20.6 Bone cancer 4709 Helen Hatcher

20.6 Bone cancer 4709 Helen Hatcher

ESSENTIALS Benign bone tumours are common, usually asymptomatic, and discovered incidentally. Malignant primary bone tumours are un- common but cause significant morbidity and mortality, particularly in adolescents and young adults. Bony metastases are the tumours most frequently seen in bone. Malignant bone tumours typically present with localized pain or swelling. With patients in whom the diagnosis is not clearly meta- static disease, determination of tumour size and extent is best achieved by magnetic resonance imaging, and bone biopsy is man- datory to establish a precise histological diagnosis. Osteosarcoma, chondrosarcoma, and Ewing sarcoma are the three commonest primary bone tumours. In determining management, the main clinical distinction is between localized and metastatic disease.
Non​metastatic primary tumours are treated with surgery (when possible) and chemotherapy (osteosarcoma and Ewing sarcoma, sometimes chondrosarcoma). Symptomatic bony metastases are usually treated with external beam radiotherapy. Introduction Benign bone tumours are common, with most being asymptom­ atic and discovered incidentally when a patient has an X-​ray taken for some unrelated reason. By contrast, malignant primary bone tumours are uncommon, but a cause of significant morbidity and mortality, particularly in adolescents and young adults. A  clas­ sification of bone tumours is shown in Table 20.6.1. The com­ monest three malignant primary bone tumours—​osteosarcoma, chondrosarcoma, and Ewing sarcoma—​are briefly discussed in this chapter, as are bony metastases, which are the tumours most fre­ quently seen in bone. Presentation, investigation, and staging The typical presentation of a malignant bone tumour is with local­ ized pain or swelling that develops over a few weeks or months. Pain can be precipitated by minor trauma, be exacerbated by exercise, and is often worse at night, waking the patient from sleep, and worsening despite rest. A tender bony mass may be palpable. Initial investigation is with a plain radiograph, which may sug­ gest a diagnosis, but determination of tumour size and extent is best achieved by magnetic resonance imaging. Computed tomog­ raphy (CT) scanning is used to evaluate for lung metastases, and radionucleide bone scanning or 18-​fluorodeoxyglucose positron emission tomography (FDG-​PET) for evidence of bone metastases. Bone biopsy is mandatory in establishing a precise histological diag­ nosis if the patient is fit and well because no imaging is 100% diag­ nostic and treatment is very different for different diagnoses. In an older patient where metastatic disease in the bone is more likely, 20.6 Bone cancer Helen Hatcher Table 20.6.1  Classification of malignant primary bone tumours Chondrogenic tumours (1) Atypical cartilaginous tumour/​ chondrosarcoma (grade I) (2) Chondrosarcoma (grades II/​III) (3) Dedifferentiated chondrosarcoma (4) Mesenchymal chondrosarcoma (5) Clear cell chondrosarcoma Osteogenic tumours (1) Low-​grade central osteosarcoma (2) Conventional (high-​grade) osteosarcoma (chondroblastic, fibroblastic, osteoblastic) (3) Telangiectatic osteosarcoma (4) Small cell osteosarcoma (5) Secondary osteosarcoma (6) Parosteal osteosarcoma (7) Periosteal osteosarcoma (8) High-​grade surface osteosarcoma Notochordal tumours Chordoma Vascular tumours (1) Epithelioid haemangioendothelioma (2) Angiosarcoma Other malignant mesenchymal tumours Fibrosarcoma, leiomyosarcoma, liposarcoma, and so on Miscellaneous tumours (1) Ewing sarcoma (2) Adamantinoma (3) Undifferentiated high-​grade pleomorphic sarcoma of bone Osteosarcomas account for 35% of primary bone tumours, chondrosarcomas for 26%, Ewing sarcoma for 16%, and chordoma for 8% Adapted from Gerrand C, et al. (2016). UK guidelines for the management of bone sarcomas. Clinical Sarcoma Research, 6, 7, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.org/​ licenses/​by/​4.0/​).

