Technology The advent of PET-CT has allowed the anatomic localisa- tion of these areas with far greater precision than when PET was performed without CT. Consequently the diag- nosti c accuracy of PET-CT is far greater than PET alone. The ability to assess the metabolic act ivity of lymphaden- opathy seen on CT and the increased sensitivity of PET compared to CT i n most areas of the body has also resulted in PET-CT having a greater diagnostic accuracy f or lung cancer than CT. The use of CT has also reduced the total scan time. Measurement It is also possible to quantify the degree of FDG activity seen in areas of upt ake. Apart from quanti \201 cation meas- ures used in research, most reporters use the sem i- quantitative standardized uptake value (SUV). The SUV is reported from over a region of interest such as a lung cancer, and is calculated using the dose of 18FDG injected, and the patients bodyweight. The time from injection is an important variable that is recorded to allow the measure- ment to be repeated on follow-up scans if necessary. Various thresholds for reporting a nodule, mass or lymph node have been used, the most common being an SUV of greater than 2.5, although subjective analysis ie whether it looks \200\230hot \200\231 is possibly just as effective in experienced hands. Mediastinal assessment FDG-PET performance is dependent on node size and the likelihood of other causes of increased uptake such as granulomatous disease. A meta-analysis of node siz e in FDG-PET has shown a 5% likelihood of maligancy for nodes measuring 10 \200\22315mm on CT when PET negative, and a 21% likelihood for nodes measuring >16mm. False positive scanni ng is dependent on the underlying prevalence of granulomatous disease. The ranges of report ed sensitivity and specificity are 61% \200\22386% and 73% \200\22396%. Clinical utility in thoracic disease 1 Investigating the solitary pulmonary nodule. 2 Stagi ng lung cancer. 3 Assessing treatment response in lung cancer. 4 Staging and assessing trea tment response in mesothelioma. CHAPTER 13.6 PET-CT 301 Detection of distant metastases: Several studies have shown that PET-CT detects unsus- pect ed metastases in 10 \200\22314% of patients. Adrenal metastatic disease \200\223 PET-CT ap pears of real value in assessing adrenal disease, with a near 100% sensitivity and very hig h, 96% speci \201 city. Bone metastases \200\223 this is in part dependent on correlation with the appearance of the area of FDG activity on CT. If the CT appearances are of metast atic disease, PET has a positive predictive value of 98%, if the CT appearance is not of me tastatic disease PET has a positive predictive value of 61%. Overall PET has a greater sens itivity than 99mTc diphosphonate bone scans. Liver metastases \200\223 PET-CT appears more accurate than CT or US, but may not detect sub 1 cm lesions. Brain metastases are not read ily assessed on conventional FDG-PET due to the high metabolic brain activity. Pleural dise ase \200\223 it appears relatively insensitive, 25%, but of good speci \201 city 90% Prognosis PET-CT appears of value in predicting survival. This may be by assessing the SUV of the primary tumor or by assessing the degree of FDG marrow activity. Fig. 13.6.1 FDG avid left upper lobe tumor (long arrow) with FDG avid left hilar (short arr ow) and aortopulmonary leymphadenopathy (fat arrow). Fig. 13.6.2 FDG avid right hilar tumor (fat arrow) with subtle FDG avid right femoral bone metastasis (thin arrow). F GLEESON 302 Additional abnormalities Up to 5 \200\22310% of all patients undergoing PET-CT have addi- t ional abnormalities such as colonic polyps and thyroid nodules detected. Its main role may be in the early evaluation of patients undergoing chemotherapy, with a re duction in metabolic activity correlating with continued disease response and survival. Fig. 13.6.4 Markedly FDG avid mesothelioma (arrowed) in keeping with sarcomatoid histology and a poor prognosis. Further reading Ceresoli GL, Chiti A, Zucali PA, et al. Early Response Evaluation in Malign ant Pleural Mesothelioma by Positron Emission Tomography with [18F]Fluorodeoxyglucose. J Cl in Oncol 2006; 24: 4587 \200\2234593. Fig. 13.6.3 Small coincidentally detected FDG rectal polyp (arrowed) detected in a patient with lung cancer. De Geus-Oei L, Oyen WJ. Predictive and Prognostic Value of FDG- PET in Nonsmall-Cell Lung C ancer. A Systematic Review Cancer 2007; 119:1654 \200\2231664. Radiation therapy planning PET-CT has been shown to potentially reduce the volume of non-tu mor within the treatment \201 eld, reducing toxicity and potentially allowing an increase in dose to the target tissue De Langen AJ, Raijmakers P, Riphagen I, et al. The size of mediastinal lymph nodes and its relation with metastatic involvement: a meta-analysis. Eur J Cardiothorac Surg 2006; 29: 26 \200\22329. Effectiveness of positron emission tomography in the preoperative assessment of patients wi th suspected non-small-cell-lung can- cer: The PLUS multicentre randomized trial. Lancet 20 02; 359:1388 \200\2231393. 