as a whole. Radiological \201 ndings are of diffuse pulmonary in \201 ltrates At 5 years a survival \201 gure of 67 \200\22378% is reported for WG, 63 \200\22369% is r eported for CSS and 45 \200\22353% for MP. \200 Predictors of disease relapse include a d iagnosis of WG, ENT or pulmonary or gastrointestinal involvement, PR-3 ANCA and carriage of Staphylococcus aureus and ground glass changes on HRCT (Fig. 12.3.4). If a baseline value is available for comparison DAH is associated with a drop in hemoglobin. If patients are well enough to undertake a diffusing capacity for carbon monoxide (DLCO) te st it is elevated. Management of airway stenosis in WG Stenotic airways disease can occur in up to 30% of pati ents. At the time of bronchoscopy only a minority have active endobronchial disease. Manage ment should be to actively treat WG and avoid interventions. If this is not possible a mini mal invasive procedure should be undertaken. These include dilation, corticosteroid injecti ons and conservative laser surgery. Tracheostomy and stenting should be avoided if possible . Bronchoscopic lavage is characterized by lavage return that fails to clear in contrast to e ndobronchial bleeding. Lavage should be sent for culture to exclude infection. Speci \201 c test including urine analysis and serological tests for ANCA, anti-GBM antibo dies, anti-nuclear antibodies, anti-phospholipid antibodies and rheumatoid factor as well a s complement together with creatinine kinase should be considered. Diffuse alveolar hemorrhage Biopsies of the kidneys should be considered if a Damage to the alveolar-capillary basement membrane results in \201 lling of the alveolar spaces with blood. Bleeding pulmonary-renal syndrome is suspected. P SIVASOTHY 278 Epidemiology \200 It is a rare disorder occurring in one in million. \200 It is associa ted with cigarette smoking or exposure to Treatment \200 In severe cases treatment cannot be delayed pending the results of serological or biopsy results. If infection and DAH without capillaritis have been excluded immunesuppres and DAH without capillaritis have with corticosteroid (methylprednisolone 1g/day for 3 \200\2235 days) with cyclophosphamide (2 mg/kg/day). inhaled hydrocarbons. Young men are prone to develop pulmonary hemorrhage. \200 Pulmonary hemorrhage without re nal disease is rare. \200 DAH can occur due to bland hemorrhage as well as In unstable severe disease due to systemic autoimmune pulmonary capillaritis. process plasma exchange should considered. An overlap syndrome of AASV and anti-GBM disease Factor VII concentrate have been used achieve haemos- exists. tasis in severe bleeding. Clinical features \200 In 25 \200\22330% of patients, a prodromal period of \202 u like Prognosis \200 Repeated DAH can result in pulmonary \201 brosis espe- cially in patient s with MP, WG, idiopathic haemosiderosis and mitral stenosis. illness occurs. Pulmonary manifestations: The insidious onset with symptoms lethargy, dyspnoea upon exertion, and, sometimes, dry cou gh. Occasionally acute onset with fever, massive haemo- ptysis and acute respiratory failur e. Obstructive features can also develop post DAH. Anti-glomerular basement antibody disease ( Goodpasture \200\231s syndrome) Renal manifestations: Pathogenesis The role of anti-GBM antibodies in the pathogenicity of Goodpastures syndrome has been shown in vivo studies. Antibodies were passively transferred from humans to mon- k eys who went on to develop glomerulonephritis. The pri- mary antigen was subsequently ident i \201 ed as component of the A3 chain of type IV collagen of basement membranes. Usually presents with an abrupt onset of oliguria or anuria. Rarely, the patient \200\231s renal involvement is more insidi- ous in onset and he or she remains asymptomatic, progress ing slowly until the development of uraemia symptoms Diagnosis \200 Urine analysis. \200 Anti-GBM antibodies. \200 ANCA, up to 32% of pati ents testing positive for Table 12.3.5 Causes of diffuse alveolar hemorrhage with pulmonary capillaritis Primary vasculitis anti-GBM will test positive for ANCA. ANCA associated vasculitis Renal biopsy. Typical features are a crescentric glomeru- lonephritis with immunefluorescen ce microscopy demonstrates a linear deposit along the capillaries. WG Beh ets disease CSS Henoch \200\223Sch nlein purpura Treatment \200 Plasmapheresis with concomitant use of corticosteroids Microscopic polyangiitis Pauci-immune pulmonary capillaritis and cyclophosphamide. Secondary vasculitis Patients should be asked to stop smoking. Prognosis \200 Patients who survive the \201 rst year with near normal Collagen vascular disease Mixed connective tissue disease Rheumatoid arthritis Polymyositis Systemic lupus erythematosus Anti-phospholipid syndrome renal function do well. Relapses are rare and when they do occur