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 Lymphoblastic lymphoma Presents with or without leukemia, is commoner in children than adul ts, and is most often T-cell type; typically featuring a mediastinal mass and pleural effus ion. Treatment includes emergency management of mediastinal obstruction and prevention of t he tumor lysis syndrome. Intensive combination chemotherapy schedules similar to those used in ALL and including CNS-directed therapy have improved the outlook in children, but resul ts in adults remain less good. Poor prognostic features include bone marrow and/or CNS involve- ment, LDH > 300 iu/l, age > 30 years, and delayed achievement of CR. Allogeneic and autologous progenitor cell transp lantation may improve survival in these cases. OHO-27(489-514) 11/18/02 8:38 AM Page 506 hematological MALIGNANCIES 506 Diffuse large B-cell NHL This, the commonest high-grade NHL, presents as nodal or extra- no dal disease. Radiotherapy can cure 90% of non-bulky Stage IA disease. For other stages, CHO P chemotherapy with radiotherapy to bulk disease remains the gold standard treatment with 4 0 \200\22350% cure. Relapsed patients who respond to salvage chemotherapy have been shown t o have a survival bene \201t with autologous progenitor cell transplantation. OHO-27(489-514) 11/18/02 8:38 AM Page 507 NON-HODGKIN \200\231S LYMPHOMAS 507 OHO-27(489-514) 11/18/02 8:38 AM Page 508 hematological MALIGNANCIES 508 Myeloma Myeloma (multiple myeloma, myelomatosis) is due to the unregulated proliferation of monoclo nal plasma cells in the bone marrow. Their accumulation leads to marrow failure and, indire ctly, to bone resorption resulting in osteoporosis and fracture. The cell of origin has not been conclusively identi \201ed but may be a memory B lymphocyte. The cause is unknown. A n important mechanism is local production of interleukin 6, which stimulates plasma cell pr oliferation. Both paracrine and autocrine sources of the cytokine have been demonstrated. The overall incidence of the disease is 4 per 100 000 in the UK, but over 30 per 100 000 in subjects over 80 years of age. It is higher amongst African \200\223Americans and much low er in Chinese and Japanese \200\223Asian populations. It is rare under the age of 40, the m edian age at presentation being 70 years. The clonal plasma cells in myeloma synthesize, and usually secrete, a monoclonal protein (M protein, paraprotein). This is most common- ly intact immunoglobulin, but may be immunoglo bulin together with free light chain, or free light chain only. IgG is secreted in 60% of c ases. IgA in 20%, and free light chain only in 20%. Light chains can pass through the glome rular \201lter and appear in the urine as Bence \200\223Jones protein. In rare cases ther e is synthesis of monoclonal IgD, IgE, or IgM, or of two clonal proteins. Also uncommon are non-secretory and non-synthesizing variants of the disease. Pathology Monoclonal gammopathy associated pathology: (cid:2) Monoclonal gammopathy of unce rtain signi \201cance (MGUS) (cid:2) Solitary plasmacytoma (cid:2) Lymphoma (cid:2) Walden strom \200\231s macroglobulinaemia (cid:2) Chronic lymphatic leukemia (cid:2) Amyloidosis Clinical features These are explained by the accumulation of plasma cells in bone mar- row, induction of bone resorption, and paraprotein synthesis. Marrow in \201ltration Malignant plasma cells accumulate in the red marrow of the axial sk eleton and \202at bones. Anemia and thrombocytopenia are com- mon, and frequently present at diagnosis. OHO-27(489-514) 11/18/02 8:38 AM Page 509 MYELOMA 509 Bone resorption There is abnormal bone remodeling with increased, cytokine-driven osteoclas tic bone resorption and inhibition of osteoblastic bone for- mation. Interleukin 6 is a maj or stimulus to osteoclastic activity. Bone pain is the most common presenting complaint, es pecially severe back pain. There may be fractures. The increased bone resorption also leads to hypercalcaemia and associated