Further information Conway R et al. What happens to people after malignant cord compression ? Survival, function, quality of life, emotional well-being and place of care 1 month after diagnosis. Clin Oncol 2007; 19: 56 \200\22362 Eriks IE et al. Epidural metastatic spinal cord compression: functional outcome and surviva l after in-patient rehabilitation. Spinal Cord 2004; 42: 235 \200\2239 CHAPTER 31 Lung cancer 310 Pulmonary carcinoid tumors These are uncommon primary lung tumors, comprising 1 \200\2232% of all lung tumors. Equal male/female incidence; typical age at presentation is 40 \200\223 50 years. They are a form of neuroendocrine tumor and can have similar histological appeara nces to small cell lung cancer. Pathophysiology Although typically slow growing benign tumo rs, more aggressive subtypes exist, with metastatic potential. Commonly they are located en dobronchially, but can also be located peripherally in the lung parenchyma. Clinical features \200 Endobronchial carcinoids can cause isolated wheeze, dyspnoea, infection, haemoptysis, or pe rsistent lobar collapse Parenchymal carcinoids are often asymptomatic, being detected on ro utine CXR Carcinoid syndrome, with \202 ushing, tachycardia, sweats, diarrhea, wheeze, an d hypotension, occurs in 1% of pulmonary carcinoid tumors Carcinoid tumors can also be asso ciated with Cushing \200\231s syndrome, due to ectopic tumor ACTH production. Investigations \200 CXR may reveal a well-de \201 ned tumor, which should be further characterized on CT. Tumo urlets is the description given to multiple endobronchial or parenchymal carcinoid tumors. PET has decreased sensitivity for detecting carcinoid tumors compared with NSCLC (75% in on e study) Bronchoscopy is performed for accessible endobronchial carcinoid tumors. They typi cally appear to be intraluminal, cherry red, and covered with intact epithelium. Bronchial brushings may be adequate for a histological diagnosis. Bronchial biopsy can be associated with brisk or torrential bleeding, so care should be taken. Some avoid biopsy altogether an d proceed to surgical resection based on a clinical diagnosis. CT-guided biopsy may be pref erred for peripheral tumors Histological diagnosis can be dif \201 cult as the appearances can be similar to those of small cell lung cancer. Special stains and immunohisto- chemist ry are used to help differentiate between the two. Clinically, however, these tend to be qu ite different conditions and clinical details can aid pathological diagnosis. Carcinoid tum ors are characterized as being typical or atypical. They each have a characteristic pattern : \200 Typical carcinoids have no necrosis, occasional nuclear pleomor- phism, and absent or late mitoses. Distant metastases are rare and metastasis to lymph nodes occurs in 5 \200\22315% of cases. The 5-year survival is 100% and 10-year survival is 87% Atypical carcinoids may s how focal necrosis and often have nuclear pleomorphism. There is increased mitotic activity . They have distant metastases in 20% and metastasize to the lymph nodes in up to 48% of ca ses. The 5-year survival is 69% and 10-year survival is 52% PULMONARY CARCINOID tumors 311 Management \200 Patients with isolated pulmonary carcinoid tumors should be considered for surgical resecti on. Resection is ideally limited, removing minimal amounts of normal lung parenchyma. Tumor resection is associated with resolution of any features of the carcinoid syndrome If the t umor is atypical or close to the resection margin, patients should be followed up with repe at CXR on an annual basis. Radiotherapy is not performed Tumor size does not relate to the presence of lymph node metastases and therefore local lymph nodes should be sampled peri-op eratively In the 1% with carcinoid syndrome, serotonin antagonists, such as octreotide, can be used for treatment. Isolated liver metastases can be treated with arterial embolization . Metastatic aggressive carcinoid tumors can be treated with chemotherapy, such as etoposid e, cisplatin, 5- \202 uorouracil, and streptozotocin. Further information Hage R et al. Update in pulmonary carcinoid tumors: a review article. A nn Surg Oncol. 