Pleural Lavage Cytology in Patients with Resectable Lung Cancer

International Pleural Newsletter A Publication of the International Pleural Network Volume 8 Issue 1 January 2010 Editors: Richard W. Light Y.C. Gary Lee José M. Porcel Co-Editors: Michael H. Baumann Robert J.O. Davies John E. Heffner International Advisors: P Astoul France V C Broaddus USA A Ernst USA G Hillerdal Sweden Y Kalomenidis Greece R Loddenkemper Germany M Noppen Belgium S Romero-Candeira Spain G F Tassi Italy F S Vargas Brazil A P C Yim Hong Kong Nashville, TN, USA Perth, Australia Lleida, Spain Jackson, MS, USA Oxford, UK Portland, OR, USA D Bouros Greece T E Eaton New Zealand F V Gleeson UK S Idell USA T K Lim Singapore S E Mutsaers Australia F Rodriguez-Panadero Spain S A Sahn USA L R Teixeira Brazil C Xie China Administrator: Emma Hedley Oxford, UK gary.lee@uwa.edu.au The International Pleural Newsletter is distributed or web-posted by the: American College of Chest Physicians Asian Pacific Society of Respirology Asociación Latino Americana del Tórax Belgian Society of Pulmonology Brazilian Thoracic Society British Thoracic Society Costa Rican Thoracic Society European Respiratory Society International Mesothelioma Interest Group Italian Association of Hospital Pulmonologists Singapore Thoracic Society South African Thoracic Society Thoracic Society of Australia & New Zealand Turkish Thoracic Society The Newsletter is on line: www.musc.edu/pleuralnews Pleural Lavage Cytology in Patients with Resectable Lung Cancer Eric Lim MD The Royal Brompton Hospital, London e.lim@rbht.nhs.uk Pleural lavage cytology (PLC) is the microscopic study of cells obtained from saline instilled into and retrieved from the chest cavity (in patients without pre-operative pleural effusion) during surgery for non-small cell lung cancer. The solution is aspirated and cytological analysis performed to screen for malignant cells (figure). Results from this procedure have been published from Japan as early as 1989 1 and, internationally, an increasing number of centers have adopted this practice. The frequency of positive results in the literature varies according to amount of solution used, timing of the procedure and center, but in general is <10% in the larger published series. It has been reported that patients with a positive result have a poorer prognosis. A recent metaanalysis of individual patient data (8763 patients from 11 centers) has identified positive pleural lavage cytology as an independent predictor of adverse survival (hazard ratio 1.46, 95%CI 1.29-1.66), with a magnitude similar to upstaging of patients by a single T category 2. The clinical implication is the ability to identify and offer patients with early stage lung cancer post-operative (adjuvant) chemotherapy. 1

Although pleural lavage cytology is inexpensive, simple to perform and does not require specialized equipment or facilities for analysis, few centers offer this additional surgical staging modality. The techniques used differ widely, and there is a need for international standardization. We recommend 100 ml of saline be irrigated over the lung surface immediately after thoracotomy and prior to lung resection. The saline should then be aspirated and sent for cytological screening for malignant cells 3. In the 7 th Edition of the TNM staging for lung cancer, surgeons and pathologists are encouraged to undertake this additional form of staging. Despite complete resection, if the pleural lavage cytology results are positive, then the resection is classified as R1(cy+) 4. In summary, pleural lavage cytology should be considered in all patients with early stage lung cancer suitable for resection. A positive result is an independent predictor of poor outcome and can help to identify patients with early stage lung cancer who can be offered post-operative (adjuvant) chemotherapy with an aim to improve survival. 1. Kondo H, et al. Jpn J Cancer Res 1989; 80:233-237. 2. International Pleural Lavage Cytology Collaborators. J Thorac Cardiovasc Surg (in press) 3. Lim E, et al. J Thorac Cardiovasc Surg 2004; 127:1113-1118. 