symptoms of thirst, polyuria, nausea, constipation, drows iness, and even coma. X-ray examination typically reveals osteoporosis and lytic lesions th at are often visualized on skull \201lms. Secretion of paraprotein Accumulation of M protein in the plasma may result in hyperviscosi ty with lethargy and confusion, progressing to \201ts and coma. There is a characteristic retinopathy in hyperviscosity syndrome, with disten- sion of retinal veins and irregular v essel constrictions; hemorrhages and papilloedema may be present. IgA and IgG paraproteins are espe- cially likely to induce hyperviscosity. Bence \200\223Jones protein is deposited in the renal tubules and may lead to renal failure. Other factors contributing to renal fai lures are: (cid:2) Hypercalcaemia (cid:2) Amyloid deposition Infection (cid:2) Paraproteinaemia is typically accompanied by immune paresis, which contributes to the infec tion risk. In non-secretory myeloma the only immunological abnormality may be immune paresi s, giving rise to diagnostic confusion. Other features Plasmacytomas may be palpable and also cause pressure effects. Spinal cord c ompression is most frequent and constitutes a medical emer- gency with the need for urgent assessment and local radiotherapy and/or decompressive surgery. Amyloidosis is frequently p resent and may dominate the clinical picture: macroglossia, renal failure, peri- pheral neu ropathy, and cardiac failure occur. A syndrome of high- output cardiac failure is an occasi onal feature, unrelated to cardiac amyloid. Very occasionally the bone lesions appear sclerotic, and this variant of the disease is oft en accompanied by severe progressive peripheral neuropathy. This combination of sclerotic l esions and neuropathy may also occur as part of the \200\230POEMS \200\231 syndrome, where plasma cell dyscrasia is accompanied by: (cid:2) Sensorimotor Polyneuropathy (cid:2) Organ omegaly (principally hepatomegaly) (cid:2) Endocrinopathy (diabetes mellitus, amenorrhoea, gynaecomastia) OHO-27(489-514) 11/18/02 8:38 AM Page 510 hematological MALIGNANCIES 510 (cid:2) M protein (cid:2) Skin changes (predominantly pigmentation) Diagnosis The classic diagnostic triad consists of bone marrow in \201ltration with monocl onal plasma cells, osteolytic lesions on skeletal X-rays, and paraproteinaemia/Bence \200 \223Jones \200\231 proteinuria. The plasma cell count may be only 5 \200\22310% in marrow, but is often over 30%, usually with morphologically abnormal forms. Cytogenetic abnormalities, most commonly on chromosomes 13 and 14, and aneuploidy, are usua lly present, although their demon- stration is not necessary for diagnostic purposes. The m yeloma cells tend to be positive for CD 19, 38, 56, and syndecan-1. Additional com- mon fea tures are: (cid:2) Raised ESR (cid:2) Normocytic anemia (cid:2) Pancytopaenia (cid:2) Renal impairment (present in 20% of cases) In approximately 30%, hypercalcaemia is present at di agnosis and, typically, the serum alkaline phosphatase concentration is normal and the isot ope bone scan negative (due to suppressed osteoblastic acti- vity). The serum albumin may b e low. The main differential diagnosis is \200\230monoclonal gammopathy of uncertain signi \201c ance \200\231 (MGUS), de \201ned as the presence of a serum paraprotein without the featur es of myeloma. Its prevalence is around 20 times higher than that of multiple myeloma and i t is age-related \200\224 3% of subjects over 80 years of age have detectable paraprotein. The serum concentration of the M protein is usually less than 30 g/l of IgG (less than 20 g /l of IgA), with no immune paresis. The blood count is normal as are skeletal X-rays. An ex cess of clonal plasma cells may be detected in the marrow, but these total less than 5% of nucleated cells. In \200\230smoldering \200\231 myeloma there are more than 10% plasma cells in bone marrow and a serum paraprotein concentration greater than 30 g/l, but no bone symptoms, radiologi cal