2003; 10: 697 \200\223704 CHAPTER 31 Lung cancer 312 Pulmonary nodules 1 De \201 nition These are focal, round, or oval areas of increased opac ity in the lung, measuring less than 3 cm in diameter. They are detected on CXR or CT. Grea ter use of CT and thinner slice spiral CT scanning has led to increased detection rates. CT allows the precise localization of a nodule and reliable determination of its features. It has a high sensitivity of detecting nodules of >5 mm in diameter. Volumetric analysis usin g CT-aided software means that a 3D nodule can be simulated, to aid nodule characterization and assess whether its volume has increased over time. Table 31.1 Causes of pulmonary nodules Benign Malignant Infectious granulomata Lung cancer Non-infectious granulomata Solitary metastasis Bronchial adenoma Benign hamartoma (developmental abnormality, containing cartilage, epithelium, and fat. Can contain smooth muscle. Slow growing. Can be seen at any age, especially 40+; often calcify .) The majority of pulmonary nodules are benign, although exact numbers depend on the characte ristics of the population screened 20 \200\22330% of patients with lung cancer may present with a solitary pulmonary nodule Of the nodules detected on CT in smokers with a normal CXR , between 1% and 2.5% will be malignant The Early Lung Cancer Action Project screening prog ram in the USA used CT scans in over-60-year-olds, with at least a 10-pack year history of smoking, and found non-calci \201 ed nodules in 23%, which were seen on CXR in 7%. 11% of these nodules were malignant on biopsy Early detection of these malignant nodules might alt er the management of the patient, with surgical resection of a stage 1 cancer. PULMONARY NODULES 1 313 Management options for patients with pulmonary nodules Observation Baseline CT scan showing nodule \211 4 mm, then repeat after an arbitrary tim e interval, such as 3 and 12 months, or 3, 6, and 12 months. If the nodule has increased in size or shows features of malignancy, con- sider biopsy or proceed straight to surgical re section. PET scan may be helpful in combination with CT if the nodule is indeterminate or i ncreasing in size, but cannot be biopsied. CT-PET scan useful in lesions >7 mm Biopsy Dif \201 cult on small nodules <7 mm, and those behind a rib or scapula. Resection If nodule has features of malignancy and biopsy not possible. Local practice vari es. Chemotherapy or radiotherapy If nodule proven to be malignant, but sur- gical treatment is not indicated due to performance status. Combined modality treatment CHAPTER 31 Lung cancer 314 Pulmonary nodules 2 Factors that suggest a pulmonary nodule is malignant \200 \200 \200 \200 Size >1 cm Smokers, older age Increasing volumetrically determined growth rates over time I ncreased enhancement with contrast, suggesting increased vascularity (>15 Houns \201 eld u nits) Increased FDG uptake with PET compared with normal tissue. Estimated sensitivity of P ET is 97% for identifying a malignant process Occult extrathoracic disease identi \201 ed on PET scanning Irregular or spiculated margin, with distortion of adjacent vessels \200 \224the \200\230corona radiata \200\231 sign Associated ground-glass shadowing Cavitation with thick irregular walls Pseudocavitation within nodule \200\224bronchoalveolar cell carc inoma. \200 \200 \200 Factors that suggest a pulmonary nodule is benign \200 \200 \200 \200 \200 Stable or decreasing size for 2 years Nodule resolves during follow-up Non-smoker Lack of e nhancement with contrast Smooth, well-de \201 ned margins (although 21% of smooth nodules may be malignant) Benign pattern of calci \201 cation: central, diffuse solid, laminated, or \200\230popcorn like \200\231 \200\224related to prior infections or calci \201 cation in a hamartoma Intranodular fat \200\224likely hamartoma Cavitation with thin smooth walls Younger age Resident in histoplasmosis endemic areas, such as North America. \200 \200 \200 Pulmonary nodule with extrathoracic malignancy In a patient with pre-existing malignancy, a pulmonary nodule could be a metastasis, new lung cancer, or benign disease. The histology of the extra- pulmonary neoplasm and the patient \200\231s smoking history in \202 uence t his. These cases need discussion within the cancer MDT to determine whether nodule biopsy o r treatment of the underlying primary cancer would be the most appropriate management. One study determined the likelihood of a pulmonary nodule being a new primary or metastasis based on the site of the original cancer: \200 New lung primary more likely if the primary tumor is head and neck, bladder, breast, bile d ucts, esophagus, ovary, prostate, stomach Metastasis more likely if the primary tumor is me lanoma, sarcoma, testes Either new primary or metastasis possible if the primary tumor is s alivary gland, adrenal, colon, parotid, kidney, thyroid, thymus, uterus. PULMONARY NODULES 2 315 Further information Ost D et al. The solitary pulmonary nodule. NEJM 2003; 348: 2535 \200 \22342 Erasmus J et al. Solitary pulmonary nodules. Radiographics 2000; 20: 43 \200\22366 Quint L et al. Solitary pulmonary nodule with extra pulmonary neoplasms. Radiology 2000; 217: 257 \200\22361 Henschke CI et al. Early lung cancer action project: overall design and \201 ndings from baseline screening. Lancet 1999; 354: 99 \200\223105 CHAPTER 31 Lung cancer 316 Lung cancer screening This is an area that is currently under investigation. Screening prog rams are based on the premise that the early detection of lung cancer and any subsequent in tervention will improve the patient \200\231s survival. There is no evidence yet of reducti on in lung cancer mortality from screening studies. To be detectable on CXR, a lung cancer needs to be 1 cm diameter, and 3 \200\2234 mm diameter to be detectable on CT. Screening studies \200 Four previous CXR screening studies in the 1970s were negative, of which the Mayo Lung Proj ect has been the most studied. This compared 4-monthly CXR and sputum cytology for 6 years in smokers 45 years old or older of 20+ per day, with infrequent or no screening in a contr ol group. 