may re \202 ect Drug-induced vasculitis relapse of the AASV. Good pastures syndrome Bone marrow transplant Summary \200 Pulmonary involvement in primary systemic vasculitis is common especially in the AASV. Table 12.3.6 Causes of diffuse alveolar hemorrhage without pulmonary capillaritis Management relies on early clinical diagnosis and treat- ment to minimize the morbidity and mortality associ- ated with the disease and its treatment. Inhalation toxins Mitral stenosis Severe coagulopathy Anti-glomerular basement membrane dis ease Infections ARDS Idiopathic pulmonary haemosiderosis Lymphangioleiomyomatosis Tuberous sclerosis Pulmonary capillary haemangiomatosis Pulmonary veno-occlusive disease Neoplasms \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Choice of treatment depends on the clinical severity of disease. Advances current medical therapy is unlikely to result in disease free remission and cure t he disease in the majority of patients. Support groups \200 http://www.vasculitisfoundation.org \200 http://www.vasculitis-uk.o rg.uk CHAPTER 12.3 Pulmonary vasculitis and hemorrhage 279 Further reading Bosch X, Guilabert A, Font J. Antineutrophilic cytoplasmic antibodies. Lancet 2006; 368: 404 \200\223414. Brown K. Pulmonary Vasculitis. Proc Am Thorac Soc 2007; 3:48 \200\22357. Jennette JC, Xiao H, Falk RJ. Pathogenesis of vascular in \202 ammation by anti-neutrophil cytoplasmic antib odies J Am Soc Nephrol 2006; 17: 1235 \200\2231242. Lane SE, Watts RA, Shepstone L, et al. Primary systemic vasculitis: clinical features and m ortality. QJM 2005; 98: 97 \200\223111. Lee AS, Specks U. Papillary capillaritis. Semin Res pir Crit Care 2004; 25:547 \200\223555. Pesci A and Manganelli P. Respiratory system involvement in antineutrophil cytoplasmic-asso ciated systemic vasculitides. Drugs RD 2007; 8:25 \200\22342. Smyth L, Gaskin G, Pusey G. Microscopic polyangittis. Semin Respir Crit Care Med 2004; 25: 523 \200\223533. Watt RA, Lane SE, Bentham G, Scott DG. Epidemiology of systemic vasculitis. A ten year stud y in the United Kingdom. Arthritis and Rheumatism 2000; 43: 414 \200\223419. (a) (b) 12.3.4 Radiographic appearance of diffuse alveolar hemorrhage (a) CXR showing bilateral gro und in \201 ltrates (b) HRCT showing ground glass changes within which areas of consolidat ion are seen. This page intentionally left blank 281 Chapter 13 Lung cancer Chapter contents 13.1 Epidemiology of lung cancer 282 13.2 Symptoms and signs (including SVCO) 284 13.3 Work -up of patients with a suspected diagnosis of lung cancer 288 13.4 Treatment of non-small c ell lung cancer 292 13.5 Treatment of small cell lung cancer 298 13.6 PET-CT 300 13.7 Lung cancer screening 304 13.8 Carcinoid 306 13.9 Benign lung tumors 310 13.10 Transbronchial \201 ne needle aspiration 316 13.11 Interventional bronchoscopy techniques 318 R HUBBARD 282 13.1 Epidemiology of lung cancer Incidence and mortality \200 AUTHOR \200\231S TIPS \200 Lung cancer \201 rst emerged as a threat to the public health during the early part of th e 20th century and since this time an epidemic of the disease has evolved. Lung cancer is n ow the leading cause of cancer deaths in the UK and a number of other developed countries. In 2004 in England and Wales lung cancer was the sec- ond most common cancer diagnosed in t he UK (exclud- ing non-melanomatous skin cancer), with more than 30,000 new cases being reg istered. The most common cancer was breast cancer with 37,000 new cases. Lung cancer is pre dominantly a disease of older people. The commonest age of presentation is between 75 \200 \22379 years of age and 85% of registrations occur in people over the age of 60 years and 6 0% of registrations in people over the age of 70 years. The male to female lung cancer inci dence ratio is approximately 1.5 to 1. The lung cancer epidemic is women is slightly differ ent to that in men in that the peak will occur later and will probably not be as high. At p resent lung cancer incidence rates continue to increase in older age groups in both men and women, but in younger men the incidence is beginning to fall re \202 ecting a fall in smo king prevalence. The incidence of lung cancer rises steeply with increas- ing levels of soc ial deprivation, and the size of this gradi- ent is higher than that seen for other cancers . In people of working age mortality rates from lung cancer are 4.6 times higher in people who are unskilled manual work- ers compared to professional people. An analysis of the Heal th Survey for England found a strong social class gradient in plasma cotinine levels in smo kers, even after allowing for number of cigarettes smoked per day. These data suggests that the level of nicotine dependence may well be related to socio-economic status. Data from t he USA demonstrate that lung cancer inci- dence rates are higher amongst