4. Goldstraw P. International Association for the Study of Lung Cancer Staging Handbook in Thoracic Oncology. Florida, USA: Editorial Rx Press, 2009. Pleural Publications from 2009 that Influence Clinical Care Imran Bin Mohamed Noor MD Changi General Hospital, Singapore Andrew Rosenstengel MD Prince Charles Hospital, Queensland, Australia andrew_rosenstengel@health.qld.gov.au The authors selected seven articles published in 2009 that will most likely impact on clinical pleural practice. Pleural procedure safety is a topical issue. A Mayo Clinic study demonstrated a significant reduction of complications from thoracentesis (from 8.7% to 1.1% in iatrogenic pneumothorax; p=0.01) through a comprehensive program, that involved granting privilege of performing pleural procedures only to pulmonologists who had passed a proficiency assessment, a structured educational program for junior staff, and mandatory ultrasound guidance for pleural procedures 1. This is a must-read article for all clinicians and consideration should be given to adapt these safety measures. Qureshi et al identified, in 52 consecutive patients, features from ultrasound that were highly suggestive of malignant diseases 2. Pleural thickening >1 cm, pleural nodularity and diaphragmatic thickening >7 mm had a positive predictive value of 100% and negative predictive value of 79%. As ultrasound guidance is being increasingly used worldwide for pleural procedures, clinicians need to be aware of these implications. Abouzgheib et al conducted a study looking at the volume of fluid required for a positive cytology in malignant pleural effusions 3. The authors sent one 50 ml specimen of fluid and the remaining large volume from each of 45 patients for cytological analyses. The diagnostic sensitivities were identical between the 50 ml sample and the large volume specimen. This study adds to previous publications conclusions that large volume thoracentesis is not necessary to improve diagnostic yield in malignant pleural effusions. Terra et al randomized 60 patients with malignant pleural effusion to talc slurry pleurodesis or videoassisted thoracic surgery (VATS) talc poudrage. Although VATS provided a higher rate of immediate total lung re-expansion (p=0.027) 4, it offered no advantage in pleurodesis success rates (by radiological or clinical criteria) and the incidence of complications were comparable. This is in keeping with findings from two previous randomized studies that VATS talc poudrage is not superior to talc slurry. Mesothelin levels in pleural fluid were significantly raised in mesothelioma effusions compared with those from metastatic pleural carcinomas or benign pleuritis, and had an adjunct role to cytological examination in a study of 167 undiagnosed pleural effusions 5. Serial monitoring of mesothelin levels showed it increasing with time and disease progression, raising a potential role for disease monitoring 5. Gregoriu et al 6 further confirmed 2

a good correlation between blood mesothelin levels and clinical responses in 40 patients treated with gene therapy for mesothelioma. Light s criteria are useful in differentiating between transudates and exudates. However, misclassification can occur especially in patients with congestive heart failure who are on diuretics. Porcel et al demonstrated pleural fluid N terminal pro-brain natriuretic peptide (NT-proBNP) as a valuable marker in identifying 91 cardiac failure related effusions7. In particular, NT-proBNP correctly identified 90% of 20 cardiac failure effusions misclassified by Light s criteria as exudates, which compared favorably against BNP and serum-pleural protein gradient (70% and 50% respectively). Measurement of pleural fluid NT-proBNP is a useful addition to the currently available tests in the workup of patients with cardiac failure related effusions. 1. 2. 3. 4. 5. 6. 7. lymphadenopathy was evident in the contralateral lung. An exudative lymphocyterich effusion was initially drained to alleviate dyspnea. Subsequently, surgical biopsy of the pleura and a mediastinal lymph node revealed well-formed non-caseating granulomata consisting of epithelioid and multinucleated giant cells. Prolonged culture did not yield a pathogen. The patient died of myocardial sarcoidosis one year after the initial diagnosis. Case 2. A 71-year-old Indian female presented with insidious-onset breathlessness, dry cough and constitutional symptoms. Numerous small nodules scattered in a perilymphatic distribution were present in the upper lobes, together with other larger subpleural nodules (right). VATS pleural biopsy secured a diagnosis of sarcoidosis. Seven months later, hospitalisation was necessitated by symptomatic worsening whilst taking low-dose prednisone. Chest radiograph demonstrated a unilateral pleural effusion, aspiration