206 cancers were found in the study group and 160 in the control group, but all-c ause mortality was not affected by screening, even at 20 years More recent studies have use d low-dose spiral CT scanning. The Early Lung Cancer Action Project (ELCAP) in New York rec ruited 1000 symptom-free volunteers aged 60+ with a 10 pack-year history of smoking, who wo uld be \201 t for a thoracotomy. There was no control group. Baseline CXR and CT were per formed. Non-calci \201 ed nodules were present in 23% of patients at baseline on CT. Repea t CT was performed for nodules <5 mm; nodules >6 mm were biopsied and nodules >11 mm receiv ed standard care. 2.7% of all the patients entered had malignant nodules with stage 1 disea se in 2.3%. All but one patient had their cancer surgically resected International ELCAP sc reened 31 567 asymptomatic over-40-year-olds at risk for lung cancer between 1993 and 2005. The median age was 61. 13% had a positive result requiring follow-up at baseline CT and 5% at annual CT. Lung cancer was diagnosed in 1.5% of people (85% stage 1), with 411 having r esection and 57 having radiotherapy chemotherapy. There was no non-treatment randomized control group, so it is still dif \201 cult to interpret whether the earlier diagnosis and intervention led to longer survival. (Henschke CI et al. NEJM 2006;355:1763-71) Further re search is needed to demonstrate a clear detection survival bene \201 t, before national sc reening programs are instituted. Large randomized studies of CT vs. CXR are ongoing and the results are awaited. The role of PET in screening also needs to be evaluated. Further information Ellis JRC et al. Lung cancer screening. Br J Radiol 2001; 74: 478 \200 \22385 Marcus PM. Lung cancer screening: an update. J Clin Oncol 2001; 19: 83s \200\2236s Kawahara M. Screening for lung cancer. Curr Opin Oncol 2004; 16: 141 \200\2235 317 Chapter 32 Lung transplantation Patient selection 318 Speci \201 c conditions 320 Investigations and surgical approaches 3 22 Follow-up 324 Complications 1 326 Complications 2 328 CHAPTER 32 Lung transplantation 318 Patient selection Lung transplantation was \201 rst performed successfully in the early 1 980s, and since then the number of candidates for transplantation has increased signi \201 cantly. However, there is a signi \201 cant shortage of donor organs, and so an increasin g number of patients (up to 10 \200\22315%) die on the waiting list. There are \201 ve tr ansplant centers in the UK: Hare \201 eld, Papworth, Birmingham, Manchester, and Newcastle . Approximately 100 lung trans- plants and 50 heart \200\223lung transplants are carried ou t in the UK annually. Average waiting times in the UK are around 12 months for lung trans- plantation and 16 months for heart \200\223lung transplantation. Matching is carried out ac cording to size and major blood groups; HLA matching is not carried out. Underlying conditi ons Most common diagnoses, in order: - COPD (including A1-antitrypsin de \201 ciency) - Cy stic \201 brosis - Idiopathic pulmonary \201 brosis - Idiopathic pulmonary arterial hyp ertension - Pulmonary hypertension secondary to congenital cardiac disease (Eisenmenger \200\231s syndrome) Others, including sarcoidosis, lymphangioleiomyomatosis, Langerhans \200\231 cell histiocytosis, collagen vascular disease-related lung disease, bronchoalveolar cell ca rcinoma (successful transplantation has been carried out, although tumor recurrence in the donor lung is common). Indications Referral for transplant assessment should be considered in patients with chronic end-stage lung disease despite maximal medical therapy, whose life expectancy is 2 \200\2233 years or less (so that transplantation would be expected to prol ong their survival). Candidates should be func- tionally disabled but still able to walk, w ith no signi \201 cant cardiac, renal, or hepatic impairment. Suggested age limits are 55 years for heart \200\223lung, 60 years for bilateral lung, and 65 years for single lung tra nsplant. General referral criteria for lung transplantation - Normal renal function, with creatinine clearance >50 mL/min - Normal left ventricular function and normal coronary arteries - Pre served liver synthetic function - No osteoporosis - No systemic sepsis - BMI >17 - No psych iatric disorder - No history of malignancy within 5 years. PATIENT SELECTION 319 Contraindications Absolute - Severe