skeletal abnormality, anemia, or renal failure. It is associated with an initially stab le course and relatively long survival. In plasma cell leukemia there are greater than 20% plasma cells in peripheral blood. It may be a presenting feature or develop late in the disease course and is typically poorly resp onsive to therapy. Solitary plasmacytoma presents as a single bone lesion with normal bone marrow and absent, or only low titre, paraprotein in serum. The tumor is radio-sensitive, but myeloma subseque ntly develops in most cases. OHO-27(489-514) 11/18/02 8:38 AM Page 511 MYELOMA 511 Extramedullary plasmacytoma is a rare soft-tissue plasma cell tumor, most commonly affectin g the head and neck areas, especially the nasopharynx, nasal sinuses, and tonsils. Again th e bone marrow is normal and there is no paraprotein. The tumor is radio-sensitive. Multiple myeloma develops in up to 40% of cases. Management Untreated, death usually occurs within months, especially from infec- tion and r enal failure, and is often preceded by intractable bone pain. Initial therapy should includ e: (cid:2) Adequate analgesia, often necessitating the use of opiates, with radiotherapy to areas of persisting local bone pain. (cid:2) Rehydration and vigorous management of hypercalcaemia using intravenous bisphosphon ate. Dialysis is occasionally necessary for management of renal impairment, and plasma exch ange for rapid correction of hyperviscosity syndrome. Chemotherapy (cid:2) Cures are rare (cid:2) Palliation to improve symptoms and reduce paraprotein (cid:2 ) Chemotherapy for 3 months is suf \201cient (cid:2) Maintenance chemotherapy is of no val ue (cid:2) Plateau phase lasts 3 months to 3 years (cid:2) Oral melphalan is best \200\2244 -day pulses every 4 weeks \200\22450% of patients achieve 50% reduction in M protein (cid:2) Median survival, 3 months A more intensive regimen \200\224VAD (vincristine and adr iamycin by IV infusion and oral dexamethasone) \200\224may produce a rapid response, but th is is often poorly sustained. Combination chemo- therapy (e.g. doxorubicin, BCNU, cyclophos phamide, melphalan) has improved the response rate in some trials, at the expense of greate r toxicity. Complete remission is uncommon. High-dose (marrow ablative) melphalan with autologous stem cell transplantation induces com- plete remission in around 20% of recipients, and prolongs survival. It can be considered in younger patients. Long-term survival has been reported a fter allogeneic transplantation, but treatment-related mortality is high (up to 40%). Additional therapy Oral clodronate appears to reduce the fracture rate, when adminis- tered continuously. Pamidromate \200\224a more potent bisphosphonate \200\224 administered by mo nthly IV infusion, reduces fracture rate, pain, and OHO-27(489-514) 11/18/02 8:38 AM Page 512 hematological MALIGNANCIES 512 hypercalcaemia and improves quality of life. Interferon-(cid:3), adminis- tered as maintena nce therapy, appears to extend the duration of the plateau phase. It is unclear whether sur vival is meaningfully prolonged. The therapy is associated with signi \201cant side-effect s and is expensive. Erythropoietin can be used to reduce transfusion requirements in a mino rity of cases. OHO-27(489-514) 11/18/02 8:38 AM Page 513 MYELOMA 513 Further reading Bartlett, N.L., Rosenberg, S.A., Hoppe, R.T., et al. (1995) Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced stage Hodgkin \200\231s disease : a preliminary report. J Clin Oncol 13, 1080 \200\2238. Canellos, G.P., Anderson, J.R., Pr opert, K.J. et al.