black people than white people, particularly in the people with more years of education. Within Great Britain and Ireland lung cancer mortality rates are highest in people who were born in Scotland, f ollowed by Ireland and then West Africa. Lung cancer occurs throughout the world wherever p eople smoke. Although some of the lowest lung cancer incidence rates are currently found in Africa and other developing countries, as smoking becomes more com- mon the lung cancer ep idemic will inevitably follow. A diagnosis of lung cancer carries a poor prognosis and the outlook for people with lung ca ncer is far worse than that for people with cancers at other sites. Only 25% of people diag nosed with lung cancer are alive at one year and this \201 gure drops to 7% at 5 years. ( http://info.cancerresearchuk. org/cancerstats) Without treatment SCLC has a median survival or only a few months. With treatment people with exten- sive disease have a median surviva l of about 6 months, and those with limited disease have a median survival of 9 \200\22312 months. The prognosis of non-small cell lung cancer (NSCLC) is slightly better with one yea r sur- vival rates of between 25 to 45%. Etiology Cigarette smoking Cigarette smoking is by some way the most important cause of lun g cancer and is believe to be implicated in the etiology of approximately 90% of lung cance rs. The link between smoking and lung cancer was reported in land- mark mark studies by Dol l and Hill in the UK and Wynder and Graham in the USA both reported in 1950. These studies were important not only in showing the strength of the association between smoking and lung cancer but also in driving the development of epidemiology. There are ear- lier studies wh ich reported a link between lung cancer and smoking, notably a case \200\223control study f rom Germany re- ported in 1943. The results of the 50 year follow-up of the British Doctors cohort suggest that in comparison to lifelong non-smokers the incidence of dying from lung cancer is 15 times higher in current smokers and 4 times higher in former smokers. Amongst current smokers the incidence of lung cancer is also strongly related to cigarettes smoked per day (Fig. 13.1.1). r a e y 450 400 350 300 250 200 150 100 50 0 r e p 0 0 0 0 0 1 , r e p y t i l a t r o M Lifelong non- smoker Former smoker Current smoker 1 \200\22314 CPD 15 \200\22324 CPD >25 CPD Changes in histological type In early studies of lung cancer in the 1950s squamous cell car cinoma was by some way the most prominent histological type, followed by small cell lung ca ncer (SCLC). From the late 1970s a progressive increase in the incidence of adenocarcinoma has occurred, perhaps because the level of some tobacco speci \201 c nitrosamines have inc rease. Recent studies suggest that in women adenocarcinoma is now the most common type of l ung cancer, followed by squamous cell, small cell and then large cell, whilst in men adenoc arcinoma is now as common as squamous cell lung cancer. Smoking category Fig.13.1.1 Lung cancer in the British Doctor cohort. Cigarette smoking is strongly related to the risk of devel- oping all histological types of lung cancer but overall the associations are strongest with SCLC and squamous cell lung ca ncer and weaker with adenocarcinoma. The risk of lung cancer is more strongly related to th e dura- tion of smoking that the number of cigarettes smoked per day. In other words amongs t people with the same number of pack-years of smoking the risk of developing lung cancer i s higher amongst those who have smoked for longer. CHAPTER 13.1 Epidemiology of lung cancer 283 Further reading Albano JD, Ward E, Jemal A, et al. Cancer mortality in the United States by education level and race. J Natl Cancer Inst 2007; 99(18):1384 \200\2231394. The risk of lung cancer falls with time after people stop smoking, but there is still a dou bling of lung cancer risk for moderate to heavy smokers compared to never-smokers 30 years after quitting. The move towards lower tar and nicotine cigarettes has not reduced the risk s associated with smoking because smokers rapidly learn to compensate by taking greater puf f volumes and blocking ventilation holes and thereby maintain their supply of nicotine. The association between exposure to environmental tobacco smoke and lung cancer risk is more d if \201 cult to study than the association with active smoking, but current estimates sugg est a 20 to 30% increase with regular exposure. Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest 2003; 123(1 Suppl): 21S \200\22349S. Doll R, Peto R, Boreham J, et al. Mortality from cancer in relation to smoking: 50 years ob servations on British doctors. Br J Cancer 2005; 92(3):426 \200\223429. Kiyohara C, Otsu A, Shirakawa T, et al. Genetic polymorphisms and lung cancer susceptibilit y: a review. Lung Cancer 2002; 37(3):241 \200\223256. Of \201 ce for National Statistics. Cancer statistics: registrations of can- cer diagnosed in 2004, England. MB1 no. 35, 1-88. 