extrapulmonary organ dysfunction (including renal, hepa tic, and cardiac disease) Active cancer or recent history (within 2 years) of cancer with substantial likelihood of r ecurrence; a 5-year disease-free interval is recommended (excluding cutaneous squamous or b asal cell carcinomas) Severe psychiatric illness or non-compliance with treatment/follow-up - Incurable chronic e xtrapulmonary infection (including HIV, active hepatitis B and C) Active or recent (6 months) substance addiction (cigarette smoking, alcohol, narcotics) Signi \201 cant chest wall/spinal deformity Relative - Age >65 years - Chronic medical con ditions that are poorly controlled or associated with target-organ damage (hypertension, di abetes, coronary artery disease) Severe or symptomatic osteoporosis (risk of post-transplant fractures and poor quality of life; start treatment prior to transplant) Daily requirement for >20 mg prednisolone - Severe obesity (BMI >30) or malnutrition (BMI < 17) - Inability to walk, with poor rehabilitation potential - Mechanical ventilation (exclu ding NIV) or acute critical illness - Extensive pleural thickening (from infection or prior surgery, e.g. pleurodesis) \200\224procedure is technically more dif \201 cult Active collagen vascular disease - Pre-operative colonization of the airway with pan-resist ant bacteria, fungi, or mycobacterium in cystic \201 brosis: there are no clear data to s upport exclusion of pan-resistant Pseudomonas, although it remains a relative contraindicat ion in some centers. B. cepacia colonization (particularly with genomovar III), however, is high risk and an absolute contraindication in many centers Contentious - Non-tuberculous mycobacterium, especially M. chelonae - Aspergilloma (ABPA is not generally a contraindication, though patients would not be transplanted during an exacerbation, and would be treated with prophylactic vo riconazole) Portal hypertension (prophylactic variceal sclerotherapy may be offered). Further information Orens JB et al., International guidelines for the selection of lung tra nsplant candidates: 2006 update. J Heart Lung Transplant 2006; 25: 745 \200\22355 Glanville AR, Estenne M. Indications, patient selection and timing of referral for lung tra nsplantation. Eur Resp J. 2003; 22: 845 \200\22352 CHAPTER 32 Lung transplantation 320 Speci \201 c conditions Timing of referral This can be dif \201 cult; life expectancy sho uld be <2 \200\2233 years, but patients must be \201 t for the procedure during a waiting time of up to 16 months. The decision should not be based on a single factor; instead, a c ombination of clinical, laboratory, and functional assessments should be considered. Patien ts with CF and IPF have particularly high waiting list mortalities, suggesting inappropriat ely late referral for these conditions. Disease-speci \201 c guidelines for referral: Chronic obstructive pulmonary disease - BODE index (incorporating BMI, FEV1, degree of dysp noea, and 6-min walk; p 169) >5 History of hospitalization for exacerbation associated with acute hypercapnia (PaCO2 >6.7kPa; 49% 2-year survival) Pulmonary hypertension or cor pulmonale, despite oxygen therapy - FEV1 <20% predicted and e ither TLCO <20% or homogeneous distribution of emphysema (median survival 3 years with medi cal therapy) Patients should be on maximal medical therapy, have completed pulmonary rehabilitation, have stopped smoking for at least 6 months (if in doubt, check ur inary cotinine levels), and ideally <60 years old Cystic \201 brosis - De \201 ning referral criteria is especially dif \201 cult for pat ients with CF, due to considerable inter-individual variation in course and prognosis FEV1 \211 30% predicted or FEV1 >30% with rapid progressive deterioration, e.g. increasing frequency of exacerbations, rapid fall in FEV1 History of ITU admission for pulmonary exacerbation - Oxygen-dependent respiratory failure, hypercapnia, or pulmonary hypertension Severe recurrent haemoptysis despite embolization - Refractory and/or recurrent pneumothora x - Young (<20 years) female patients with rapid deterioration have a poor prognosis and should be considered for early referral - Invasive ventilation is a contraind ication in most centers Idiopathic pulmonary \201 brosis - Given the poor prognosis and h igh waiting-list mortality associated with IPF, guidelines recommend referral of all suitab le patients with histological or radiographic evidence of UIP, irrespective of vital capaci ty and without delaying for trials of treatment; these are not widely applied in the UK TLCO <40% predicted, fall in FVC \211 10% over 6 months, oxygen desaturation <88% on 6-mi n walk, honeycombing on HRCT (each associated with high mortality) SPECIFIC CONDITIONS 321 Idiopathic pulmonary arterial hypertension \200 New York Heart Association (NYHA) functio nal class III or IV, rapidly progressive disease/failing medical