(1992) Chemotherapy of advanced Hodgkin \200\231s disease with MOPP, ABVD or MOPP alternating with ABVD. New Engl J Med 327, 1478 \200\22384. Hasenclever, D. and Diehl, V. (for the International Prognostic Factors Project on Advanced Hodgkin \200\231s Disease) (1998) A prognostic score for advanced Hodgkin \200\231s diseas e. New Engl J Med 339, 1506 \200\22314. OHO-27(489-514) 11/18/02 8:38 AM Page 514 This page intentionally left blank OHO-28(515-530) 11/18/02 8:43 AM Page 515 Chapter 28 Bone and soft tissue malignanicies Osteosarcoma 516 Ewing \200\231s sarcoma 520 Other primary bone tumors 524 Soft tissue sarc omas 526 OHO-28(515-530) 11/18/02 8:43 AM Page 516 BONE AND SOFT TISSUE MALIGNANCIES 516 Osteosarcoma Background Malignant bone tumors are rare, accounting for only 0.2% of all new cancers. Ost eosarcoma is the commonest primary bone tumor and occurs predominantly in adolescence with a peak incidence coincid- ing with the growth spurt. Cases occurring over the age of 40 yea rs are usually associated with: (cid:2) Paget \200\231s disease Irradiated bone (cid:2) (cid:2) Multiple hereditary exostosis (cid:2) Polyostotic \201brous dysplasia The majorit y of tumors arise in the region of the metaphysis, most commonly in the tibia close to the knee joint. Other long bones may be involved, but presentation in the axial skeleton is rel atively rare. Pain at the site of the tumor, often with overlying erythema and tenderness, is the usual mode of presentation. More rarely, fracture through a tumor site can occur. Se rum alkaline phosphatase is elevated in 50% of cases. Pathology Osteosarcomas are composed of malignant spindle cells and osteoblasts that produc e osteoid or immature bone. The \200\230classic \200\231 subtype is a central medullary tu mor but rarer types with a better prognosis exist \200\224 parosteal, periosteal, and low-g rade intra-osseous osteosarcoma. Radiological evaluation Plain X-rays of the affected area are usually suf \201cient to mak e a diag- nosis of osteosarcoma. The classic features of osteosarcoma are: (cid:2) Poorly d elineated or absent margins around the bone lesion (cid:2) Bone destruction (cid:2) New bon e formation with calci \201cation of the matrix (cid:2) Periosteal reaction, usually non-c ontinuous and thin, with multiple laminations Note: histological con \201rmation of the radiological diagnosis must be deferred until th e patient is assessed by a surgeon with expertise in the management of bone malignancies. Staging Bone tumors disseminate almost exclusively via the bloodstream. Lymph node metastas is is rare (less than 5% of patients) and, if pre- OHO-28(515-530) 11/18/02 8:43 AM Page 517 OSTEOSARCOMA 517 sent, represents a very poor prognosis. Metastases may be within the same bone (skip lesion s) or to other organs, most commonly the lungs. Several staging systems exist, the most commonly used being that described by Enneking. Thi s stages patients from Ia \200\223III. The stage is derived from a combination of the histo logical grade of the tumor, the presence or absence of distant metastases, and the extent o f local spread of disease. Management of patients with osteosarcoma Surgical resection (usually amputation of a limb) alone was used to treat osteosarcomas until the 1970s. Overall survival was only 15 \200 \22320%, largely because of the development of pulmonary metas- tases. Subsequent use of ch emotherapy in the adjuvant (post-opera- tive) or neo-adjuvant (pre- and post-operative) set ting has improved the survival rate to 55 \200\22380%. Surgical management has also improve d in the past 20 years, with amputation being replaced in the majority of patients by limb- sparing surgery. Pre-operative assessment When plain radiology suggests an osteosarcoma, staging should be p erformed prior to biopsy. Investigations include: (cid:2) Bone scan \200\224determines mult iple sites of involvement and provides a guide to the intra-osseous extension of disease. (cid:2) CT scanning of bone \200\224this allows accurate determination of intra- and extra- osseous extension of disease. The entire bone and adja- cent joint should be imaged and con trast used to identify vascular structures. (cid:2) MRI of bone \200\224this provides excellent contrast discrimination and is particul arly valuable for imaging the medullary marrow. It is the most useful method for detecting skip