496 hematological MALIGNANCIES 496 Table 27.2 NCI Working Group revised criteria for diagnosis of CLL Peripheral blood lymphocytosis: (1) absolute lymphocyte count >5 \227 109/l (2) morphologically mature appearing cells Characteristic phenotype: (1) predominance of CD19+, CD20+, CD23+ and CD5+ B-cells (2) light chain restriction i.e. monoclonal \200\224 or(cid:2) expression (3) low-density surface immunoglobulin (sIg) expression Bone marrow examination: >30% lymphocytes in bone marrow if peripheral blood lymphocytosis is relatively low i.e. cl ose to 5 \227 109/l (cid:2) Progressive thrombocytopenia with platelets <100 \227 109/1 (cid:2) Progressive ly mphocytosis >300 \227 109/1 or rapid rate of increase (cid:2) Autoimmune disease refractor y to prednisolone (cid:2) Repeated infections with or without hypogammaglobulinaemia Chlorambucil Remains \201rst-line therapy. Generally produces a partial response: reducti on in peripheral blood lymphocytosis and improvement in hemoglobin and platelet count, shri nking of lymphadenopathy and splenomegaly, and improvement in constitutional symptoms in >5 0% of patients. Complete responses rare. Discontinue when normal lymphocyte count is achieved or con- tinue as long as patient respo nds, usually some 6 \200\22312 months. Restart on progression. Median survival in responding patients, four years. Corticosteroids Single-agent prednisolone (1 mg/kg/day) produces reduction in lymphocytic i n \201ltration of bone marrow and can result in signi \201cant improvement in cytopenia a nd symptoms. Useful initial treatment (1 \200\2232 weeks) for patients with advanced diseas e and pancytopenia at diagnosis. Combination chemotherapy No survival advantage of COP \200 or CHOP \200 over chlorambucil . Higher response rate in advanced disease. Response rate low when resistant to chlorambuci l. Purine analogs better second-line therapy. \200 COP: Cyclophosphamide, Oncovin (vincristine); Prednisolone; CHOP: Cyclophosphamide, Adriamycin, Oncovin, Prednisolone. OHO-27(489-514) 11/18/02 8:38 AM Page 497 CHRONIC LYMPHOID LEUKAEMIAS 497 Purine analogs Effective treatment of CLL. Cause profound depletion of normal lymphocytes e specially CD4+ T-cells and predispose to oppor- tunistic infection, in particular P. carini i, Listeria monocytogenes, M. tuberculosis, Norcardia and herpes viruses. Single-agent \202udarabine produces higher response rate than chlo- rambucil \200\224prev iously untreated patients (70 vs. 40%), CR rate (27 vs. 3%), and disease-free survival (33 vs. 17 months). Also effective in previously treated patients (31 \200\22357% response rate , 13% CRs). No evi- dence of improved overall survival. Generally administered at a dose of 25 mg/m2 Intravenously for 5 days on a 4 \200\2236 week cycle until maxi- mum response or 6 cycles. Complications include: (cid:2) Myelosuppression (cid:2) Prolonged CD4+ T-lymphocy topenia Infection (cid:2) (cid:2) Autoimmune haemolysis Routine prophylaxis of P. carinii pneumonia with either co-tr imoxa- zole or pentamidine advisable for one year after treatment, with or without acyclovi r prophylaxis of Herpes zoster reactivation. Caution is needed in patients with previous hi story of autoimmune haemolysis. Fludarabine is an option for \201rst-line therapy and als o an effective second-line therapy for alkylator-resistant CLL. Radiotherapy Effective local treatment for lymph nodes compromising vital organ function. S plenic irradiation is effective for painful splenomegaly, though splenectomy better for mas sive splenomegaly if patient is \201t for surgery. Splenectomy Effective for massive splenomegaly, anemia, or thrombocytopenia due to hyperspl enism and for autoimmune haemolytic anemia refractory to prednisolone and cytotoxic therapy OHO-27(489-514) 11/18/02 8:38 AM Page 498 hematological MALIGNANCIES 498 Hodgkin \200\231s disease Epidemiology and etiology Hodgkin \200\231s disease (HD) is a rare malignancy, with an annu al UK inci- dence of 1000 \200\2231500 new cases. The age distribution is bimodal, with a l arge peak in the 20 \200\22330 year age group, and a smaller peak at 50 \200\22360 years. T he cause is unknown, and may differ between the various histological