of which revealed mixed lymphocytosis and eosinophilia. Extensive tests for infection were negative and clinical improvement was produced with increased doses of corticosteroid. Duncan DR, et al. Chest 2009; 135:1315-1320. Qureshi NR, et al. Thorax 2009; 64:139-143. Abouzgheib W, et al. Chest 2009;135:999-1001. Terra RM, et al. Chest 2009; 136:361-368. Davies HE, et al. Am J Respir Crit Care Med 2009; 180:437-444. Grigoriu BD, et al. Am J Respir Crit Care Med 2009; 179:950 954. Porcel JM, et al. Chest 2009; 136:671-677. CASE REPORTS Pleural Manifestations of Sarcoidosis Penelope Tinga MBBS Felix Chua MRCP PhD St. George s Hospital, London, UK felix.chua@stgeorges.nhs.uk Case 3. A young Afro-Caribbean patient with pulmonary, cutaneous and ocular sarcoidosis developed increased dyspnea, palpitations and cardiac failure over a matter of months. A chest radiograph (see left) demonstrated an enlarged cardiac contour, bilateral pleural effusions and the presence of a Reveal device (loop recorder). Cardiovascular MRI demonstrated a dilated proximal Pleural involvement is an unusual complication of sarcoidosis, as highlighted in the following illustrative cases. Case 1. Two years following the diagnosis of tissue-proven, but untreated, pulmonary sarcoidosis, a 46-year-old Afro-Caribbean female presented with marked dyspnea, which had developed over a twoweek period. Plain radiography showed a large leftsided pleural effusion causing mediastinal deviation to the opposite side (left). Enlarged hilar 3

pulmonary arterial trunk, right ventricular dilatation and delayed gadolinium enhancement in a pattern consistent with established myocardial sarcoidosis. Right heart catheterization showed a raised pulmonary arterial pressure. Analysis of the pleural fluid confirmed transudative characteristics and elevated levels of circulating NT-proBNP, in keeping with cardiac failure. Pleural sarcoidosis has been described in 1-5% of patients with pulmonary manifestations of the disease 1,2. The prevalence of bilateral effusions is unknown. Although sarcoid pleural effusions tend to be exudative, transudative collections have also been encountered 3. The finding of pleural fluid eosinophilia has been described as highly unusual 4. From limited studies, there is no evidence that exacerbations of parenchymal sarcoidosis per se increase the likelihood of pleural complications 2. Sarcoid pleural effusions may spontaneously resolve, but in practice many patients are likely to be offered corticosteroid treatment. While pleural thickening may itself be an uncommon finding, the appearance of subpleural sarcoid nodules and inflammation (as in case 2) may produce an impression of pleural abnormalities on plain radiography or CT. Cardiac failure due to sarcoid cardiomyopathy is a rare cause of pleural effusions (case 3). In patients known to have sarcoidosis, an alternative cause for a new pleural effusion must be excluded, including tuberculous pleuritis. pain. The chest x-ray showed an oval-shaped mass (28 mm size) close to the 7th left rib (below left). A chest CT scan showed some highly enhanced and confluent masses on the lateral and posterior chest wall. These findings were suggestive of a pleural neoplasm. A thoracic ultrasound revealed a small left pleural effusion. The pleural fluid was an exudate with no malignant cells on cytological examination. Thoracoscopy revealed a smooth, round, rosy and pedunculated tumor on the parietal pleura (right), in addition to other smaller lesions. Histopathological examination of pleural biopsies revealed digit-like aspects, papillary axis bundles and a dense fibrotic desmoplastic stroma with proliferative aspects (see below). The immunohistochemical examination demonstrated diffuse positivity for cytokeratins, HBME1, calretinin, p53 and 10% Ki67 proliferation index. CEA, TTF1 and BEREP4 markers were all negative. According to the WHO criteria, these findings were indicative of a well-differentiated papillary mesothelioma (WDPM). 1. Sharma OP, et al. Thorax 1975; 30:95-101. 2. Huggins JT, et al. Chest 2006; 129:1599-1604. 3. Wilen SB, et al. Am J Med 1974; 57:200-209. 4. Vafiadis E, et al. South Med J 2005; 98:1218-1222. A Well-differentiated Papillary Mesothelioma of the Pleura Angelo Gianni Casalini MD Giuseppina Bertorelli MD Lisa Lasagna MD Pier Anselmo Mori MD University of Parma, Italy giuseppina.bertorelli@unipr.it A 76-year-old woman, with no history of asbestos exposure, was admitted complaining of left thoracic Due to the patient s age and comorbidities, as well as the presence of multiple pleural lesions, we decided not to perform surgery. Five months after the first hospitalization, a new chest X-ray and CT showed a significant increase in the size of the pleural mass (maximum diameter 80 mm). Eight months after the initial diagnosis and without therapy, the patient remains stable clinically and radiologically. WDPM is an uncommon tumor arising principally in the peritoneum of women of reproductive age 1. WDPM rarely occurs at other sites, including the pericardium, tunica vaginalis, and pleura 1,2. Only 33 4