metastases. (cid:2) Angiography \200\224this is used when limb-sparing procedures are planned to determ ine individual vascular patterns before resection. It is especially valuable in proximal ti bial lesions. (cid:2) Biopsy \200\224biopsies of suspected osteosarcomas must be performed by orthopedic specialists with experience of this technique. Ideally, the biopsy should be performed by t he surgeon who will undertake the de \201nitive resection. Trephine or core biopsy is reco mmended. It must be assumed that there is potential tumor contamination of all tissue plane s and compartments traversed by the biopsy needle. The site of biopsy must be carefully cho sen as it will have to be removed en bloc during de \201nitive resection. An incorrectly s ited biopsy may necessitate amputation instead of limb-sparing surgery. Frozen section shou ld be obtained during OHO-28(515-530) 11/18/02 8:43 AM Page 518 BONE AND SOFT TISSUE MALIGNANCIES 518 the biopsy to ensure that the tumor has been obtained. Clearance biopsies are normally take n during this procedure. (cid:2) CT scan of the thorax \200\224to detect pulmonary metastases. Surgery Sarcomas grow radially and produce a pseudo-capsule. The tumor invariably spreads t hrough the capsule and expert surgery is necessary to ensure an adequate resection margin t o remove all locally viable tumor. While previously amputation was almost always necessary, approximately 80% of osteosarcomas are now treated successfully with limb-sparing techniqu es. A wide variety of endo-prosthetic devices are available including extendable prostheses for growing children. Chemotherapy The outcome for patients with osteosarcomas has been markedly improved with th e addition of chemotherapy to surgery. The most active agents are doxorubicin, cisplatin, i fosfamide, and high-dose methotrexate. Chemotherapy may be given pre-operatively and post- operatively (neo-adjuvant treatment). This has several potential bene \201ts: (cid:2) Trea tment starts without delay before surgery (time is taken obtaining a customized endoprosthesis). (cid:2) The bulk of viable tumor is reduced and thus, perhaps, the risk of dissemination of tumor at surgery. (cid:2) Reduction of tumor volume makes surgery technically simpler. It allows assessment of the pathological response to chemotherapy when examining the de \201nitive resection specimen. (cid:2) On the other hand, this approach delays the time of resection in patients who do not respon d to chemotherapy. Post-operative adju- vant chemotherapy may be used instead with the adva ntages that only microscopic disease, if any, remains, and de \201nitive local treatment w ith surgery is not delayed. Clearly, pathological response to chemotherapy cannot be assessed and alternative regimens cannot therefore be considered in those fail- ing to respond to \201rst-line chemotherapy . The optimum regimen has not been de \201ned and, wherever possible, patients with this r are tumor are included in clinical trials. Radiotherapy Osteosarcomas are relatively radio-resistant. Radiotherapy is rarely used in t he primary treatment of this disease. Its use is limited to the palliative care of patients who refuse surgery, have lesions in axial sites which are not resectable, or have bone met astases. OHO-28(515-530) 11/18/02 8:43 AM Page 519 OSTEOSARCOMA 519 Metastatic osteosarcoma The majority of patients developing recurrent disease will have pul - monary metastases. Up to 30% may be salvaged with surgical resec- tion of the metastases. Metastasectomy may be considered on several occasions. Local recurrences are managed with surgical resection or palliative irradiation. The role of chemotherapy in relapsed disease is uncertain but patients with lung metastases at presentation undoubt- edly bene \201t fr om combined modality treatment, and a few will be long-term survivors after chemotherapy an d surgery for both the primary and residual metastases. OHO-28(515-530) 11/18/02 8:43 AM Page 520 