SECTION 20  Disorders of the skeleton 4710 further investigations should be undertaken, which may rule out the need for bone biopsy (e.g. prostate-​specific antigen (PSA) in a man older than 60 years). It is important that bone biopsies are carefully planned and only undertaken in a bone sarcoma surgical centre: they need to obtain enough tissue for diagnosis in a manner that does not compromise subsequent outcome, for example, be­ cause of the danger of tumour implantation the technique used must permit excision of the biopsy tract if the diagnosis turns out to be a primary sarcoma. In determining treatment, the main clinical distinction is between localized and metastatic disease. Two staging systems are in wide­ spread use. The Enneking system is based on histological grade (low [grade I] or high [grade III]) and anatomy (intracompartmental or extracompartmental within a limb). Some tumours such as Ewings are so aggressive they are graded as grade IV. Staging takes into account the extent of the disease, whereas grade reflects the aggres­ siveness of the histology. High grade, however, does often result in a late diagnosis with metastasis (stage IV), whereas lower grade histologies such as some chondrosarcomas often present as local dis­ ease only (most often stage II). The tumour-​node metastasis (TNM) system—​based on tumour grade, size, and the presence of metas­ tases—​is widely used for most cancers: a modified system is used by most specialists in bone cancer because other systems map better to patient outcomes. Particular types of primary bone cancer Osteosarcoma Epidemiology and clinical features Osteosarcomas account of about 1% of all tumours, with incidence peaking at ages 13–​16 years and more than 65 years. Most cases are sporadic, but risk factors include previous radiotherapy and chemo­ therapy, genetic predisposition (p53 mutation), and (in older adults) Paget’s disease. Osteosarcomas preferentially affect long bone metaphases, most commonly the distal femur and proximal tibia. Plain radiography typically reveals a lesion that destroys the normal trabecular bone pattern, has indistinct margins, and is not associated with an endosteal response (Fig. 20.6.1). Histological appearance is of a ma­ lignant sarcomatous stroma with production of osteoid and bone. Several histological subtypes are recognized, but without significant clinical differences between them. Serum alkaline phosphatase and lactate dehydrogenase may be elevated. Metastases can be detected at time of presentation in 10–​20% of cases, most commonly in the lung, but occult (undetect­ able) metastases are present in most others. Management and prognosis Patients with non​metastatic osteosarcoma are typically treated with neoadjuvant chemotherapy comprising high-​dose methotrexate, doxorubicin, and cisplatin (termed MAP), followed by surgery. Limb sparing surgery is used when possible. Patients over the age of 40 years, whose bone marrow will not tolerate high-​dose metho­ trexate, are given just the doxorubicin and cisplatin. Radiotherapy is very rarely employed unless surgery is not possible or is declined by the patient because this tumour is relatively resistant to it. The best treatment for patients presenting with metastatic osteo­ sarcoma is not known. A very few patients with lung metastases are curable. The most commonly used approach is to give MAP, as for non​metastatic disease. The Euramos trial demonstrated no benefit with ifosfamide and etoposide, but these agents are some­ times given if the disease progresses on MAP. After successful treatment, the commonest site of disease relapse is the lung. Resection may be curative in some cases, but for patients in whom this is not an option treatment is palliative, usually with chemotherapy and occasionally radiotherapy. Overall, five-​year survival of patients presenting with a primary tumour in the limb without evident metastases is about 70%, reducing to 50% if the primary tumour is in the pelvis or axial skeleton, and only 10–​50% in those who present with overt metastases. Chondrosarcoma Epidemiology and clinical features About 25% of all primary bone malignancies are chondrosarcomas, typically affecting patients aged 30–​60  years with a slight male preponderence. Most of these tumours (90%) are slow growing with low metastatic tendency, but 5–​10% are high grade and have a high propensity to metastasize, usually to the lungs. They may arise in be­ nign cartilaginous lesions (osteochondromas and enchondromas), but most are thought to arise de novo, usually within the medul­ lary cavity, most commonly of the femur, pelvic bones, and proximal humerus. The typical appearance on plain radiography is of a fusiform expansion in the metaphysis or diaphysis, with the tumour con­ taining areas of both radiolucency and sclerosis, and the cortex being thickened, without notable periosteal reaction (Fig. 20.6.2). Chondrosarcomas are distinguished histologically from osteosar­ comas by the lack of woven bone matrix. Their histological grade (World Health Organization (WHO) classification grade 1, less (a) (b) Fig. 20.6.1  Osteosarcoma. (a) An anterior–​posterior (AP) radiograph of the left knee with a large lytic lesion involving the medial femoral condyle and distal shaft (arrows) with a wide zone of transition and extension into adjacent soft tissues. The lesion contains extensive, cloud-​like densities compatible with osteoid matrix (see arrow heads). (b) A lateral view of the same lesion. Reprinted from Anderson MW, Smith SE (2013). Musculoskeletal Imaging Cases.