therapy, low (<350 m) or d eclining 6-min walk test, mean right atrial pressure >15 mmHg, cardiac index <2 L/min/m2. CHAPTER 32 Lung transplantation 322 Investigations and surgical approaches Investigations prior to referral Consult transplant referral center for details and avoid repetition of investigations. Important investigation s include full PFTs, tests of exercise performance (e.g. 6-min walk), sputum microbiology, ECG, echo, HRCT chest, LFTs, viral serology (e.g. HIV, CMV, hepatitis B and C), 24-h creati nine clearance, stress echo, and/or coronary angiography. If on waiting list, inform transp lant center of changes in clinical condition. Remember that the referring physician remains responsible for continuing regular medical care of the patient, to ensure they remain opti mally treated during the waiting period, with particular attention to: - Maintenance of nut rition (may require PEG feeding) - Avoidance of obesity - Maintenance of mobility, continui ng exercise and rehabilitation - Monitoring comorbid disease: heart, kidney, liver, bones. Optimize treatment of diabetes, systemic hypertension, osteoporosis, peptic ulcer disease, gastro-oesophageal re \202 ux and sinus disease Early NIV if indicated - Avoiding intubation, if possible. Surgical approaches for transplant Single lung (50% of procedures) - Technically easier, al lows two recipients from one donor - Used successfully in all patients except CF and bronch iectasis - Over-distension of the compliant native lung in emphysema is uncommon, but may be problematic Bilateral sequential (25%) - Sequential right and left single lung transplants at one time - Selective lung ventilation may render cardiopulmonary bypass unnecessary Heart \200\223lung (25%) - Indicated in Eisenmenger \200\231s syndrome, or advanced lung di sease with concurrent LV dysfunction or coronary disease Cor pulmonale is not in itself an indication, as right ventricular hyper- trophy resolves rapidly following lung transplantation alone Certain patients without cardiac disease may undergo a \200\230domino \200\231 pro- cedure , where they receive a combined heart \200\223lung transplant, because this is technically easier, and their healthy heart is then used for a patient needing a heart transplant Living lobar transplantation - Bilateral grafting of lower lobes from two living adult dono rs to replace lungs of child or small adult Appears to be safe for the donor, with lung volume reductions of about 15%, but potential f or 300% overall mortality (2 donors and one recipient) Not widely performed in the UK This page intentionally left blank CHAPTER 32 Lung transplantation 324 Follow-up Patients are usually discharged about one month after transplant, following post- transplant bronchoscopy with BAL and biopsy. They will be fol- lowed up closely by their tr ansplant center, but may also attend general respiratory clinics intermittently between tra nsplant center visits. Be alert to possible complications (pp 326 \200\2239). Spirometric v alues are gener- ally very stable from 3 months after transplantation, and sustained falls \211 10 \200\22315% warrant further investigation. Remember drug interactions (particularl y ciclosporin and tacrolimus) if new medications are added. Check immunosuppressant drug bl ood levels and perform routine blood tests according to the local transplant center policy. Outcomes Survival - Survival rates: 85% 1-year, 63% 3-year, 50% 5-year. Median survival is 4.5 years Compared with patients on the waiting list, lung transplant conveys a survival bene \201 t to patients with CF and IPF, but not emphysema - Rate of death is hig hest in \201 rst year (infection, primary graft failure) - Risk factors for early death a re pre-existing pulmonary hypertension, ventilator dependence, recipient age >50, donor age >50 No survival difference between single- and double-lung transplant. Functional - Lung functi on usually normalizes after bilateral transplant and markedly improves following single-lun g transplant. In COPD, FEV1 increases to 50 \200\22360% of predicted value after single-lun g transplant Arterial oxygenation rapidly normalizes - 6-min walk distance typically doubles; most patie nts resume active life- style although fewer than 40% of patients return to work Limited data on quality of life: initial improvement suggested, but effects after 1 year are unclear. Routine surgery after lung transplant Routine surgery >3 months after transplant can be car ried out locally, but inform the transplant center. Routine antibiotic prophylaxis is adequ ate; there is no increased risk of SBE. The morning dose of calcineurin inhibitor (ciclospo rin, tacrolimus) should be omitted, as there is a risk of nephrotox- icity with hypovolaemi a. Future developments are likely to address both the shortage of donor organs (e.g. living lobar transplantation, the \200\230non-heart beating