benign disease (100% vs. 45–50%) and is more likely to obtain suf cient tissue for mutation analysis in lung cancer [2, 3].

Thoracentesis and Pleural Biopsy

Pleural involvement in lung cancer can be by direct extension of the primary tumor into visceral (T2) or parietal pleura (T3), or by metastasis as pleural-based nodules and/or malignant cells in a pleural effusion (M1a). When there is a suspicion of pleural metastasis, sampling of pleural space is performed by thoracentesis and/or pleural biopsy.

Thoracentesis

In patients with pleural effusions, thoracentesis is performed to obtain at least 50–60 mL of pleural fuid sample for pleural fuid cytology and cell block preparation. Blind thoracentesis can be performed in cases with moderate-large and free-­ fowing effusions but image-guidance usually with US is recommended, particularly in small, loculated and/or hard-to-localize effusions. The mean sensitivity of thoracentesis for malignancy is 72% (49–91%). If cytology is negative or indeterminate for cancer, sampling should be repeated before considering pleural biopsy by medical or surgical thoracoscopy, image-guided pleural biopsy, or closed pleural biopsy. Repeated thoracentesis increases sensitivity. Positivity for malignancy is 30% in the second, and 5–25% in the third thoracentesis. Molecular tumor markers on pleural fuid can be evaluated although its sensitivity is low and assay methodology is variable [61].

Pleural Biopsy

If pleural fuid cytology is negative, or if there are pleural masses or thickening, pleural biopsy is indicated. Pleural biopsy options are surgical or medical thoracoscopy, USor CT-guided pleural biopsy, and closed pleural biopsy.

Surgical or Medical Thoracoscopy

Surgical thoracoscopy is generally performed under general anesthesia and video assistance in the operating room. Medical thoracoscopy (pleu-

roscopy) is an endoscopic procedure performed usually under conscious sedation in the endoscopy unit. By using either procedure, biopsy samples can be obtained randomly or from macroscopically visible lesions on the parietal and visceral pleura under direct visualization. Among the three options for pleural biopsy, the highest diagnostic performance can be achieved by thoracoscopy (sensitivity: 80–99%, negative predictive value: 93–96%). Furthermore, thoracoscopy provides therapeutic options to prevent recurrent effusion (pleurodesis, insertion of an in-dwelling catheter) [61–63].

Image-Guided Pleural Biopsy

CTor US-guidance is used for image-guided pleural biopsy that can be performed with or without sedation in the interventional radiology suite. Focal pleural lesions/abnormalities with or without associated pleural effusions are the main indications for this modality. Its sensitivity and negative predictive value are 76–88% 75–80%, respectively. Image-guided CNB of pleura can have a sensitivity comparable to thoracoscopy in identifying lung cancer (93% vs. 100%, respectively), and CT-guided CNB can be more sensitive than US-guided CNB (82% versus 67%) [61, 62].

Closed Pleural Biopsy

In current practice, blind closed pleural biopsy is rarely performed for diagnosing and staging lung cancer. It can only be performed if pleural fuid is present and can obtain samples only from the parietal pleura. Low sensitivity and consequent limited utility of closed pleural biopsy may be due to the occurence of pleural metastases more commonly on the visceral pleura as well as decreasing utilization and expertise in this method [61].

Image-Guided Biopsies for Extrathoracic Metastases

Histologic con rmation of extrathoracic metastases of lung cancer is necessary to determine isolated (M1b) and multiple metastases (M1c) in sites such as liver, adrenal gland, brain, bone, and