3. Assessment of treatment effect in lung cancer PET has been used post neodadjuvant treatm ent, as an early assessment during chemotherapy and after comple- tion of therapy. A good r esponse and an early response appear to predict survival. Erasmus JJ, Macapinlac HA, Swisher SG. Positron Emission Tomography Imaging in Nonsmall-Cel l Lung Cancer. Cancer 2007; 110: 2155 \200\2232168. Gould MK, Maclean CC, Kuscher WG, et al. Accuracy of Positron Emission Tomography for Diagn osis of Pulmonary Nodules and Mass Lesions: a Meta-analysis. JAMA 2001; 285:914 \200\223924 . 4. Mesothelioma FDG-PET has been shown to be of value in detecting areas of disease suitabl e for biopsy in patients with mesotheli- oma. It is not suf \201 ciently sensitive to be o f value in screen- ing high risk patients, and is not speci \201 c, with false positive sc ans seen post pleurodesis and in patients with other causes of pleural in \202 ammation. I t has been shown to have similar diagnostic accuracy in the detection of mediastinal lympha denopathy as lung cancer. It detects up to an additional 15% distant metastases compared to CT, and should be performed in all patients being assessed for curative surgery. Hellwig D, Graeter TP, Ukena D, et al.18F-FDG PET for Mediastinal Staging of Lung Cancer: W hich SUV Threshold Makes Sense? J Nucl Med 2007; 48:1761 \200\2231765. Truong MT, Marom EM, Erasmus JJ. Preoperative Evaluation of Patients with Malignant Pleural Mesothelioma: Role of Integrated CT-PET Imaging. J Thorac Imaging 2006; 21:146 \200\223153 . This page intentionally left blank M PEAKE RICHARD HUBBORD 304 13.7 Lung cancer screening Background Around 80% of lung cancer patients have locally advanced or metastatic disease b y the time of diagnosis. Although efforts to improve early diagnosis in symptomatic patient s may improve this situation in some patients, it is likely that the bulk of individuals wi th very limited stage disease will only be detected by some form of population-based screen ing. Key elements For a screening test to be accepted it has to succeed in at least three key ar eas: \200 Provide bene \201 t (usually prolong survival) to the individ- uals who are found to have the disease. Confer no signi \201 cant danger to the screened population who do not have t he disease. Should be cost-effective in health economic terms, in other words not impair th e capacity of the health service in providing care for others. CXRs and sputum cytology Between 1960 and the early 1990s there were \201 ve large- scale studies of screening for lung cancer using CXRs, some with and others without the addition of sputum cy- tology. These were carried out in the UK (as a follow on from the program of Mass Radiography for TB), the US, and Czechoslovakia. Several of these found a larger numb er of lung cancers in the screened group and in some a higher proportion of these were surg ically resectable. However, in none was an improvement in either lung cancer speci \201 c or overall survival demonstrated. All five studies are now recognized to have signi \201 c ant \202 aws, for example they did not include a proper unscreened \200\230control \200 \231 arm, the sample sizes were inadequate and the follow up was not long enough. They are therefore best considered as incon- clusive rather than negative. There is one case \200 \223control study from Japan that suggests that CXR screening might still be of value and t he current Prostate, Lung, Colo-rectal and Ovarian Trial, funded by the National Cancer Ins titute, includes randomizing the use of plain CXRs in low risk populations. Fig. 13.7.1 Image of 7mm peripheral pulmonary nodule from a low dose CT scan. One study (the Early Lung Cancer Action Program \200\223 ELCAP - has estimated an 88% 10-y ear survival rate in those screen-detected patients with stage I disease. No study has yet demonstrated an improvement in mor- tality outcomes in the screened population, even in hig h- risk populations. The results of the randomized trials that are currently underway will not be available for several years. Problems of LDSCT screening Overdiagnosis bias This is the detection of very slowly growing tumors that are clinically unimportant for the individual patient who is more likely to di e of other conditions. There are reports of such clinically undiagnosed lung cancers in pos t-mortem studies. Low-dose spiral CT scanning During the 1990s, CT technology advanced signi \201 cantly, en abling studies using low-dose spiral CT scanning (LDSCT) as a screening tool to be establis hed. The imaging technology has been paralleled by computing power allow- ing for automated measurements of the dimensions and volume of sub-centimeter