2004. London, Of \201 ce for National Statistics. Of \201 ce for National Statistics. Mortality statistics: Cause. Review of the Registrar G eneral on deaths by cause, sex and age, in England and Wales, 2004. DH2 no. 31, i-280. 2005 . London, Of \201 ce for National Statistics. Other factors Diet There are data from a number of studies which suggest that diets which h ave higher levels of fruit and vegetables may reduce the risk of developing lung cancer. Th e main methodological problems with these studies are issue of accurately measuring diet an d the problem of not control- ling completely for the effect of cigarette smoking. Pershagen G, Akerblom G, Axelson O, et al. Residential radon exposure and lung cancer in Sw eden. N Engl J Med 1994; 330(3):159 \200\223164. Peto R, Darby S, Deo H, et al. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ 2000; 321(7257) :323 \200\223329. Schairer E, Schoniger E. Lung cancer and tobacco consumption. Int Occupation Studies of asbestos textile workers in the UK and insula- tion workers in the Un ited States suggest that working with asbestos is associated with a 7 \200\22310-fold incre ase in the risk of lung cancer and that this risk peaks 30 \200\22335 years after the \201 rst exposure to asbestos. Workers who are exposed to tar and soot, arsenic, chromium a nd nickel may also have an increased risk of lung cancer. J Epidemiol 2001; 30(1):24 \200\22327. Silvestri GA, Spiro SG. Carcinoma of the bronchus 60 years later. Thorax 2006; 61(12):1023 \200\2231028. The British Thoracic Society. The burden of lung disease: a statisti- cal report from the B ritish Thoracic Society 2006. 2006. London, The British Thoracic Society. Wild SH, Fischbacher CM, Brock A, et al. Mortality from all cancers and lung, colorectal, b reast and prostate cancer by country of birth in England and Wales, 2001-2003. Br J Cancer 2006; 94(7):1079 \200\2231085. Radiation Exposure to high levels of radon, for instance in uranium miners, is an establish ed cause of lung cancer. Radon expo- sure at a much lower level occurs as an indoor polluta nt and there are data from a case control study which suggest that this is associated with an increased risk of lung cancer, the risk being approximately double in those people livin g in houses with the highest level of exposure compared to those with the lowest exposure. Wynder EL, Hoffmann D. Re: Cigarette smoking and the histopa- thology of lung cancer. J Nat l Cancer Inst 1998; 90(19): 1486 \200\2231488. Wynder EL. Tobacco as a cause of lung cancer: some re \202 ections. Am J Epidemiol 1997; 146(9):687 \200\223694. Genetics There is some evidence that polymorphisms in genes which code for enzymes which ma y metabolize cigarette carcinogens may have an in \202 uence on the risk of developing lun g cancer. Such genes include: \200 Enzymes in the cytochrome p450 system (CYP1A1 and CYP2D6). Glutathione S-transferase. Micro somal epoxide hydrolase. NAD(P)H quinine oxidoreductase. Myeloperoxidase. \200 \200 \200 C HOOPER 284 13.2 Symptoms and signs (including SVCO) Lung cancer presents clinically at an advanced stage with 80% of patients having inoperable disease at diagnosis. \200 subclavian artery, near to the brachial plexus. Non-small cell lung cancer (NSCLC) is the m ost common cause with 5% of NSCLC arising in this area. Other neoplasms, in addition to var ious in \202 ammatory and infective processes can cause \200\230Pancoast syndrome \200 \231 so histological diagnosis is essential. Only 5-10% of newly diagnosed lung cancers present incidentally with asymptomatic lesions o n CXRs or CT scans. This proportion is set to increase with the availa- bility of total bod y screening scans to the asymptomatic general public, and ongoing interval CT scanning foll ow- ing treatment for other malignancies. At least 90% of patients with lung cancer are sym pto- matic at diagnosis and many report having new symptoms for up to a year prior to prese ntation. Patients may present with symptoms relating to the primary tumor, metastatic sprea d, paraneoplastic phe- nomena or a combination of these. Clinical features of \200\230Pancoast syndrome \200\231 \200 In \201 ltration of C8, T1, T2 nerve roots causes gnawing pain over the shoulder medial bo rder of the scapula, pro- gressing down the medial aspect of the arm to the little and ring \201 ngers. Often delayed diagnosis as a mechanical, musculoskeletal cause is pursued. W eakness of the intrinsic hand muscles and loss of the triceps re \202 ex occur. Horners sy ndrome (ptsosis, meiosis, enopthalmos, narrowed palpebral \201 ssure and anhydrosis) may also occur ipsilaterally when C6 and T1 segments of the sympathetic chain