By permission of Oxford University Press, USA.

20.6  Bone cancer 4711 cellular, through grade 3, highly cellular) is an important predictor of tumour behaviour and prognosis. Management and prognosis Non​metastatic chondrosarcoma is treated surgically. The nature of the surgery depends critically on the site and grade of the tumour. Low-​grade central tumours of the axial skeleton and pelvis are gen­ erally treated with wide local excision, and intermediate and high-​ grade tumours with wide en bloc local excision, which may require considerable reconstruction. Most chondrosarcomas are slow growing and hence resistant to radiotherapy, but radiotherapy may be used to try to increase the chances of local control after incomplete excision of a high-​grade tumour, or palliatively in circumstances where surgery would not be possible or sensible. Protons are also used in lesions close to the spinal cord if resected and high grade or thought to be high risk of relapse. In traditional low-​grade chondrosarcomas, chemo­ therapy is generally ineffective and not used routinely, but trials with newer targeted drugs (e.g. Pazopanib, hedgehog inhibitors) are proving interesting. In higher grade tumours, cisplatin and doxorubicin-​based combination treatments may be employed in some circumstances. Ten-​year survival of patients with grade 1 chondrosarcomas is about 90%, with grade 2 about 75%, and with grade 3 about 40%. Ewing sarcoma Epidemiology and clinical features The Ewing sarcoma family of tumours are the second most common primary bone tumours (after osteosarcoma) of children and ado­ lescents, but 30% of cases are in those aged more than 20 years. Tumours most often arise in the femur, tibia, fibula, humerus, and pelvis. Constitutional symptoms (fever, sweats, weight loss) are pre­ sent in 10–​20%. The commonest sites for metastases are the lungs and skeleton. Most cases are sporadic, but some are associated with cancer pre­ disposition syndromes. Nearly all express a reciprocal translocation, typically clustered within the ESWR1 gene, which encodes an RNA binding protein. The typical radiological appearance is of a destructive lesion with a moth-​eaten appearance, a poorly defined margin, and often an as­ sociated soft tissue mass (known as onion skinning) (Fig. 20.6.3). Histological appearances range from classic Ewing sarcoma (a primi­ tive undifferentiated neoplasm) to atypical Ewing sarcoma (with larger and more pleomorphic cells) to a primitive neuroectodermal tumour (with neural immunophenotype or differentiation). Genetic analysis is now a cornerstone of diagnosis and frequently done by fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR). Management and prognosis Treatment of patients with localized disease typically begins with six to nine cycles of induction or neoadjuvant chemotherapy to reduce tumour bulk, followed by surgical resection (if possible) and/​or radiotherapy, with a further six to eight cycles of chemo­ therapy given postoperatively. The most active agents are doxo­ rubicin, cyclophosphamide, ifosfamide, vincristine, dactinomycin, and etoposide, and most protocols are based on combinations of four to six of these drugs. Radiotherapy is used when surgical resection is not possible, or sometimes preoperatively or in add­ ition to surgery. Patients with metastases often respond to chemotherapy as used for localized disease. Five-​year survival of patients presenting with localized disease is about 70% in limb tumours and 50% for pelvic tumours, compared to about one in three for those with metastases revealed at diagnosis. Long-​term survivors have a high incidence of second malignancies, pathological fractures and other complications of chemotherapy and radiotherapy, including myelodysplasia and leukaemia. (b) (c) (a) Fig. 20.6.2  Low-​grade chondrosarcoma. (a) AP radiograph showing ring and arc lobular mineralization within the distal left femoral diametaphysis (large arrows) with endosteal scalloping of the medial femoral cortex (small arrows). (b) Coronal T1 and (c) coronal short TI inversion recovery (STIR) are MR images demonstrating the same lobulated intramedullary metadiaphyseal femoral mass (large arrows), predominantly T1 hypointense and STIR heterogeneously hyperintense, demonstrating both T1 and STIR ring and arc-​like marked hypointensities consistent with mineralization. MR confirms endosteal scalloping (small arrows), extension into the epiphysis abutting the intercondylar notch without soft tissue extension, periosteal reaction, surrounding bone marrow oedema, or fracture. Reprinted from Anderson MW, Smith SE (2013). Musculoskeletal Imaging Cases. By permission of Oxford University Press, USA.