nodules to within very low err or limits. An example of an image generated in these single-breath hold scans is shown in F ig. 13.7.1. The current status of research can be summarized as follows: \200 Indeterminate nodules and clinical effectiveness CT can detect very small abnormalities wit hin the lung \201 elds and one of the main issues is how to handle nodules of indetermina te signi \201 cance. There is morbidity and a small mortality associated with the biopsy a nd resection of pulmonary nodules. Unfortunately, CT abnormalities are not speci \201 c fo r malignancy and some series report more than 90% of CT nodules to be benign. In a non-rand omized Swedish study 78% of the 1520 screened individuals were found to have non-calci \201 ed pulmonary nodules but only 68 lung cancers were detected, exposing a very large num ber of patients to the need for investigation and the associated risks and anxie- ties. The frequency of benign pulmonary nodules varies widely in different parts of the world, which probably means that each country needs to make its own assess- ment of the clinical effect iveness and risk of such a program. The currently published studies of this approach have all been in volunteer groups. LDSCT i s clearly superior to plain CXRs in detecting early stage disease. Over 80% of individuals found to have lung cancer in populations screened using LDSCT have had stage I dis- ease. ( This compares with no more than 10% in symp- tom-detected lung cancer populations.) CHAPTER 13.7 Lung cancer screening 305 Analysis of the exhaled breath for abnormal patterns of volatile organic substances. Cost effectiveness The published estimates of the cost-effectiveness of screening using LDS CT vary hugely and appear to depend as much on the enthusiasm of the authors as the science underlying the analyzes. At one extreme, the ELCAP inves- tigators calculated an increment al cost effectiveness ratio of the baseline scan as US$2500 per year of life saved. Oth- er s studies have reached very different conclusion with estimates ranging from US$51,001 to U S$2,322,700 quality life year adjusted gained. The Health Technology Appraisal panel conclu ded: \200\230There are serious shortcomings in the eco- nomic data currently available in UK concerning treatment of lung cancer patients. New research is required to provide inform ation needed for a comprehensive economic assess- ment of lung cancer screening in UK. \200 \231 Summary Currently there is no screening technique that has been demonstrated to alter morta lity outcomes even in high- risk populations. Thus screening is currently regarded as a sub ject of ongoing research by most authorities. Further reading Bach PB, Kelley MJ, Tate RC, et al. Screening for lung cancer: A review of the current literature. Chest 2003; 123: 72S \200\22382S. Bach PB, Silvestri GA, Hanger M, et al. Screening for lung cancer: ACCP evidence-based clinical practice guidelines (2nd edn ). Chest 2007; 132: 69S \200\22377S. Gleeson FV. Is screening for lung cancer using low dose spiral CT scanning worthwhile? Thorax 2006; 61: 5 \200\2237. Other potential screening techniques Several other approaches to the early detection of lun g cancer which may, in time lead to technologies useful in population screening are under i nvestigation, though none of them have yet been applied in the context of a ran- domised tr ial. They include: \200 Henschke CI, Yankelevitz DF, Naidich DP, et al. CT screening for lung cancer: Suspiciousnes s of nodules according to size on baseline scans. Radiology 2004; 231(1):164 \200\223168. Okamotoe N, Suzuki T, Hasegawa H, et al. Evaluation of a clinic- based screnning program fo r lung cancer with a case-control design in Kanagawa, Japan. Lung Cancer 1999; 25:77 \200 \22385 Swenson SJ, Jett JR, Sloan JA, et al. Screening for lung cancer with low-dose spiral comput ed tomography. Am J Respir Crit Care Med 2002; 165: 433 \200\223434. Identi \201 cation of genetic pro \201 les that can identify popula- tions at especially high risk. Serum proteomics. Assessment of methylation biomarkers free circulating plasma D NA. Advanced, automated sputum cytometry followed by LDSCT and/or auto \202 uorescence bro nchoscopy. \200 The International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Eng J Med 2006; 355:1763 \200\2231771. D BALDWIN 306 13.8 Carcinoid Epidemiology Carcinoid is an uncommon tumor: \200 and dilatation as well as platelet aggregation. 5HT and other vaso-active substances are th ought to cause carcinoid syndrome and carcinoid heart disease. Annual incidence of carcinoid tumors is 1 \200\2232 cases per 100,000. 1 \200\2232% of all primary lung cancers. 