are involved. The re may be associated rib, vertebral body, spinal cord or mediastinal invasion and destructi on. Local tumor effects Cough, dyspnoea, chest pain and haemoptysis are common in patients pres enting with lung cancer. Cough occurs in response to bronchial mucosal ulcera- tion, interr uption of bronchial peristalsis, post-obstructive pneumonia and infection; all more common in central air- way tumors. Dyspnoea (new or worsening) is present in up to 60% of patients . It is caused by: \200 \200 Diagnosis and staging \200 CXR may reveal subtle opacity at the lung apex while CT thorax allows visualization of the tumor and initial staging. CT guided biopsy has a diagnostic yield of 90% and is the method of choice for obtaining histology in superior sul- cus tumors ( \201 breoptic bronchoscop y carries a 30 \200\22340% success rate) MRI scan is essential in potential surgical candid ates, to establish the degree of brachial plexus involvement and adds useful information re garding chest wall and vascular invasion. A total body PET scan should be performed as in o ther lung cancer patients considered for radical therapy. Accurate staging is particularly important given the delicate anatomy of the region and high peri-operative mortality. Panco ast tumors are typically staged IIB (T3 N0 M0) or greater. Persistent infection or atelectasis. Central airway obstruction ( \201 xed unilateral insp iratory wheeze or stridor may be audible). Pleural and pericardial effusions, thromboemboli , and lymphangitis carcinomatosis (occurring in more advanced disease). Chest pain is common in localized, operable disease when patients describe an intermittent ache on the side of the tumor. Intractable pain may arise from invasion of chest wall struc tures in more advanced disease. Haemoptysis in lung cancer is usually low volume blood stre aking of sputum, occurring over a number of days prior to presentation. Massive haemoptysis due to erosion through bronchial or pulmonary vessels occurs infre- quently. Lung cancer a ccounts for around 30% of haemoptysis. In smokers over 40 years of age with hae- moptysis, if the CXR is normal, CT thorax followed by bronchoscopy should be pursued as a lung cancer will be diagnosed in 6%. Management and prognosis Aquequate analgesia should be prescribed, however pain is often re sistant to such simple measures. \200 Effects due to intrathoracic spread Dysphagia, hoarse voice, pleural effusion, hydropneumo- thorax, and pericardial effusion or tamponade are usually associated with invasion of intr athoracic structures in this setting. Pancoast syndrome and superior vena cava obstruction are examples of locally invasive disease, associated with unique symptoms, signs, diagnosti c and management challenges. Clinical practice is moving towards a tri modality approach to treatment (chemotherapy, rad iotherapy and surgery following restaging, to render locally extensive disease operable) wh ich has been associated with 5-year survival rates of up to 46%. Vertebral body, rib, subcl avian artery or sympathetic chain invasion or N2/3 nodes have a poor prognosis. Superior su lcus tumors carry a particularly high risk of brain metastases, however routine pre operati ve brain scanning and prophylactic cranial irradiation remain controversial areas. Pancoast tumors (superior sulcus tumors) Superior sulcus tumors arise posteriorly in the ap ex of an upper lobe, in the groove created by the passage of the CHAPTER 13. 2 Symptoms and signs (including SVCO) 285 Clinical features Reduction of venous return from the upper body is responsible for the dis tressing symptoms of \200\230SVC syndrome \200\231 (SVCS): \200 Oedema, venous distension and plethora of the head, neck, arms and thorax. Headache. Breath lessness, hypoxia, pulmonary oedema. Laryngeal oedema with stridor. Symptoms exacerbated by bending forward, lifting arms above the head and lying \202 at. Symptoms and signs of a lung primary or mediastinal mass (cough, hoarse voice, dysphagia). \200 \200 \200 Severity is determined by the speed and anatomical level (lower is more severe) of vascular occlusion. Chronic obstruction allows the development of collateral venous drainage, in wh ich context patients may be relatively asymptomatic. In lung cancer, SVCO commonly progress es rapidly over weeks resulting in a \202 orid presentation. Etiology Malignancy accounts for 90% of SVCO with SCLC and NHL being responsible for the ma jority. Metastatic tumors and primary malignancies arising from the medi- astinum are less common causes. Thrombus propagated by central venous lines and pacemaker wires may result i n SVCO. There are many other recognized non-malignant, vascular, infective and in \202 amm atory causes. Investigation CTX may demonstrate mediastinal widening, pleural effusion or clear evidence of the