BONE AND SOFT TISSUE MALIGNANCIES 520 Ewing \200\231s sarcoma Introduction First described by James Ewing, New York pathologist, in 1926, this is one of the two common bone tumors occurring in young people, with a peak age of incidence of 15 \200\22318 years. It occurs with an annual incidence of 0.6 per million in most populations but is extremely rare in non-Caucasians. Etiology is unknown and is not generally associated with cancer \200\230syndromes \200\231 . Any bone in the body can be affected, with 55% in the axial skeleton and 45% in the limbs . Within the long bones, the tumor tends to be more centrally situated in the diaphysis rat her than at the ends of the bone. Clinical presentation is usually with a painful swelling that may be warm and/or red. Those occurring in central sites may present with severe pain, signs of abdominal organ or urina ry tract compression, or nerve compression from those arising in the vertebral bodies. Abou t 10% present with a hot, swollen bone, along with a substantial fever, and in this situati on osteomyelitis is part of the differential diagnosis. Diagnosis (cid:2) X-ray \200\224destructive, osteolytic lesions \200\224elevation of periosteum \200\224onion skin appearance (cid:2) CT (cid:2) MRI (cid:2) Aspiration biopsy rarely suf \201cient (cid:2) Open biopsy \200\224send to laboratory fresh (cid:2) Histology \200\224small, blue, round cell tumor \200\224glycogen within cells (PAS, neural markers positive \200\223 S \200\223 100, vimentin, NSE) (cid:2) EM \200\224glycogen granules (cid:2) Cyogenetics \200\224t(11,:22) translocation \200\224EWS/FL11 gene rearrangement (cid:2) Subtypes \200\224typical Ewing \200\231s sarcoma \200\224atypical Ewing \200\231s sarcoma \200\224primitive neuroectodermal tumor of bone (PNET) In practical terms, treatment and outcome are identical for all three subtypes. Other pre-t reatment investigations that can be helpful are: OHO-28(515-530) 11/18/02 8:43 AM Page 521 EWING \200\231S SARCOMA 521 (cid:2) Full blood count (cid:2) Alkaline phosphatase (cid:2) LDH (cid:2) Plasma creatinine Prior to therapy, a test of renal function (e.g. Cr51EDTA) and cardiac function (e.g. echo cardiogram) should be undertaken. The most important prognostic factor is the presence of m etastases at diagnosis and, in order to ascertain such lesions, it is important to undertak e an isotope bone scan, a CT of the lungs, and a bone marrow aspirate/ trephine from a bone not affected by the primary tumor. The basic treatment plan is similar for all patients \200\224but chemo- therapy \206\222 d e \201nitive treatment of primary \206\222 chemotherapy \206\222 follow-up \200\224needs to be individualized depending on the site of the primary tumor and the presence of metast atic disease. This is a rare tumor and should be treated in a specialist center. Chemotherapy There are six drugs that have substantial proven activity in this disease: (ci d:2) Vincristine (cid:2) Doxorubicin (cid:2) Actinomycin D (cid:2) Etoposide (cid:2) Cyclop hosphamide Ifosfamide (cid:2) While there is some controversy as to whether maximally tolerable doses of cyclophosphamide are inferior to ifosfamide, the latter is usually used. Treatment of the primary tumor Surgery and/or radiotherapy may be used. Surgery should be c onsid- ered in all cases and if it is possible to remove the tumor without undue mutilation , then it is the treatment of choice. Surgical develop- ments mean that there are few bones in the body which are not amenable to surgery. Complete removal is recommended but if it i s incomplete, radiotherapy should be given in addition. The latter should be given to the w hole bone, but the most distant epiphysis may be spared in tumors arising at the end of the long bone. Patients with metastases Lung metastases should be treated with conventional chemotherapy a s detailed, with whole-lung irradiation to any residual disease. However, those with bony m etastases have a dismal prognosis and it