donor \200\231, xenotransplantation, and further research in lung preservation) and the development of more effective treatment s for chronic rejection (new immunosuppressive drugs, induction of immune tolerance). This page intentionally left blank CHAPTER 32 Lung transplantation 326 Complications 1 Early graft dysfunction - Characterized by pulmonary in \201 ltrates, hypo xaemia, and diffuse alveolar damage or organizing pneumonia on biopsy; not uncommon during \201 rst few days after transplant. Clinical severity ranges from very mild acute lung in jury to acute respiratory distress syndrome Presumably related to preservation and ischaemia \200\223reperfusion injury - Exclude other causes, e.g. volume overload, pneumonia, rejection, occlusion of venous anastomosis, aspiration - Treatment is supportive (mechanical ventilati on) - High mortality (40 \200\22360%). Airway complications - Anastomotic stenosis most common and typically occurs weeks \200\223 months after transplant; suggested clinically by localized wheeze, recurrent pneumonia, or suboptimal lung function. Treat with stent placement via bronchoscopy Complete dehiscence of bronchial anastomosis now rare, and requires immediate surgery or retransplantation Partial dehiscence is managed conservatively: drain pneumothorax, reduce steroid dose. Infection Bacteria - May occur early ( \201 rst month after transplant) or late (associate d with bronchiolitis obliterans syndrome) Most commonly due to Gram-negative organisms, particularly Pseudomonas aeruginosa Recipients with cystic \201 brosis are not at greater risk than other patients; an except ion is B. cepacia colonization, which is associated with a high risk of often lethal postop erative infections. CMV - CMV-seronegative recipients from seropositive donors are at particular risk of severe infection, including pneumonitis; this is usually treated successfully with ganciclovir Increases risk of bacterial or fungal superinfection - Ganciclovir prophylaxis probably res ults in later, less severe infection. - CMV infection may be a risk factor for development of bronchiolitis obliterans syndrome. COMPLICATIONS 1 327 Aspergillus - Aspergillus frequently colonizes the airways after lung transplant, but clini cally apparent infection develops in only a minority of patients Peak disease incidence at 2 months after transplant - Sites of disease include airways (may lead to mucosal oedema, ulceration, and pseudomembranes; usually responds to itraconazole, voriconazole, or amphote ricin B), fresh bronchial anastomosis, lung parenchyma, and disseminated aspergillosis (ass ociated with high mortality). Drug-related Immunosuppressive drugs must be taken lifelong following transplantation. Agen ts used include ciclosporin or tacrolimus, azathio- prine or mycophenolate mofetil, and pre dnisolone. They are associated with many drug interactions and side-effects, particularly n ephrotoxicity and osteoporosis. Ciclosporin and tacrolimus blood levels need to be closely monitored. Further information Kotloff A Medical complications of lung transplantation. Eur Resp J, 2004; 23: 334 \200\223 42 Knoop et al. Immunosuppressive therapy after human lung transplantation. Eur Resp J 2004; 2 3: 159 \200\22371 CHAPTER 32 Lung transplantation 328 Complications 2 Acute rejection - Very common, particularly within 3 months of transplant. Rare after 12 months Asymptomatic, or may be associated with malaise, fever, dyspnoea, cough, hypoxia. May present similarly to pneumonia or COP CXR may be normal or show non-speci \201 c in \201 ltrates - Common \201 nding is fall in spirometry >10%, although this does not distinguish from other complications, particularly infection Refer back to the transplant center if these problems develop within 3 months of the transplant Ideally con \201 rm histologically: transbronchial biopsies are safe and typically show perivascular lymphocytic in \201 ltrates. Routine surveillance transbronchi al biopsies are increasingly used to detect acute rejection prior to falls in lung function . Treatment IV methylprednisolone pulses. The majority of patients respond quickly; consider switch in immunosuppressive agent from cyclosporin A to tacrolimus if ongoing or recurrent acute rejection - Acute rejection is the main risk factor for the development of chronic rejection Acute rejection is an uncommon cause of breathlessness after 3 months and other common causes of SOB should be considered. Chronic rejection - A signi \201 cant problem, accounting for poor long-term prognosis following lung transplant Uncommon in \201 rst 6 months, but prevalence subsequently increases steadily, affecting 50 \200\22360% of patients at 5 years Pathogenesis incompletely understood, likely involves immune-mediated injury to epithelial and endothelial cells, possibly with an environmental trigger; risk factors for development include previous episodes