primary tumor. Abnormal in 85%. CT thorax will con \201 rm the presence of a medias tinal mass or other causative process in addition to staging the tumor and confirming the p resence of intravascular thrombus and degree and level of venous collaterals. Tissue diagno sis is obtained by the most minimally invasive approach available and is guided by the radi ological appearances. Fig. 13.2.1 Presentation CXR and MRI of a patient with a left Pancoast tumor invading the b rachial plexus. Management Immediate. sit the patient up, prescribe oxygen, and analgesia.Treat pulmonary o edema if present. De \201 nitive oncological management reflects histological cell type, s tage and performance status. Radiotherapy prior to obtaining histology may compromise an ac curate tissue diagnosis and the planning of optimal therapy thereafter. Likewise, corticost eroids may alter histology in lymphoma and should be avoided if this diagnosis is a possibi lity until it can be con \201 rmed. Chemotherapy provides relief of SVCOS in up to 77% of patients with SCLC and radio- therapy in 60 \200\22365% of NSCLC. Combined modality approac hes may be taken with similar response rates. SVCO relapse rates are 17% and 19% respective ly. Sympto- matic resolution occurs within 7 \200\22321 days of initiating de \201 nitive treatment. Intravascular stenting is performed under radiological guidance and can achieve resolution of headache and facial oedema within 24 hours with improvement of other symptoms within three days. KEY ISSUES Pancoast tumors The CXR may be falsely reassuring. MRI scanning of the brachial plexus is essential in staging potentially resectable tumors. Superior vena cava obstruction (SVCO) Lung cancer is the most common cause of SVCO. It occu rs due to invasion or extrinsic compression by tumor or lymph nodes and is frequently accom panied by intravascular thrombosis. \200 Present at diagnosis in around 10% of patients with small cell and 2% with NSCLC. Its prese nce at diagnosis is a poor prognostic indicator, particularly in NSCLC where it is a marker of advanced stage. C HOOPER 286 Stenting does not preclude obtaining histology at a later time or subsequent chemo or radio therapy and can be performed when the SVC is completely occluded with tumor or thrombus. In lung cancer, symptomatic response rates are 95% with an 11% relapse rate, comparing favor- ably with chemo and radiotherapy. Stent occlusion can be managed with repeat stenting. Ste nt migration, vascular trauma and bleeding have been infrequently reported. Current evidenc e supports a move towards \201 rst line use of stenting, particularly in patients with NS CLC. Anticoagulation is controversial. Some advocate pro- phylactic anticoagulation in the presence of SVCO and use of low dose warfarin in stented patients to achieve an INR of arou nd 1.6 is common practice. This is not supported by trial data at present and carries a sli ghtly increased risk of intracranial hemorrhage. Steroids are frequently used in patients w ith SVCO despite an absence of evidence to support their effective- ness. If prescribed, hi stology should be obtained \201 rst and prolonged, high dose courses avoided. 70% of patients presenting with symptomatic brain metastases have a primary lung malignancy . Non-speci \201 c systemic effects Cachexia, anorexia, malaise, fever occur in around 20% o f patients with metastatic disease and may result in a fall in performance status that prec ludes palliative chemothera- peutic approaches. Tumor necrosis factor-A is thought to be an important mediator of these symptoms. Although more common in the presence of a heavy tumo r load, the syndrome can occur in localized disease. Paraneoplastic syndromes These disorders are usually mediated by peptide-proteins with horm onal or immunological activity, produced by the tumor or in response to it, having effects distant from the primary tumor and unrelated to metastases. \200 Paraneoplastic syndromes occur in a clinically signi \201 cant form in 10 \200\22320% of p atients with lung cancer. Importantly, the syndromes may predate diagnosis of malignancy by years when they should stimulate a detailed search for an underlying tumor which may be at a curable stage. They also occur in advanced disease or may herald a recurrence. Although speci \201 c symptomatic treatment is available for some syndromes, the majority respond t o conventional management of the underlying tumor. KEY POINTS SVCO Obtain an urgent histological diagnosis and staging before de \201 nitive treatment i s initiated. The majority of patients with SVCO do not experience a signi \201 cant deteri oration in the time taken to achieve this. Clubbing is the most common paraneoplastic presentation, occurring in up to 30% of patients with lung cancer, most frequently in NSCLC. It is usually asymptomatic. The