subtypes. An associati on between infection with Epstein \200\223Barr virus and HD is well documented, although it s precise aetiological role is unclear. Pathology The characteristic diagnostic feature is the binucleate Reed \200\223Sternberg (R S) cell, seen in an appropriate cellular background of small lympho- cytes, eosinophils, ne utrophils, histiocytes, and plasma cells. The RS cell is the malignant cell in HD, and rece nt molecular studies have con \201rmed its B-cell lineage. The major subtypes are: (cid:2) Nodular sclerozing (NS) ( 50%) (cid:2) Mixed cellularity (MC) (30-40%) (cid:2) Lymphocyte/ histiocyte predominant (LP, HP) ( 10%) Lymphocyte-depleted HD is very rare \200\224studies have showed that cases previously diagnosed as lymphocyte-depleted HD were mostly B-cell no n-Hodgkin \200\231s lymphoma (NHL). Lymphocyte/histiocyte- predominant HD is a distinct ent ity, characterized by \200\230L&H Hodgkin \200\231s cells \200\231 which are of B-cell lin eage. A small proportion develop into diffuse, large, B-cell NHL. This subtype has a favora ble prognosis, as does a recently described similar entity \200\224lymphocyte-rich classica l HD. Some subtypes of NHL, particularly anaplastic large-cell lym- phoma, can be confused with HD. Expert review of the pathology is an essential component of management. Presentation (cid:2) Painless lymphadenopathy (cervical nodes especially) (cid:2) May be generalized lym phadenopathy (cid:2) Later spread to liver, lungs, marrow \200\230B \200\231 symptoms \200\224fever (cid:2) \200\224night sweats \200\224weight loss >10% \200\224itch \200\224alcohol-induced pain in nodes OHO-27(489-514) 11/18/02 8:38 AM Page 499 HODGKIN \200\231S DISEASE 499 Table 27.3 Ann Arbor staging system Stage Feature I Disease in a single lymph node region II Disease in two or more regions on the same side of the diaphragm III Disease in two or more regions on both sides of the diaphragm IV Diffuse or disseminated disease in extra lymphatic sites including liver and bone marrow Various suf \201xes are added to each anatomical stage: A No systemic symptoms B Systemic symptoms present E Extranodal disease Staging Spread of HD is typically to contiguous lymph node groups. As a result, anatomical staging using the Ann Arbor system has been the basis of treatment decisions in HD. However , the identi \201cation of other prognostic factors has re \201ned treatment decisions, w hich are now rarely made on the basis of anatomical stage only. Prognostic factors Recent studies have identi \201ed various presenting factors that may i n \202uence outcome in HD. For patients with early stage (I and IIA) disease, several stud ies have identi \201ed prognostic groups based on histological subtype, age, sex, symptom status, number of nodal regions involved, and the presence of bulky mediastinal disease. Fo r patients with advanced (Stage IIB to IVB) disease, various prog- nostic factors have been identi \201ed in an analysis of over 5000 patients. The adverse factors are as follows: ( cid:2) Albumin <4 g/l (cid:2) Hemoglobin <10.5 g/l (cid:2) Male gender Table 27.4 EORTC prognostic groups in early-stage HD Group Prognostic factors Very favorable Stage I and age <40 or \200\230A \200\231 + ESR <50 or female and MT ratio* <0.35 Favorable All other patients Age \211 40, or \200\230A \200\231 and ESR \211 50, or \200\230B \200\231 and ESR \211 30, or Stage II4/5, or MT ratio \211 0.35 Unfavorable MT ratio = size of mediastinal mass compared with transverse diameter of the chest on chest X-ray. OHO-27(489-514) 11/18/02 8:38 AM Page 500 hematological MALIGNANCIES 500 (cid:2) Age 45 years or over (cid:2) Stage IV (cid:2) Leukocytosis 15 \227 109/1 (cid:2) L ymphocytopenia <0.6 \227 109/l In the absence of any adverse factors, the \201ve-year fa ilure-free survival (FFS) rate is 84%. The presence of each of these factors reduces the ex pected \201ve-year FFS by about 8%. Treatment Since HD predominantly affects young adults, potential long-term toxicities of th erapy are of major importance. The recognition of the long-term toxicities of radiation the rapy, particularly to the medi- astinum (second malignancies, including lung and breast can cer; pul- monary \201brosis; coronary artery disease) and alkylating agent-based chemothe rapy (secondary leukemia and NHL; infertility; early ovarian failure) has had a major impac t on therapy. Early stage The majority of patients with early-stage HD present with supra- diaphragmatic disease. For these patients, treatment should be deter- mined by prognostic factors that pr edict the likelihood of occult subdiaphragmatic disease not detected by routine clinical st aging techniques. Standard therapy for these patients comprises nodal irradiation with the classic mantle \201eld (occipital, cervical, supraclavicular, axil- lary, mediastinal, and hilar nodes). I n the US this is commonly extended to the upper abdomen to incorporate the coeliac nodes, s plenic hilar nodes, and spleen (subtotal nodal irradiation \200\224STNI). 70 \200\22380% of patients achieve long-term Disease Free Survival (DFS) with this approach. Although relaps e occurs in up to 30% of patients, subsequent salvage with chemotherapy is very successful, in around 80 \200\22390% of patients. In view of the long-term toxicity of extended \201eld radiotherapy, the role of chemother apy combined with limited (involved \201eld) radio- therapy has been explored in many cen ters, and is currently being assessed in randomized clinical trials. Regimens such as VBM ( vinblas- tine, bleomycin, methotrexate) and ABVD (doxorubicin, bleomycin, vinblastine, daca rbazine) combined with involved \201eld radiotherapy can produce long-term DFS equivalent to STNI, with fewer relapses after initial therapy and less long-term toxicity. Patients with very favorable prognostic features (e.g. female patients with LP or NS histol ogy, low ESR, and presentation with high cervical nodes) are at very low risk of subdiaphra gmatic relapse and are treated in some centers with involved \201eld radiotherapy alone. OHO-27(489-514) 11/18/02 8:38 AM Page 501 HODGKIN \200\231S DISEASE 501 Advanced stage MOPP (mustine, vincristine, procarbazine, and prednisone) and its variants h ave been considered standard chemotherapy for advanced HD until recently. However, doxorubi cin-based chemotherapy, par- ticularly ABVD, has now become widely accepted as standard the rapy following the completion of a major trial by the CALGB.1 This study compared MOPP, MOP P alternating with ABVD, and ABVD alone. The respective \201ve-year failure-free survival (FFS) rates were 50%, 65%, and 61%, demonstrating that ABVD and MOPP/ABVD were equivalent, and both superior to MOPP alone. More recently, brief-duration regimens such as Stanford V (mustine, doxorubicin, vinblastin e, prednisone, vincristine, bleomycin, etoposide) and BEACOPP (bleomycin, etoposide, doxoru bicin, cyclophosphamide, vincristine, procarbazine, prednisolone) have been introduced, on the basis of increased dose intensity but reduced total doses of therapy, with a lower pote ntial for long-term toxicity. These regimens are combined with limited \201eld radiothera py to sites of disease bulk. Initial reports have shown high response and FFS rates. For ex ample, Stanford V pro- duced a three-year actuarial overall survival (OS) and FFS of 96% an d 87% respectively in patients with advanced HD. Similar results have been reported for BEA COPP. These regimens are now being compared with standard regimens such as ABVD in randomiz ed trials. Salvage therapy Patients with early-stage HD who relapse after radiotherapy have high respo nse rates to subsequent chemotherapy, with most (80 \200\22390%) achieving long-term DFS. F or patients who relapse after \201rst-line chemotherapy, high response rates are seen wit h second-line conven- tional dose regimens, especially if the initial remission duration is greater than 12 months. However, only 20 \200\22325% of patients achieve long-term DFS wit h conventional-dose salvage therapy. High-dose therapy and autologous stem cell transplantation (ASCT) can produce superior long -term DFS compared with conven- tional-dose salvage and are now generally regarded as stand ard salvage therapy in HD, producing long-term DFS in 40 \200\22350% of patients. Primary r efractory HD is rare, and the role of high-dose therapy and ASCT in this setting is unknown . Future directions If adverse prognostic features, consider: (cid:2) High-dose therapy and A SCT as \201rst-line (cid:2) Antibodies against CD30 antigen on R-S cell; some responses i n Phase II trials Reference 1. Canellos, G.P., et al. (1992) Chemotherapy of advanced Hodgkin \200\231s disea se with MOPP, ABVD, or MOPP alternating with ABVD. NEJM 327: 1478 \200\22384. OHO-27(489-514) 11/18/02 8:38 AM Page 502 hematological MALIGNANCIES 502 Non-Hodgkin \200\231s lymphomas De \201nition and etiology Non-Hodgkin \200\231s lymphomas (NHL) are a group of malignant diseases arising from cells of the immune system (lymphocytes and their pre- cursors). The spectrum of NHL ranges from indolent low-grade lym- phomas which are incurable yet compatib le with a number of years of survival, to aggressive high-grade lymphomas which, left untre ated, are rapidly fatal, but which modern treatment can cure in a signi \201cant proportio n of patients. NHL is increasing in frequency, and in the USA this increase has been 3 \200\2234% per annu m since the early 1970s, with a present incidence of approximately 15 per 100 000. The path ogenesis of the majority of NHL is unknown, but identi \201ed aetiological factors include : (cid:2) Longevity (cid:2) Prolonged immunosuppression e.g. congenital immunode \201- cie ncies, HIV-associated NHL, and transplant-associated lympho- proliferative disease (cid:2) Epstein \200\223Barr virus (EBV) infection in Burkitt \200\231s lymphoma, HIV- and transplant-related lymphomas, and HTLV-1 infection in adult T-cell leukemia/lymphoma (ATLL) (cid:2) Helicobacter infection in gut lymphoma (cid:2) Lifetime accumulation of genetic ch anges to immune cells. Classi \201cation of NHL Immunological identi \201cation of lymphocytes and molecular ana lysis of immunoglobulin and T-cell receptor gene rearrangements has allowed improved classi \201cation of NHL based on the biology of the cells rather than just morphological descri ption. The majority of cases of NHL are B-cell type. The pathological classi \201cation presently employed is the Revised European and American Lymphoma (REAL) classi \201cation. This is based on whether lymphoma cells are B-lymphocy tes or T-lympho- cytes, the perceived original cell of origin of the lymphoma, and whether or not a group of expert pathologists agree that the lym- phoma can be reproducibly identi \201ed as a distinct entity. In day-to-day practice the clinical behavior of NHL (grade) is the most useful parameter, a nd treatment strategies are still based on clas- si \201cation systems which divide NHL in to indolent (low-grade) and aggressive (high-grade) diseases. The general differences betwe en low- and high-grade NHL are summarized in the table. OHO-27(489-514) 11/18/02 8:38 AM Page 503 NON-HODGKIN \200\231S LYMPHOMAS 503 Table 27.5 Outline of Revised European and American Lymphoma (REAL) classi \201cation, wit h examples of disease entities in each group B-cell lymphoma Stage I Precursor B-cell neoplasms Precursor B-lymphoblastic leukemia/lymphoma Stage II Peripheral B-cell lymphomas Follicle center cell lymphoma Diffuse large B-cell lymphoma T-cell and putative NK-cell lymphoma Stage I Precursor T-cell neoplasm Precursor T-lymphoblastic lymphoma/leukemia Stage II Peripheral T-cell and NK-cell neoplasm Mycosis fungoides/S zary syndrome Peripheral T-cell lymphomas, unspeci \201ed Table 27.6 Differences between low-grade and high-grade NHL Low-grade NHL High-grade NHL Indolent clinical course with relatively long survival Aggressive clinical course and rapidly fatal without treatment Incurable with present therapy Curable in a signi \201cant proportion of patients Non-destructive growth patterns Destructive growth pattern CNS involvement rare CNS and extranodal involvement common Clinical features and staging of NHL The majority of adult patients (60 \200\22370%) presen t with nodal disease, whereas the majority of children present with extranodal disease. One or more areas of lymph nodes are painlessly enlarged, and may remain unchanged or slowly i ncrease in size in low-grade NHL, or rapidly increase in size in high-grade lymphomas. Hepa tosplenomegaly is common and extranodal sites are protean and