12% of all carcinoid tumors arise in the lung. Clinical presentations Pulmonary carcinoid \200\231s most frequent symptoms are hae- moptys is, cough, recurrent pulmonary infection, fever, chest discomfort, unilateral wheezing (due to endobron- chial obstruction) and, if there are metastases (usually liver), then paraneo plastic syndromes can be a presenting feature. However, the frequency of metastatic disease related to pulmonary carcinoid is very low. \200 The sex distribution equal overall but the incidence in those aged <50 years for females is almost twice that of males. Peak incidence rates are at 15 \200\22325 years and 65 \200 \22375 years with a mean age of carcinoid diagnosis of approxi- mately 47 years. Atypical c arcinoid tumors occur in sig- ni \201 cantly older patients, usually in the sixth decade. Carcinoid syndrome Carcinoid syndrome occurs in approximately 2% of cases of pulmonary carc inoid. The characteristic symptoms are diarrhea, \202 ushing, palpitations, and wheezing. Symptoms will be more severe if the tumor drains directly into the systemic circulation (e specially liver metastases). Rarely, carcinoid crisis can be precipitated by the release of large volumes of vaso-active substances into the systemic circu- lation. This can occur af ter tumor manipulation, induction of anesthesia, or intubation. Pulmonary carcinoid The most frequent location is the main or lobar bronchi (70%). 30% are peripheral. Regional nodal involvement is found in 10% of cases at the time of diagnosis. S moking is a risk factor for pulmonary carcinoid and occasionally famil- ial pulmonary carci noids are found and are associated with the multiple endocrine neoplasia type 1 gene which is situ- ated on chromosome 11 (11Q13). Pathophysiology Carcinoid tumors may secrete vaso-active peptides that may be responsible f or both clinical presentation and com- plications. Carcinoids may secrete 5-hydroxytryptami ne (5HT) bradykinins, tachykinins, histamine, substance P, adenocorticotrophic hormone, pro staglandins, kallikrein, dopamine, and several other peptides. 5HT production is the most p rominent. Carcinoid tumors convert dietary tryptophan into serotonin, and serotonin is then metabo- lised to 5-hydroxyindoleacetic acid (5HIAA). If there is extensive metabolism of t ryptophan in this way as occurs in metastatic carcinoid, then this can lead to a reduction in the synthesis of nicotinamide which can lead to a diagnosis of pellagra (Fig. 13.8.1). Carcinoid heart disease This occurs as a late complication of metastatic carcinoid tumors. The heart lesions are characterized by \201 brosis of the valve on the right side of the heart due to high expo- sure to the vaso-active substances. These substances are metabolize d in the lung and this is thought to result in a signi \201 cantly lower exposure to the l eft side of the heart and hence the fact that only 10% of patients with carcinoid heart dis ease have lesions on the left side. Other syndromes Cushing \200\231s syndrome occurs in approximately 2% of patients with pulm onary carcinoid and is characterized by ectopic ACTH production. Although very rare, carcin oid tumors are the most frequent cause of ectopic growth hormone production and can lead to acromegaly. Nicotinamide (Vitamin B3) Tryptophan Diagnosis The diagnosis of carcinoid syndrome is achieved by obtain- ing a histological sam ple either by bronchoscopic biopsy or transthoracic needle biopsy. The tumor tends to be hi ghly vascular and this can result in signi \201 cant hemorrhage from bronchoscopic or tran sthoracic biopsies. However, despite some reports of signi \201 cant hemorrhage, it is usu ally not a problem. The classic appearances of the tumor at bronchos- copy are either a pin k, reddish or yellow smooth-looking tumor. Pellagra 5-HTP Carcinoid cell 5-HT Imaging Carcinoid tumors can show on CXR as a solitary pulmo- nary nodule or lobar consolid ation, where endobronchial obstruction has resulted in a post-obstructive pneumonia. Chest CT (Fig. 13.8.2) con \201 rms these \201 ndings and, as the liver is usually included in this scan, will show the presence of liver metastases. If that is the case then the primar y diag- nosis may be obtained from biopsies of the liver metas- tases. Immunoscintigraphy b y somatostatin analogs can be useful in the diagnosis of carcinoid. Carcinoids over- expres s somatostatin receptors. 111Indium-pentetreotide has a sensitivity of 80 \200\22390% for t he detection of carcinoid Monoamine oxidase 5-HIAA Fig. 13.8.1 5 \200\223HT (serotonin) metabolism. 5HT in the systemic circulation causes contraction of smooth muscle leading to bronchoconst riction, increased gastro-intestinal motility, vascular constriction CHAPTER 13.8 Carcinoid 307 Treatment Surgery Surgery is the treatment of choice for pulmonary carcinoid and has a high chance of cure. For typical carcinoids, lung- sparing operations are often performed, but in atypical carcinoid, lobectomy is recommended. In small endobron- chial carcinoids minima lly invasive resection with laser or electrocautery techniques has been successful. tumors and provides information about the localization of the tumor and is predictive of th e response to octeotride therapy (see below). 