SECTION 20  Disorders of the skeleton 4712 Bony metastases Epidemiology and clinical features Metastases are the most frequent type of tumour found in bone, with most in adults being due to breast, prostate, lung, pancreas, kidney, and thyroid cancer. Many cause no symptoms and are de­ tected during initial staging of the index cancer, but typical clinical presentations include the local manifestations of pain, pathological fracture and spinal cord compression, and the systemic manifest­ ation of hypercalcaemia. The radiological appearances of metastases can be very varied, but osteoblastic lesions are typical of prostate and breast cancer, and lytic lesions of lung, kidney, and thyroid cancer (Fig. 20.6.4). In a patient with a known primary and/​or multiple bony lesions, metastases can be safely presumed, but biopsy is required when there is a possibility of an­ other diagnosis (e.g. a benign lesion or a second primary malignancy). By contrast to the situation of suspected primary bone sarcoma, pa­ tients with a known active cancer or multiple metastases can have bone biopsies performed in any hospital with appropriate facilities. Management and prognosis Sensible management requires assessment of the complete clinical picture. An asymptomatic bony metastasis with no significant local risk should simply be observed in a patient with a limited life ex­ pectancy, and surgical intervention of any sort is almost certainly inappropriate in any circumstance in a patient who is moribund. All patients with symptomatic bony metastases require adequate analgesia. External beam radiotherapy is the standard approach and often provides effective pain relief. Osteoclast inhibition with par­ enteral bisphosphonates or denosumab have analgesic effect and re­ duce skeletal-​related events. The use of other treatments depends on assessment of the patient’s overall condition and the particular cancer type. Surgery is typically reserved for metastases with impending or actual pathological frac­ ture and is very effective in providing pain relief and in maintaining or improving function. Aggressive local resection may be appro­ priate for those with a few isolated bone lesions and a favourable tumour type (e.g. renal carcinoma). Surgery is generally followed by postoperative radiotherapy. Use of chemotherapy will depend on tumour type. (b) (c) (d) (a) Fig. 20.6.3  Ewing sarcoma. (a) AP projection and (b) lateral projection are radiographs of a moth-​eaten/​permeative, destructive distal tibial metadiaphyseal lesion with aggressive periosteal reaction and soft tissue swelling (arrows). Coronal T1-​weighted (c) and STIR (d) MR images show a low-​signal (on T1-​weighted image) and high-​signal (STIR image) distal tibial lesion (arrows) with soft tissue component extending beyond cortex (arrowheads). Reprinted from Anderson MW, Smith SE (2013). Musculoskeletal Imaging Cases. By permission of Oxford University Press, USA. Fig. 20.6.4  Cortical metastasis from primary bronchogenic carcinoma. Lateral femoral radiograph showing a concave ‘cookie bite’. There is a cortical defect and destruction (white arrows) with an associated periosteal reaction and apparent uplifting of the cortical bone (black arrows). Reprinted from Anderson MW, Smith SE (2013). Musculoskeletal Imaging Cases.
By permission of Oxford University Press, USA.

20.6  Bone cancer 4713 FURTHER READING Biermann JS, et al. (2017). NCCN guidelines insights: bone cancer, version 2.2017. J Natl Compr Canc Netw, 15, 155–​67. Fletcher CD, et al. (eds) (2013). WHO classification of tumours of soft tissue and bone, 4th edition. France IARC Press, Lyon. Gerrand C, et al. (2016). UK guidelines for the management of bone sarcomas. Clinical Sarcoma Research, 6, 7. The ESMO/​European Sarcoma Network Working Group (2014). Bone sarcomas:  ESMO clinical practice guidelines for diagnosis, treat­ ment and follow up. Ann Oncol, 25(Supp 3), iii113–​iii123.