cases of pleural WDPM have been reported in the literature 1,2. Most reported cases show a relatively good prognosis with prolonged survival without any specific treatment and lacking any association with asbestos exposure 3. In a study of 24 patients with WDPM, the average survival was 74 months (range 36 to 180 months) compared with 9.9 months for 1248 paired patients with diffuse malignant mesothelioma 2. The 10-year survival was 30.8%. However, several WDPMs in that study followed a more aggressive course, resulting in death. 1. Butnor KJ, et al. Am J Surg Pathol 2001; 25:1304-1309. 2. Galateau-Sallè F, et al. Am J Surg Pathol 2004; 28:534-40. 3. Torii I, et al. Lung Cancer 2010; 67:244-247. Hemothorax Associated with Acute Necrotizing Pancreatitis Andres F Sosa MD Paulo J Oliveira MD Oren P Schaefer MD UMass Memorial Medical Center, Worcester, MA Andres.Sosa@umassmemorial.org A 69-year-old man presented to the hospital with acute necrotizing pancreatitis. A chest x-ray showed a massive right pleural effusion (see below). Pleural fluid analyses revealed the followings: RBC 1,580000/mm 3, hematocrit 15% (serum hematocrit 29%), LDH 1,098 IU/L, and amylase 4,235 IU/L. A tube thoracostomy was performed and the effusion drained to near completion. Intra-abdominal fluid from a peripancreatic drain revealed an amylase >14,400 IU/L and lipase >396 U/L. A pancreatic duct leak was suspected and confirmed with an endoscopic retrograde pancreatography (ERCP) and a pancreatic duct stent was placed. The procedure did not reveal a pancreaticopleural fistula. The patient developed extensive pancreatic necrosis with abscess formation and died two months later. Pleural effusions have been described in 13%-50% of patients with acute pancreatitis 1. The effusions are more commonly bilateral, with unilateral effusions being usually left-sided. The presence of pleural effusions in acute pancreatitis is a negative prognostic factor related to the severity of disease 1. Most of these effusions usually resolve without intervention as the pancreatic inflammation subsides. Hemorrhagic pleural effusions rarely complicate pancreatitis and tend to be associated with a pseudocyst rupture, formation of a pancreaticopleural fistula and chronic pancreatitis 2,3. Large, recurrent effusions with amylase levels > 4,000 IU/L have been linked to the presence of fistulas. Our patient had a hemorrhagic pleural effusion with markedly elevated levels of amylase associated with acute necrotizing pancreatitis. There were no pseudocysts or fistulous tracts detectable using abdominal CT and ERCP, the gold standard for diagnosing a pancreaticopleural fistula. Magnetic resonance pancreatography may also play a role in diagnosing pancreaticopleural fistulas. Pleural hemorrhage in the setting of acute pancreatitis is thought to occur as the result of a high concentration of pancreatic enzymes entering the pleural space and disrupting the pleural surface and submesothelial vessels 3. The presence of a pancreatic duct leak in this patient, with the subsequent transdiaphragmatic seepage of pancreatic enzymes into the pleural space, may have been responsible for the hemothorax. In most of these cases, drainage of the pleural effusion and conservative management seems a reasonable approach 2. Other management strategies include draining of the pseudocyst (if present), placement of a pancreatic duct stent if a leak is noted (as in this case), treatment with somatostatin analogs in the case of high-output pancreaticopleural fistulas along with bowel rest and total parenteral nutrition and, occasionally, surgical intervention 1-3. 1. Lankisch PG, et al. Am J Gastroenterol 1994; 89:1849-51. 2. Namazi MR, et al. BMC Pulm Med 2004; 4:1-4. 3. Boudaya MS, et al. Surg Today 2007; 37:518-520. 5