OHO-28(515-530) 11/18/02 8:43 AM Page 522 BONE AND SOFT TISSUE MALIGNANCIES 522 may be worth considering megatherapy after conventional induction treatment. Either melphal an, busulphan, or TBI, or a combination, may be used as a conditioning regime. Prognosis The major prognostic factors are metastases at presentation and site and volume o f the tumor. For those with small tumors (<100 cc), usually in the long bones, over 80% can be cured. Pelvic tumors and those with lung metastases have a 30% chance of survival. With con- ventional therapy, the majority of those with bone metastases die. Ewing \200\231s tu mor may relapse up to 10 or more years after diagnosis. Late effects Cardiac and nephrotoxic late effects, as a result of chemotherapy, may occur, but these are not disease-speci \201c. Second primary tumors, most often osteosarcomas, ma y occur in the irradiation \201eld, and the late effects of major endoprosthetic surgery can be substantial. OHO-28(515-530) 11/18/02 8:43 AM Page 523 EWING \200\231S SARCOMA 523 OHO-28(515-530) 11/18/02 8:43 AM Page 524 BONE AND SOFT TISSUE MALIGNANCIES 524 Other primary bone tumors Primary malignant spindle cell sarcoma of bone Most often malignant \201brous histiocytom a, but other pathologies include: (cid:2) Liposarcoma (cid:2) Angiosarcoma (cid:2) Leiomyos arcoma (cid:2) Haemangiopericytoma All are rare; they comprise less than 1% of all bone tum ors. May arise in any bone (usually the metaphysis of a long bone) and tend to occur in mid dle age. Can occur after a previous insult to the bone, e.g. ioniz- ing radiation, bone inf arct, or \201brous dysplasia. The treatment is surgical removal of all disease but, as with osteo- sarcoma, limb-sparing surgery and insertion of a customized pro- sthesis may be feasible. The role of chemotherap y is still being explored and comparison with historical controls does suggest some bene \201t. Osteoclastoma Account for 5% of primary bone tumors and are usually benign. Occur in young adults, often in an epiphysis around the knee. Are treated by curettage and bone packing or bone resection and insertion of an endoprosthesis. Local recurrence occurs in 30 \200\2235 0%, but radio- therapy carries a de \201nite risk of malignant transformation and is only appropriate where the alternative local therapy is amputation. Rarely, these tumors can met astasize to the lung. Where possible, these should be dealed with surgically. Anecdotal res ponses to chemotherapy have been reported. Chondrosarcoma Slow-growing tumors of middle to late age and the second most common bone tu mor (approximately 20%). Occur around the pelvis and shoulders. Grade is a good guide to be havior, although about 10% of low-grade tumors transform to a higher grade. Treatment is su rgical resection with radiotherapy for incomplete resection or palliation of advanced disea se. Mesenchymal chondrosarcoma is a high-grade tumor of adoles- cence frequently involving the mandible, ribs, or spine. Combined treatment with surgery, chemotherapy, and radiotherapy p rovide a 50% cure rate. OHO-28(515-530) 11/18/02 8:43 AM Page 525 OTHER PRIMARY BONE tumors 525 Chordoma Slow-growing tumor that arises from notochord remnant cells in the sacrum/coccyx ( 50%), skull base/clivus (35%), or upper cervical vertebrae, in middle age. Presents with pe rsistent pain and often only discovered on CT or MRI after \200\230normal \200\231 plain X -rays of the bone. Metastases are rare (lung or bone) and survival is determined by the suc cess or failure of local control. Surgery is the treatment of choice but may not be feasible because of the tumor site. Radio therapy (55 \200\22360 Gy) is used after incomplete resection or as palliation. Particle th erapy with protons has shown some promise. 