main diagnosti c criteria is a digital pro \201 le angle of greater than 180 . Hypertrophic pulmonary os teoarthropathy is the presence of gross digital clubbing with painful peri-articular subper iostial bone deposition, causing swelling of the wrists, ankles and knees. Clubbing may res olve and HPOA improve with treatment of the underlying tumor. Both are recognized in other conditions, particularly chronic sup- purative lung disease. Hypercalcaemia is detected in 1% at presentation and occurs in the course of the disease in 40%. It is most frequently ca used by bone metastases but may result from PTHrP production, particularly by NSCLC. Standa rd man- agement of hypercalcaemia applies. There is little practical value in measuring PTH rP. Cushing \200\231s syndrome occurs in up to 5% of patients with SCLC although detection of high levels of ACTH in serum without related symptoms occurs in more than 50%. The syndr ome carries a poor prognosis with an increased risk of opportunistic infections and poor tu mor response to chemotherapy. Presentation is tempered by the presence of malignancy and we ight loss, psychosis and peripheral oedema are dominant symptoms. Diagnosis is based on the presence of increased 24-hour urinary free cortisol secretion, increased plasma cortisol a nd ACTH which does not reduce with a high dose dexam- ethasone suppression test. In additio n to treatment of the underlying malignancy, symptoms may respond to suppression of ACTH pr oduc- tion by octreotide and or steroid synthesis by metyrapone or ketoconazole. Bilateral adrenalectomy has been used in severe resistant cases. SIADH occurs in 1 \200\2235% of pati ents with SCLC with elevated ADH levels detectable in 70%. Severe hyponatraemia causes chan ges in mental status, lethargy and seizures. Fig. 13.2.2 SCLC causing SVCO. Multiple chest wall venous collaterals are visable on CT sca n. Effects due to distant metastases Extrathoracic metastases are present in up to 30% of patients at presentation. Many are asy mptomatic. Common sites are: Liver which may cause pain, fever, anorexia, weight loss and c arries a particularly poor prognosis. Adrenal glands \200\223 clinically silent. Usually d etected on CT and or PET scan. Bone, causing well localized pain, hypercalcaemia and pathol ogical fractures. The vertebrae, ribs, femurs and pelvis are most frequently involved. Exte nsion of vertebral metastases is the most common cause of spinal cord compression in this s etting. Brain, which may present with headache, signs of raised intracranial pressure, seiz ures, and focal neurological signs. CHAPTER 13. 2 Symptoms and signs (including SVCO) 287 Diagnosis relies on demonstrating reduced serum osmola- lity and sodium in the presence of inappropriately high urine osmolality and sodium excretion. Management with \202 uid rest riction is usually adequate but demeclocycline (which blocks the action of ADH in the dista l tubules) may be used in highly symptomatic cases. Small cell lung cancer presenting with LEMS has a better prognosis, probably due to its ear lier detection. Severely disabled patients may require plasma exchange or IV immunoglobulin s while oncological treatment is initiated. The other antibody mediated neurological syndro mes do not respond to these measures. Key points \200 Neurological paraneoplastic syndromes \200 Paraneoplastic syndromes do not independently pre- clude curative surgery. Most respond to conventional treatment of the underly- ing neoplasm. Found almost exclusively in SCLC and are auto-antibody mediated. It is useful to test for s peci \201 c auto-antibodies to make a positive diagnosis which often then leads to a searc h for an underlying malignancy. If speci \201 c auto-antibodies are present they can usual ly be identi \201 ed in serum, although CSF should also be obtained if the clinical pictur e is highly suggestive but the serum test is negative or there are any concerns regard- ing malignant involvement of the central nervous system or co-existent infective diagnoses. Other recognized paraneoplastic syndromes in lung cancer: Hematological \200 \200 \200 \200 Endocrine and metabolic \200 \200 \200 \200 \200 \200 \200 \200 Anemia Leukaemoid reactions Thrombocytosis Disseminated intravascular coagulation Hypoglycaemia Hyperthyroidism FSH/LH secretion Lactic acidosis Hyperuricaemia Carcinoid Syn drome Gynaecomastia Neurological syndromes and autoantibodies Syndrome Auto-antibody Renal \200 \200 Lambert \200\223Eaton- myasthenic syndrome P/Q type voltage gated calcium channel auto-ab. Glomerulonephritis Nephrotic syndrome Limbic encephalitis Anti-Hu (type-1 antineuronal nuclear auto-ab.) Cutaneous \200 \200 \200 \200 \200 \200 Hypertrichosis languinosa Erythema multiforme Tylosis Acanthosis nigricans Pruritus Erythro derma Cerebellar degeneration Anti-Hu Connective