131Iodine-metaiodobenzylguanidine (131IMIBG) is an analog of an amine precursor which is taken up by neuroendocrine cells. This analog h as been used for the detection and imaging of neuroendocrine tu- mours and also as a therap eutic tool. However, the sensi- tivity is rather lower than the indium analog at around 70% . FDG PET (Fig. 13.8.3) has limited utility in carcinoid tumors because of a relatively low proliferative activity in these tumors and may have more of an application where there are metastases. Bone scintigraphy shows a high sen- sitivity for bone metastases than any of t he aforementioned analogs. Somatostatin analogs Somatostatin receptors have five subtypes and are expressed in more th an 80% of carcinoid tumors, espe- cially subtypes 2 and 5. Octreotide has a high af \201 n ity for these subtypes and can be administered subcutaneously 6 \200\2238-hourly. Octreotid e improves symptoms in up to 80% of patients and reduces 5HIAA excretion in 72%. 131I-MIBG This therapy involves higher doses of isotope to deliver a local internal radiation effect to the tumor cells than is used in patients with a positive diagnostic scan. The reported r esponse rates are 60% but the duration of effect is a median of eight months. Radio-labeled somatostatin analogs A variety of radio-labeled analogs have been used in pat ients with 111indium-pentetreotide scintigraphy. The lat- ter analog has shown bene \201 t s for treatment of small tumors or micro-metastases with improvement in up to 60% of patien ts. However, side effects include signi \201 cant renal and hematological toxicity as well as distressing nausea and vomiting. Interferon alpha Interferon alpha treatment decreases urinary 5HIAA in around 40% of patien ts but reduces tumor size in only 15%. Side effects include anorexia and weight loss, fever and fatigue. Interferon alpha therefore has a low therapeutic index and is not usually use d. Fig. 13.8.2 CT scan of carcinoid. Systemic chemotherapy This tends to be used as second-line therapy because of the low thera peutic response of 20-30%. Regimens used include streptozocin and cyclophosphamide or strep - tozocin and 5-fluorouracil. Third-line therapy using a combination of cisplatin and etopo side may be used in particularly aggressive carcinoid tumor as this regimen tends to help i n small cell lung cancer and neuroendocrine carcinomas. Radiotherapy Radiotherapy is effective palliation in bone and central nervous system metast ases. Supportive care Supportive care is particularly important where there are distressing sympt oms secondary to the carcinoid syn- drome. Flushes may be avoided by not taking food that i s known to provoke symptoms, and diarrhea can be treated with anti-diarrhea medications. It is also important to consider vitamin supplementation to avoid pellagra. Fig. 13.8.3 PET-CT scan of carcinoid. Tumor markers Urinary 5HIAA is the gold standard for the diagnosis and follow-up of carcino id tumors. It has a speci \201 city of al- most 100% but a much lower sensitivity (35%). U rinary 5HIAA levels are in \202 uenced by certain foods such as ba- nanas, pineapples and walnuts, and some medications. Platelet 5HT level is a sensitive marker for the detection o f small amounts of serotonin production but is not in general usage. Chromogranin A (CgA) i s a glycoprotein produced in most neuroendocrine tumors. It is therefore a non-speci \201 c detector of such tumors. Hepatic metastases Surgical resection of liver metastases may bene \201 t patients with li mited hepatic disease. However, this is applicable to only a minority of patients. Alternat ively, hepatic artery embolisation may be used and is applicable in carefully selected pati ents to reduce the tumor burden. Median duration of response is 12 months and there are D BALDWIN 308 important side effects to consider including renal toxicity and occasional hepatorenal synd rome. The role of liver transplantation in carcinoid syndrome is still under investigation. Summary Pulmonary carcinoid is an uncommon lung tumor that generally has a good prognosis e xcept where the tumor is atypical. Treatment is usually by surgical resection. Metas- tases may occur and rarely lead to the carcinoid syndrome. Outcomes from chemotherapy and other therapies are improving and new therapies are under investigation. KEY FACT Prognosis Typical carcinoid has 5- and 10-year survival of 87 \200\223100% and 82 \200\22387% respectively. The prognosis for atypical tumors is lower \200\223 5- and 10-ye ar survival 56 \200\22375% and 35 \200\22356%. Further reading Kosmidis PA Treatment of Carcinoid of the Lung. Curr Opin Oncol 2004; 16(2):146 \200\223149. Kulke MH, Mayer RJ. Carcinoid Tumors. N Eng J Med 1999; 340: 858 \200\223868. This page intentionally left blank R MILROY & K KERR RICHARD HUBBORD 310 13.9 Benign lung tumors Introduction Benign lung tumors are relatively rare, accounting for less than 1% of all lun g tumors. They comprise a very broad and heterogeneous group of lesions and may be divided or grouped according to their putative cell or tissue of origin. Thus this chapter will con sider, amongst others, lesions of bronchial gland, and airway epithelial origin, connective tissue tumors, benign tumors arising from pulmonary lymphoid tissue, vascular tumors and t umors showing neural differentiation. Tumor-like conditions will also be covered. Bronchial carcinoid tumors are low grade malig- nant lesions and will not be considered in this chap ter. In a clinical sense it is useful to consider whether the tumor is sited predominantly in an airway, or within the lung parenchyma or the pleura, as each location of tumor will h ave different clinical features. Benign tumors arising in a parenchymal location are often asymptomatic whilst those occurring in a large airway e.g. hamartomas, may have a symptomat ic presentation. For each tumor, etiology (if known or relevant), speci \201 c clinical fe atures and pathol- ogy will be discussed. Differential diagnosis for each will be considere d and treatment, if required, and outcomes will be considered. and may weigh up to 3 kg. Histologically these tumors are low grade spindle cell neoplasms showing a characteristic pattern of variable cellularity, collagen bundles and thick- walle d vessels. They have characteristic ultra structural and immunocyto chemical features, the most important diagnostically useful being the frequent expression of CD34 and bcl2. Malign ant forms are rare. Surgical resection is the recommended treatment and is usually curative although rarely local recurrence with a fatal outcome has been described. Thus it is essen tial to remove the tumor completely to avoid the risk of recur- rence, especially since any recurrence may be a higher grade, more aggressive disease. Solitary \201 brous tumors ma y also occur in the pulmonary parenchyma but these are much rarer than in the pleura. Calcifying \201 brous pseudotumour This tumor is very rare. They are well circumscribed b ut not encapsulated and involve the visceral pleura. Surgical resection is the recommended treatment and recurrence is unusual. Adenomatoid tumor This is a distinctive mesothelial tumor which is entirely benign and has rarely been reported arising in the pleura. Benign pleural tumors All of these lesions are rare, and some are true neoplasms. The main differential diagnoses for benign pleural tumors include primary or secondary malignancy an d organizing empyema. Blesovsky \200\231s Disease (folded lung) Localized areas of pleural thickening and \201 brosis are often identi \201 ed by chance on a CXR when they may mimic a peripheral lung t umor. They do not usually cause symp- toms or functional embarrassment. The contracting ple ural \201 brosis and scarring causes adjacent lung tissue to fold in- wards and collapse and this is particularly seen at the lung bases. Radiologically the characteristic feature is the so-called comet \200\231s tail sign and this is particularly well seen on cross sect ional imaging. A variety of terms have been used to describe Blesovsky \200\231s Disease an d include folded lung and rounded atelectasis. Localized \201 brous tumor of the pleura Although sometimes an incidental radiological \201 nding, patients often complain of chest discomfort, which may be accompanied by cough or breathlessness. This condition is associated with both \201 nger clubbing and hypertro phic pulmonary osteoarthropathy. Some patients can develop spontaneous hypoglycaemia, possi bly related to secretion of insulin like growth factors. These benign tumors usually arise from the visceral pleura but have rarely been described arising from the parietal or medias tinal pleura. Typically they are smooth pedunculated tumors, which can grow to a substantia l size (up to 30 cm) Pleural splenosis This may occur following trauma, rupture of the spleen and diaphragmatic damage, allowing splenic tissue to be implanted in the pleural cavity. It follows that pleu ral sple- nosis almost always occurs on the left side of the chest. Usually patients are as ymptomatic and the abnormality is detected as an incidental radiological \201 nding many years after the traumatic episode. Histologically the lesions show normal splenic tissue. P leural thymoma and pleural endometriosis are extremely uncommon lesions and are discussed u nder the section on their pulmonary counterparts. Benign parenchymal tumors of the lung These often present as asymptomatic peripheral masses seen on a CXR taken for unrelated reasons. A wide range of tumors are included in this cat egory. These are listed in Table 13.9.1, categorized