30 \200\22350% survive \201ve years but late r ecurrences are possible. Solitary plasmacytoma Isolated lytic lesion rich in plasma cells. The diagnosis depends on the exclusion of myeloma (no other skeletal lesions, no hypercalcaemia, no suppression of o ther immunoglobulins, and bone marrow con- tains <5% plasma cells). Paraproteinaemia is com mon. Treatment is either surgical excision of the lesion or, more common- ly, radiotherapy (45 \200\22350 Gy). Prognosis is good, with a median survival of over 5 years, but about a half will transform into myeloma. Primary bone lymphoma One of the differential diagnoses of malignant, small, round, dark ce ll tumors of bone (Ewing \200\231s neuroblastoma). Full staging with CT, bone scan, and bon e marrow examination is required to exclude systemic lymphoma. Localized high-grade NHL is treated with initial chemo- therapy (e.g. CHOP) followed by either radiotherapy or surgical exci- sion and endoprosthesis (latter is preferred for long, weight-bearing bones, where t here is otherwise a high risk of fracture). Multifocal disease is usually low-grade NHL. Tr eatment is with chlorambucil chemotherapy and radiotherapy. OHO-28(515-530) 11/18/02 8:43 AM Page 526 BONE AND SOFT TISSUE MALIGNANCIES 526 Soft tissue sarcomas Diagnosis and management of sarcomas (cid:2) Any enlarging mass, deep to deep fascia should be regarded as a potential sarcoma. (cid:2) Tissue for histology should be obtained by cutting needle (e.g. Trucut), not incisi onal biopsy. The biggest surgical problems are caused by injudicious incisions. Incision bi opsy should never be performed \200\224this disseminates the tumor and is never curative. S urgery should be preceded by appropriate CT or MRI. (cid:2) (cid:2) Multidisciplinary care of sarcomas is best carried out in centers with appropriate expertise \200\224including surgery, pathology, radio- therapy, and chemotherapy. Rhabdomyosarcoma (RMS) The commonest soft tissue tumor in childhood and adolescence. More t han half the cases occur in children under 10 years and is rare in adults over 40. Male to female ratio is approximately 1.3:1. Arises from primitive mesenchymal cells with the capac ity for rhabdomyoblastic development. Commonest sites of origin are: (cid:2) Head and neck (cid:2) Genitourinary tract (cid:2) Retroperitoneum (cid:2) Extremities Disease may spread locally (e.g. from the orbit to the meninges and central nervous system) and disseminates t o lymph nodes, lungs, bones, marrow, and brain. An aggressive disease requiring multi- moda lity treatment. Outlook depends on the disease site and histolog- ical subtype. Pleomorphic RMS is a rather rare adult soft tissue tumor, which behaves in a similar fashio n to other adult soft tissue tumors in that while it may be curable if localized it is not as chemosensitive as the childhood variety and carries a poor prognosis once metastatic. Diagnosis Presents with swelling or other local symptoms such as displacement of the eye, v aginal bleeding, dysuria, etc. In establishing a histological diagnosis it is currently adv isable to obtain fresh tissue for chromoso- mal studies. OHO-28(515-530) 11/18/02 8:43 AM Page 527 SOFT TISSUE SARCOMAS 527 Embryonal RMS Accounts for about 60% of cases. Occurs mainly in children under 15, most com monly affecting: (cid:2) Head and neck, including orbit (cid:2) Genitourinary tract (cid:2) Retroperitoneum \200\230Embryonal \200\231 refers to the spectrum of cell type, from prim itive round cells to rhabdomyoblasts, which may be thought to mimic the stages in muscle em bryogenesis. Botryoid RMS is a subtype characterized by polypoid growth, like a \200\230bu nch of grapes \200\231, and is usually found in hol- low organs such as the vagina, bladder , and nasopharyngeal sinuses. Alveolar RMS Characterized by poorly differentiated round or oval cells forming irregular s paces and separated by \201brous septae, giving the appear- ance of \200\230alveoli \200 \231. Sometimes this appearance is absent but the uniform appearance of the cells is distin ct from that of the embryonal variety. Multinucleate giant cells may be observed. Alveolar RMS has a signi \201cantly worse prognosis than embryonal.