include the gut, testes, thyr oid gland, bone, muscle, lung, CNS, facial sinuses, and skin. Systemic symptoms include dre nching night sweats, loss of weight, and culture-negative fever. Medical emergencies associated with NHL include mediastinal obstruction, obstructive nephro pathy, spinal cord compression, hypercalcaemia, and metabolic derangement. Ascites and pleu ral effu- sions (sometimes chylous) are common end stage features, especially in high-grade NHL. Patients may develop bone marrow failure from OHO-27(489-514) 11/18/02 8:38 AM Page 504 hematological MALIGNANCIES 504 lymphomatous involvement, and low-grade NHL can cause immune- mediated haemolysis or thromb ocytopenia. Diagnosis requires a lymph node biopsy or, in the absence of lym- phadenopathy, biopsy of a n involved extranodal site. Morphological diagnosis is aided by immunohistochemistry and cy togenetic and molecular techniques. The extent or stage of the disease should be determined by clinical rather than pathological (surgical) staging. This involves: (cid:2) CXR (cid:2) CT scanning of the chest, abdomen, and pelvis to de \201ne areas of nodal and extranodal involvement (cid:2) Blood count and blood \201lm for leukaemic involvement (cid:2) Bone marrow aspira tion and trephine biopsy for morphology, immunophenotyping, and cytogenetic analysis (cid:2) Renal biochemistry, liver function, calcium, and uric acid (cid:2) Markers of tumor burden: serum LDH and (cid:3)2-microglobulin (cid:2) Others, depending on circumstances e. g. CT head scan, MRI of spine, lumbar puncture, bone scan Clinical staging is based on a modi \201cation of the Ann Arbor clas- si \201cation of Ho dgkin \200\231s disease. Low-grade NHL The low-grade lymphomas comprise 20 \200\22345% of NHL. They tend to be disse minated at the time of presentation with widespread lym- phadenopathy, hepatosplenomegaly, and, often, blood and marrow involvement. B-cell follicle center cell NHL (follicular NHL) This is the archetypal low-grade NHL. It t ypically presents in older age, though is also seen in young people. Rarely, it presents as an apparent true Stage I, when it may be cured by radiotherapy. More commonly, it presents as Stage III or IV, when it remains incurable with present treatments. This lymphoma can transform to high-grade NHL. The lymphoma cells contain a reciprocal chro mosomal translocation \200\224t(14; 18) (q32; q21). This leads to the oncogene Bcl-2, from chromosome 18, coming under the regulation of the immunoglobulin heavy chain gene (IgH) on chromosome 14. The increased production of Bcl-2 protects the lymphoma cell from apoptosis (programmed cell death) and, as such, follicle center cell lymphoma represents a relentless accumulation of malignant cells. Indolent disease (cid:2) Fatal in 10 years (cid:2) No active treatment until signi \201can t symptoms (cid:2) OHO-27(489-514) 11/18/02 8:38 AM Page 505 NON-HODGKIN \200\231S LYMPHOMAS 505 (cid:2) Local radiotherapy to bulky disease sites (cid:2) Single-agent chemotherapy \200 \224chlorambucil (cid:2) Combination chemotherapy \200\224CHOP Initial remission; relapse i nevitable (cid:2) (cid:2) New treatments \200\224purine analogs: \202udarabine and 2-CDA \200\224autologou s transplant \200\224 interferon \200\224palliation with anti-CD20 antibody (rituximab) \200\224antisense therapy to suppress Bcl-2 protein High-grade NHL High-grade NHLs are best considered as those with a strong tendency to invol ve the CNS \200\224lymphoblastic, Burkitt \200\231s, ATLL, primary CNS lymphoma (PCL), and those others with a lesser tendency to do so. However, these latter histological types have an increased risk of CNS disease if they involve marrow, testes, or facial sinuses, and su ch patients require CNS examination and prophylaxis. Burkitt \200\231s lymphoma (cid:2) Endemic \200\224endemic in equatorial Africa \200\22490% associated with EBV infection \200\224y oung adults/children, present with head/neck tumors (cid:2) Non-endemic \200\224NHL associated with EBV in 20% \200\224abdominal disease more common \200\224ass ociated with HIV infection (cid:2) Treatment \200\224intensive chemotherapy with methotrexate, cyclophosamide, ifosamide, with intrathecal therapy