according to their pathologic classi \201 cation. Some lesions occur in both peripheral paren- chymal and endobronchial location s and will be discussed in the context of the site where they are more frequently encounter ed. The commonest type of benign parenchymal lung tumor is hamartoma but the list includes a number of extremely uncommon neoplasms of both epithelial and Fig. 13.9.1 This solitary \201 brous tumor is intrapulmonary rather than pleural. The les ion is well circumscribed and, in this region, densely cellular. (See Plate 10.) CHAPTER 13.9 Benign lung tumors 311 connective tissue differentiation, as well as a number of non-neoplastic tumor-like conditi ons. mal location are usually easy to resect, and recurrence or malignant change is exceedingly rare. Lipomas and chondromas are more likely to be endobron- chial. True pulmonary chondrom as are extremely unusual, usually multiple and occur more commonly in females. Radiological ly calci \201 cation is frequent, pathologically bone may be present in some lesions and t hese lesions occur in the context of Carney \200\231s triad (pulmonary chondromas, gastric stromal tumors and paragangliomas). Differential diagnosis of the histology includes chondr oid hamartoma and metastatic chondrosarcoma. Investigation of benign parenchymal lung tumors These tumors will often be found incidental ly on a CXR when they may mimic a lung cancer. Occasionally, however, they may appear unusu ally round, smooth and well-circum- scribed on chest imaging, suggesting the benign nature of the problem. CT scanning and percutaneous needle core biopsy may give a diagnosis but of ten the true nature of the lesion is only apparent after resection and full pathologic exam ination. As in lung cancer the investigative journey for an individual patient will be pred icated by the patient \200\231s performance status, comorbidity (especially lung function) and personal wishes. Leiomyoma and \201 broleiomyoma These are extremely rare tumors and usually occur in mid- dle aged women. Pulmonary leiomyomas resemble those encountered in other sites. They are w ell circumscribed. Angiomyolipoma These are also extremely rare benign tumors which are hamartomas and compose d of a mixture of blood vessels, smooth muscle and fat. Although most commonly found in the kidney they have rarely been reported in the lung. Speci \201 c types of benign parenchymal lung tumor Soft (connective) tissue tumors Chondr oid hamartoma and related lesions These tumors, although relatively uncommon, are, in terms of benign lung tumors, the commonest type and account for about 8% of coin lesions seen on CXR. They are commonest in late middle age, show a male preponderance, most are parenchyma l and consequently asymptomatic but about 10% are endobronchial and cause endobronchial sym ptoms. Massive haemoptysis has been described. They comprise a mixture of various connectiv e tissues (fat, carti- lage, smooth muscle) and epithelial tissue components, but there is debate as to whether these lesions are truly ham- artomas or are true neoplasms. The term m esenchymoma has been proposed and it is now recognized that pulmonary lipomas, chondromas a nd \201 bromas may be related neo- plasms. These monotypic examples are, however much les s common than the heterogeneous \200\230chondroid hamartoma \200\231. The connective tissu e components may calcify, giving the characteristic \200\230pop-corn \200\231 pattern of c alci \201 cation in some lesions on the chest radiograph. Fig. 13.9.3 This is an endobronchial chondroid hamartoma. The cartilage plates and seromuco us glands of the native bronchus are seen below, the lesion comprising connective and adipo se tissue and cartilage, which has ossi \201 ed and has a substantial component of bone ma rrow (top right). (See Plate 11.) In \202 ammatory myo \201 broblastic tumor This rare pulmonary lesion is a member of the rare heterogeneous group of so-called in \202 ammatory pseudo- tumors. It has many synonym s and has subsumed a number of previous \200\230entities \200\231 such as plasma cell gran u- loma and \201 brous histiocytoma. It occurs most often in patients aged under 40 years and shows an equal gender distribution. Most lesions present as localized pulmonary masses which may mimic carcinoma radiologically. Signs and symptoms are dependent on the localiza tion of the lesion. Rarer endo-bronchial lesions may cause cough, wheeze and hae- moptysis. Peripheral lesions give fewer symptoms unless the chest wall is involved. Fig. 13.9.2 CT image of a calci \201 ed chondroid hamartoma. These lesions show a heterogeneous mixture of spindles cells, macrophages and variable in \201 ltrates of chronic in \202 am- matory cells. Giant cells may be seen. Atypia is rare but the tendency to occasionally invade locally, recur after excision and even rarely metas tasise has led