SECTION 21 Disorders of the kidney and urinary tract Section editor: John D. Firth 21.1 Structure and function of the kidney  4717 Steve Harper and Robert Unwin 21.2 Electrolyte disorders  4729 21.2.1 Disorders of water and sodium homeostasis  4729 Michael L. Moritz and Juan Carlos Ayus 21.2.2 Disorders of potassium homeostasis  4748 John D. Firth 21.3 Clinical presentation of renal disease  4764 Richard E. Fielding and Ken Farrington 21.4 Clinical investigation of renal disease  4781 Andrew Davenport 21.5 Acute kidney injury  4807 John D. Firth 21.6 Chronic kidney disease  4830 Alastair Hutchison 21.7 Renal replacement therapy  4861 21.7.1 Haemodialysis  4861 Robert Mactier 21.7.2 Peritoneal dialysis  4874 Simon Davies 21.7.3 Renal transplantation  4879 Nicholas Torpey and John D. Firth 21.8 Glomerular diseases  4909 21.8.1 Immunoglobulin A nephropathy and
Henoch–​Schönlein purpura  4909 Jonathan Barratt and John Feehally 21.8.2 Thin membrane nephropathy  4918 Peter Topham and John Feehally 21.8.3 Minimal-​change nephropathy and focal segmental glomerulosclerosis  4919 Moin Saleem and Lisa Willcocks 21.8.4 Membranous nephropathy  4928 An S. De Vriese and Fernando C. Fervenza 21.8.5 Proliferative glomerulonephritis  4933 Alan D. Salama and Mark A. Little 21.8.6 Membranoproliferative glomerulonephritis  4937 Tabitha Turner-​Stokes and Mark A. Little 21.8.7 Antiglomerular basement membrane disease  4943 Mårten Segelmark and Thomas Hellmark 21.9 Tubulointerstitial diseases  4951 21.9.1 Acute interstitial nephritis  4951 Simon D. Roger 21.9.2 Chronic tubulointerstitial nephritis  4956 Marc E. De Broe, Channa Yamasumana,
Patrick C. D’Haese, Monique M. Elseviers,
and Benjamin Vervaet 21.10 The kidney in systemic disease  4975 21.10.1 Diabetes mellitus and the kidney  4975 Rudolf Bilous 21.10.2 The kidney in systemic vasculitis  4988 David Jayne 21.10.3 The kidney in rheumatological disorders  5001 Liz Lightstone and Hannah Beckwith 21.10.4 The kidney in sarcoidosis  5012 Ingeborg Hilderson and Jan Donck 21.10.5 Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias  5016 Pierre Ronco, Frank Bridoux, and
Arnaud Jaccard 21.10.6 Haemolytic uraemic syndrome  5027 Edwin K.S. Wong and David Kavanagh

21.10.7 Sickle cell disease and the kidney  5032 Claire C. Sharpe 21.10.8 Infection-​associated nephropathies  5034 A. Neil Turner 21.10.9 Malignancy-​associated renal disease  5041 A. Neil Turner 21.10.10 Atherosclerotic renovascular disease  5044 Philip A. Kalra and Diana Vassallo 21.11 Renal diseases in the tropics  5049 Vivekanand Jha 21.12 Renal involvement in genetic disease  5065 D. Joly and J.P. Grünfeld 21.13 Urinary tract infection  5074 Charles Tomson and Neil Sheerin 21.14 Disorders of renal calcium handling, urinary stones, and nephrocalcinosis  5093 Christopher Pugh, Elaine M. Worcester, Andrew P. Evan,
and Fredric L. Coe 21.15 The renal tubular acidoses  5104 John A. Sayer and Fiona E. Karet 21.16 Disorders of tubular electrolyte handling  5112 Nine V.A.M. Knoers and Elena N. Levtchenko 21.17 Urinary tract obstruction  5124 Muhammad M. Yaqoob and Kieran McCafferty 21.18 Malignant diseases of the urinary tract  5136 Tim Eisen, Freddie C. Hamdy, and Robert A. Huddart 21.19 Drugs and the kidney  5150 Aine Burns and Caroline Ashley SECTION 21  Disorders of the kidney and urinary tract