of acute rejection, CMV pneumonitis, presence of anti-HLA antibo dies pre-transplant, and perhaps gastro-oesophageal re \202 ux, community respiratory viru s infection, and medical non-compliance Clinically Insidious onset of breathlessness and cough, and progressive air \202 ow obstruction on spirometry Manifest histologically as bronchiolitis obliterans, a \201 broproliferative process affe cting small airways. Histological con \201 rmation is dif \201 cult: transbronchial biops ies have a low sensitivity, so a clinical diagnosis of \200\230bronchiolitis obliterans sy ndrome (BOS) \200\231 is de \201 ned as an unexplained and sustained ( \211 3 weeks) fall in FEV1 to <80% of peak value post- transplant. \200\230Potential BOS \200\231 is de \201 ned as FEV1 81 \200\22390% of baseline and/or forced mid-expiratory \202 ow (FEV25 \200 \22375%) to \211 75% of baseline, and indicates the need for close monitoring/further inve stigation CXR unhelpful; HRCT may show expiratory air trapping and peripheral bronchiectasis P. aeruginosa colonization is common, with recurrent purulent tracheobronchitis COMPLICATIONS 2 329 Treatment is challenging, and involves either modi \201 ed or increased immunosuppression (e.g. switch ciclosporin to tacrolimus; high-dose steroid pulses and antilymphocyte antibod ies; inhaled cyclosporin may have a role), and if effective this acts only to reduce the ra te of disease progression. Infection is investigated and treated aggressively, sometimes wi th reductions in immunosuppression. Azithromycin is often used for deteriorating BOS. Gastr o-oesophageal re \202 ux is treated, sometimes with surgery. Total lymphoid irradiation is sometimes recommended when other immunomodulatory treatments have failed - Prognosis is po or: mortality is 40% within 2 years of diagnosis; the rate of decline is very variable between individuals Retransplantation is the only de \201 nitive treatment and is controversial. Recurrence of primary disease Documented in sarcoidosis, lymphangio- leiomyomatosis, giant cell intersti tial pneumonitis, diffuse pan-bronchiolitis, and bronchoalveolar cell carcinoma. Malignancy Increased risk of certain malignancies, e.g. lymphoma (and other EBV-related post-transpla nt lymphoproliferative diseases), skin, lip, vulval, and perineal carcinomas, in situ cervi cal cancer, and Kaposi \200\231s sarcoma. - Most lymphomas appear within the \201 rst yea r, and the lung allograft is the most common site of involvement, with pulmonary nodule(s) mediastinal lymphadenopathy. Lymphocyte aggregates from acute rejection may mimic the ap pearance of post-transplant lymphoprolif- erative disease on small transbronchial biopsy sp ecimens. Lymphomas presenting after the \201 rst year are more commonly disseminated or i ntra-abdominal (e.g. presenting with tonsillar enlargement, peripheral lymphadenopathy, ski n nodules, or bowel complications such as intus- susception). Patients should be referred b ack to the transplant center for treatment, rather than the local hematologist. The usual t reatment is a reduction in immunosuppression or rituximab (monoclonal anti- body against CD 20 on B cells) Lung cancer occurs in patients with COPD and IPF. Unclear if trans- plantation itself increases the risk of lung cancer. May progress unusually rapidly, mimick ing infection. Differential diagnosis of CXR nodules following lung transplant - Post-transplant lymphopro liferative disease - Infection (Pseudomonas, Nocardia, aspergilloma, TB) - Disease recurren ce - Primary lung cancer. Further information Boehler, E. Post-transplant bronchiolitis obliterans. Eur Resp J 2003; 22: 1007 \200\22318 This page intentionally left blank 331 Chapter 33 Mediastinal abnormalities Anatomy 332 Mediastinal abnormalities 1 334 Mediastinal abnormalities 2 336 CHAPTER 33 Mediastinal abnormalities 332 The mediastinum is the area within the center of the chest containing the heart, great vess els, nerves, lymph nodes, trachea, esophagus, and thymus. Two-thirds of mediastinal masses are benign. Age 20 \200\22340, presence of symp- toms and anterior location of a mass are a ll associated with an increased likelihood of malignancy. Common symptoms of mediastinal di sease include cough, chest pain, and dyspnoea, as well as symptoms relating to any struc- t ure being compressed, such as dysphagia, stridor, or SVCO. Mediastinal disorders can also b e asymptomatic. They may be found incidentally fol- lowing a CXR. Anatomy Anterior mediastinum The area behind the body of the sternum and in front of the \201 bro us pericardium. Contains the thymus, which also extends superiorly. Posterior mediastinum The area in front of the vertebral bodies and behind the \201 brous pericardium. Contains the spinal nerve roots, the descending aorta and esophagus, the azyg os and hemiazygos veins, the thoracic duct, and vagus and splanchnic nerves. Superior mediastinum