tissue \200 Dermatomyositis \200 Polymyositis \200 Vasculitis \200 SLE Autonomic neuropathy Anti-Hu Opsiclonus/ myoclonus Anti-Hu Further reading Anderson NE, Rosenblum MK, Graus F, et al. Autoantibodies in paraneoplastic syndromes associated with small-cell lung cancer. Neurology 1988; 38: 1391 \200\2231398. Retinopathy Retinal protein auto-ab. Anti CV2 auto-ab. Sensory-motor peripheral neuropathy Beckles MA. Spiro SG. Colice GL, et al. Initial evaluation of the patient with lung cancer. Symptoms, signs, laboratory tests and paraneoplastic syndromes. Chest 2003; 123: 1. Lambert \200\223Eaton myasthenic syndrome is the most common of the paraneoplastic neurolog ical phenomena. \200 Marra A. Eberhardt W. Pottgen C, et al. Induction chemotherapy, concurrent chemoradiation a nd surgery for Pancoast tumor. Eur Respir J 2007; 29(1): 117 \200\223126. Auto-antibodies to voltage gated calcium channels block acetylcholine release at the neurom uscular junction resulting in proximal muscle weakness, reduced tendon re \202 exes and au tonomic dysfunction. Weakness tends be worse in the lower limbs and transiently improves fo llowing repeated exertion (in contrast to myasthenia gravis). Rowell, NP. Gleeson, FV. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review. Clinical Oncol 2002; 1 4: 338 \200\223351. M PEAKE 288 13.3 Work-up of patients with a suspected diagnosis of lung cancer Overview Most patients with lung cancer have advanced disease by the time of diagnosis, lim iting the treatment options and prognosis. Early identi \201 cation and referral of high r isk individuals may improve the outlook for a proportion of patients. Treatment options are more varied and complex than in the past and depend on accurate assess- ment of disease st age and \201 tness for radical therapies. Multi-Disciplinary Lung Cancer Teams are, for t hese reasons, now at the core of the management of patients with lung cancer. be referred for their work-up to a rapid access clinic run by a specialist Multi-Disciplina ry Lung Cancer Team. Further investigation Blood tests There is currently no reliable tumor marker for lung can- cer. Biochemical abnormalities are relatively common and the most important include: \200 Hyponatraemia (resulting from inappropriate ADH secretion and seen in both non-small cell a nd small cell lung cancers). Hypercalcaemia (resulting from either bony metastases and the ectopic secretion of parathormone-like sub- stances; more common in squamous cell carcinoma s). Elevated alkaline phosphatase and lactate dehydrogenase (non-speci \201 c but associat ed with a poorer prognosis). Hypokalaemic alkalosis (resulting from ectopic ACTH secretion and strongly associated with small cell lung cancer). Risk factors The major risk factors for the development of lung cancer are: \200 \200 \200 \200 \200 Smoking (current or past). Age over 50 years. The presence of COPD. Previous exposure to as bestos. Previous history of head and neck and/or bladder cancer. Family history of lung can cer occurring under 50 years of age in a \201 rst degree relative. Mild normochromic anemia and leukocytosis are com- mon and a leuco-erythroblastic anemia ca n indicate bone marrow involvement. CT scanning A CT scan is the basic imaging modality for the diagnosis of lung cancer after the initial plain CXR and all but mori- bund patients should have a contrast-enhanced, stag ing CT scan of the thorax and upper abdomen (see Figs. 13.3.1 \200\22313.3.3). CT reports s hould include an assessment of the stage of disease. A CT scan should be carried out wherev er possible, prior to any invasive investigation. This is in order to reduce the number of diagnostic tests by maximizing the yield from tests such as bronchoscopy. Symptoms In its early stages lung cancer usually causes little in the way of symptoms; tumo rs can grow to a considerable size be- fore patients seek medical advice. Screening of asym pto- matic individuals is, as yet, of unproven value and is not likely to become routinely available in the foreseeable fu- ture. It is essential, therefore, that clinicians develop a high level of awareness of the early symptoms of the disease, the risk pro \201 le of th eir patients and understand the fact that curative treatment is more likely to be possible the earlier patients are referred to a specialist team. The com- monest symptoms are: \200 \200 \200 \200 \200 \200 \200 Haemoptysis. Cough. Breathlessness. Chest and/or shoulder pain. Weight loss. Hoarseness. Fa tigue. Many of these symptoms are non-speci \201 c and their onset is often gradual. The situatio n is made more complex because many smokers put down these early symptoms to the effects of smoking itself. It is important to remember that it is not only new symptoms that are of i mportance, but changes in chronic symptoms, such as cough.