some to consider this lesion a low grade malignancy. The pathological features of pulmonary hamartomas are the same wherever they arise, be it i n the lung parenchyma or as endobronchial growths. They are usually 1 \200\2233 cm in size but can grow up to 9 cm. Those arising in a parenchy- R MILROY & K KERR 312 presentation is wide (10 \200\22360 years),with a median age at 40. Half of the patients ar e asymptomatic. The remain- der complain of cough, and of breathlessness. Typical radiologi c \201 ndings are the presence of multiple bilateral, sometimes calci \201 ed small nodu les of 1 \200\2232 cm diameter, though solitary masses may occur. Typically this condition is misinterpreted as metastatic disease or old granuloma- tous in \202 ammation. Histologi cally the tumor shows cords and nests of epithe- lioid endothelial cells set in a rather my xoid stroma. This tumor may also occur in the pleura. The multiple tumors slowly enlarge ov er a period of years and patients die of respiratory failure. Other vascular tumors Haemangioma and lymphangioma are exceedingly rare in the lung. They r esemble similar tumors elsewhere in the body and form well circumscribed lesions. They tend to be intrapulmonary but may occur endobronchially. Such a case causing haemoptysis has be en described. Fig. 13.9.4 Bronchial lipoma showing accumulations of adipose tissue deep to the respirator y mucosa. Clear cell tumor This benign lung tumor has also been named the \200\230sugar tumor \200 \231. Less than \201 fty cases have been reported in the world literature. They tend to o ccur in middle aged patients who are usually asymptomatic and the tumor is an incidental so litary \201 nding. This is probably a tumor of perivascular epithelioid cells (so-called PEC cells) and the most important differential diagnosis would be with metastatic renal cel l carcinoma since the lesion comprises large but banal looking cells with clear cytoplasm c ontaining abundant glycogen. These tumors are quite vascular. The benign pulmonary tumor wi ll not express cytokeratins but will express HMB45. The tumor is usually peripheral and res ection is generally curative. Neural tumors These include nerve sheath tumors, and granular cell tumors. They are all ext remely rare occurences in the lung. Nerve sheath tumors comprise both neuro \201 bromas an d neurilemmomas which are identical to their counterparts elsewhere. These tumors are somet imes associated with neuro \201 bromatosis. They may be parenchymal but have also been fou nd in the airways and visible on bronchoscopy. Granular cells tumors are more often endobro nchial and discussed later. Parenchymal epithelial tumors Sclerosing pneumocytoma (sclerosing haemangioma) Despite the original belief that this was a vascular tumor, hence the term \200\230haemangioma \200 \231, it now clear that this is an epithelial tumor showing pneumocyte differentiation. Vascular tumors Epithilioid haemangioendothelioma This is a low grade but potentially malig nant endothelial tumor, 80% of which occur in women. Age range at Table 13.9.1 Benign tumors and tumor-like conditions of the lung Parenchymal tumors Epithelial neoplasms Soft tissue and other neoplasms Non-neoplastic conditions Alveolar adenoma Papillary adenoma Mucinous cystadenoma Sclerosing haemangioma (pneumocytom a) Thymoma Pleomorphic adenoma Hamartoma Chondroma Lipoma Fibroma Leiomyoma Clear cell (sugar) tumor Meningioma In \202 a mmatory myo \201 broblastic tumor Granular cell tumor Epithelioid haemangioendothelioma Amyloid tumor Hyalinising granuloma Malakoplakia Endometriosis A-V malformation Lymphoproli ferative disorders Endobronchial tumors Epithelial neoplasms Soft tissue and other neoplasms Non-neoplastic conditions Papillomas Squamous papilloma Glandular papilloma Mixed papilloma Bronchial gland adenomas Mucous gland adenomas Oncocytoma Pleomorphic adenoma Hamartoma Chondroma Lipoma Granular cell tumor Fibroin \202 ammatory polyps Amyloid tumor Foreign body Bacillary angiomatosis CHAPTER 13.9 Benign lung tumors 313 These tumors are commonest in middle age and com- moner in women. These lesions are much co mmoner in East Asia, especially Japan. The are usually asymptomatic, but cough, pain and ha emoptysis may occur. Pathologically the tumors tend to compress adjacent nor- mal lung pare nchyma and most measure under 3cm, though lesions up to 8cm are described. Most are solitar y lesions though around 4% are multiple. The two basic histological features of a sclerosin g pneumocytoma are the presence of sclerosis and papillary epithelial proliferation but the y may show a very wide range of features including alveolar-like spaces and a dual populati on of larger pale cells and smaller \200\230stromal \200\231 cells. Haemorrage and heamosi derin are com- monly present. Immunohistochemistry for cytokeratins and TTF1 are key to the histologic diagnosis.