The area located between the thoracic inlet superi- orly, the manubriu m of the sternum anteriorly, by the superior 4 thoracic vertebrae posteriorly and inferiorl y where a horizontal plane would cross through the sternal angle. It contains the aortic ar ch and its large branches and the upper half of SVC. It also contains the trachea, the esop hagus, the thoracic duct, and the phrenic, vagus, cardiac, and left recurrent laryn- geal n erves. Middle mediastinum The area containing the heart and pericardium, the ascending aorta, the lower half of the SVC, part of the azygos vein, the pulmonary arteries and veins, the trach eal bifurcation, phrenic nerves, and the IVC. These areas are easily seen on a lateral CXR. Oesophageal cyst Retrosternal thyroid Great vessels Thymus Lymph nodes o ste rio r Teratoma/ dermoid cyst Anterior Neurofibroma Middle P Pleuro- pericardial cyst Heart Hiatus hernia Fat pad Fig. 33.1. Anterior, posterior, superior, and middle mediastinum ANATOMY 333 Likely nature of mediastinal mass according to anatomical site Anterior mediastinal mass - Thymoma (superior) - Thyroid (superior) - Germ-cell tumor - Lym phoma - Ascending aortic aneurysm - Pleuropericardial cyst - Pericardial fat pad - Morgagni anterior diaphragmatic hernia (p 343) Superior mediastinal mass - Bronchogenic cyst Poster ior mediastinal mass - Neural tumor - Foregut duplication or cyst - Lipoma - Descending aor tic aneurysm - Bochdalek posterior diaphragmatic hernia (p 343). Approach to the patient with a mediastinal mass - Full history - Examination, including ski n, lymphadenopathy (neck, axillae, groins) and testes Look for fatiguability: ptosis, opthalmoplegia, inability to maintain upward gaze Look for signs of SVCO or stridor - Blood tests, including AFP, BHCG, anti-acetyl choline r eceptor anti- body CXR and lateral CXR (if not already done) - Arrange CT scan of chest - Try and locate old C XRs. CHAPTER 33 Mediastinal abnormalities 334 Mediastinal abnormalities 1 Neural tumors mostly occur in the posterior mediastinum. 75% ar e benign in adults. - Schwannomas and neuro \201 bromas are benign peripheral nerve sheath tumors. They may be multiple. Usually asymptomatic, although can cause segmental pain. Slow ly enlarge and, rarely, can cause cord compression, with dumb-bell shaped tumors straddling the intervertebral foramen. Can be surgically excised Malignant peripheral nerve sheath tumors or neurosarcomas include new malignant growths and benign neuro \201 bromas that have undergone malignant change. They may cause systemic fe atures of malignancy and can invade locally and metastasize Autonomic nervous system tumors including neuroblastomas and ganglioneuromas, range from benign to malignant. Surgical removal is the treatment of choic e, with radiotherapy and chemotherapy if the tumor is malignant. Thymoma Tumor of epithelial origin arising in the thymus. May contain functioning thymic ti ssue. M = F. Rare below age 20. Myasthenia gravis is present in 30 \200\22340% of patients with a thymoma; this is often unimproved after thymectomy and may even develop after the th ymoma is removed. 20% of patients presenting with myasthenia gravis are found to have a thy moma, particularly if patients are over 50 and male. This group is likely to have positive acetylcholine receptor (AChR) autoantibodies, which bind to AChRs at the postsynaptic motor endplate, decreasing available acetylcholine binding sites, causing nerve fatigability. Patients with thymomas are usually symptomatic with pain, dyspnoea, dysphagia, or myastheni a gravis symptoms. Thymomas contained within the thymic capsule tend to be benign, although they do have malignant potential; those that have extended outside the capsule are maligna nt, and may involve local structures or metastasize. Diagnose with CT and treat with surgic al excision of the thymus, avoiding prior FNA or biopsy as this may cause tumor seeding out side the capsule. Consider post-operative radiotherapy and chemotherapy for invasive tumors , especially those not completely excised. Thymectomy is indicated in patients with myasthe nia gravis even without thymoma, as it may lead to symptomatic improvement. This gives best results in those with detectable AChR antibody levels and younger patients early in the di sease course, particularly those with severe disease. Thymic cyst may be congenital or acqu ired secondary to in \202 ammation. Asymptomatic unless large and causing symptoms of comp ression. Benign, but usually treated with surgical excision, as diagnostic certainty may be dif \201 cult. Thymic carcinoid Not associated with myasthenia gravis and behaves aggress ively, with local recurrence and metastasis. May be associated with Cushing \200\231s syndr ome. Treatment with surgery, chemotherapy, or octreotide. Also: thymic carcinoma, thymic lipoma, and thymic hyperplasia. MEDIASTINAL ABNORMALITIES 1 335