18
Thoracic Wall, Pleura, Mediastinum, & Lung
ANATOMY & PHYSIOLOGY
ANATOMY OF THE CHEST WALL & PLEURA
The physiology of respiration and the anatomy of the chest wall are tightly linked. The chest wall is an airtight, expandable, cone-shaped cage. Normal ventilation occurs when expansion of the rib cage and simultaneous diaphragmatic excursion create negative intrathoracic pressure, allowing inward flow of air.
The function of the chest wall is made possible by its segmentally arranged anatomy. The ventral wall of the bony thorax extends from the suprasternal notch to the xiphoid, approximately 18 cm in the adult. It is formed by the manubrium, sternum, and xiphoid process. The remainder of the anterior wall and the lateral walls are formed by 12 ribs. The first seven pairs of ribs articulate directly with the sternum, the next three pairs connect to the lower border of the preceding rib, and the last two terminate in the wall of the abdomen. The sides of the chest wall consist of the upper 10 ribs, which slope obliquely downward from their posterior attachments. The posterior chest wall is formed by the twelve thoracic vertebrae, their transverse processes, and the 12 ribs (Figure 18–1). The upper ventral portion of the thoracic cage is covered by the clavicle and the subclavian vessels. Laterally, it is covered by the shoulder girdle and axillary nerves and vessels; dorsally, it is covered in part by the scapula.
Figure 18–1. The thorax, showing rib cage, pleura, and lung fields.
The superior aperture of the thorax (also called either the thoracic inlet or the thoracic outlet) is a downwardly slanted 5- to 10-cm kidney-shaped opening bounded by the first costal cartilages and ribs laterally, the manubrium anteriorly, and the body of the first thoracic vertebra posteriorly. The inferior aperture of the thorax is bounded by the twelfth vertebra and ribs posteriorly and the cartilages of the seventh to tenth ribs and the xiphisternal joint anteriorly. It is much wider than the superior aperture and is occupied by the diaphragm.
The blood supply and innervation of the chest wall are via the intercostal vessels and nerves (Figures 18–2 and 18–3). The upper thorax also receives vessels and nerves from the cervical and axillary regions. The underside of the sternum’s blood supply derives from the internal thoracic artery branches, which anastomose with the intercostal vessels along the lateral aspect of the chest wall.
Figure 18–2. Transverse section of thorax.
Figure 18–3. Intercostal muscles, vessels, and nerves.
The entirety of the thoracic cavity is lined by a pleural membrane. The parietal pleura is the innermost lining of the chest wall and is divided into four parts: the cervical pleura (cupola or cupula), costal pleura, mediastinal pleura, and diaphragmatic pleura. The visceral pleura is a mesodermal layer investing the lungs and is continuous with the parietal pleura, joining it at the hilum of the lung. The potential pleural space is a capillary gap that normally contains only a few drops of serous fluid. However, this space may be enlarged when fluid (hydrothorax), blood (hemothorax), pus (pyothorax or empyema), lymphatic fluid (chylothorax), or air (pneumothorax) fills this potential cavity.
PHYSIOLOGY OF THE CHEST WALL & PLEURA
Mechanics of Respiration
Ventilation is the process of moving gas through the conducting airways, to and from the alveoli, and occurs when elevation of the rib cage and descent of the diaphragm cause an increase in thoracic volume and generate negative intrathoracic pressure. In infants, the ribs have not yet assumed their oblique contour and ventilation depends on diaphragmatic breathing. Furthermore, accessory muscles of respiration contribute to the conformational change in the thoracic cage during periods of intense exercise or respiratory distress (Figure 18–4).
Figure 18–4. Accessory muscles of respiration. (From Kapandji IA. The respiratory muscle. In: Kapandji IA, ed. The Physiology of the Joints. vol. 3. The Trunk and the Vertebral Column. Churchill Livingstone, 1974.)
Expiration is mainly passive, resulting from elastic recoil of the lungs. An exception to this is deep breathing, when the abdominal musculature contracts, pulling the rib cage downward and simultaneously elevating the diaphragm by compressing the abdominal viscera against it.
Physiology of the Pleural Space
The pleural cavity pressure is normally negative, owing to the opposing forces of elastic recoil of the lung and active expansion of the space by the chest wall. During quiet respiration, it varies from −15 cm H2O with inspiration to 2 cm H2O during expiration. Larger pressure changes (eg, −60 cm H2O during forced inspiration to +30 cm H2O during vigorous expiration) may occur with deep breathing. Because of gravity, pleural pressure at the apex is more negative when the body is upright and changes about 0.2 cm H2O per centimeter of vertical height.
The formation (transudation) and reabsorption of fluid within the pleural space depends on hydrostatic, colloid, and tissue pressures (the Starling equation) in addition to permeability of the pleural membrane. In health, fluid is formed by the parietal pleura and absorbed by the visceral pleura (Figure 18–5). Since systemic capillary hydrostatic pressure is 30 cm H2O, and intrapleural negative pressure averages –5 cm H2O there is a net hydrostatic pressure of 35 cm H2O. Additionally, the colloid osmotic pressure of the systemic capillaries is 34 cm H2O and an opposing 8 cm H2O of pleural space osmotic pressure. Thus, a net 26 cm H2O osmotic pressure draws fluid back into systemic capillaries. Since systemic hydrostatic pressure (35 cm H2O) exceeds osmotic capillary pressure (26 cm H2O) by 9 cm H2O, there is a 9 cm H2O net drive of fluid into the pleural space by systemic capillaries in the chest wall. Similar calculations for the visceral pleura involving the low-pressure pulmonary circulation will show that there is a resulting net drive of 10 cm H2O that attracts pleural fluid into pulmonary capillaries. Thus, there is normally a balance favoring neither loss nor gain of fluid in this space.
Figure 18–5. Movement of fluid across the pleural space, showing production and absorption of pleural fluid.
In health, pleural fluid is low in protein (<100 mg/dL). When it increases in disease to about 1 g/dL, the net colloid osmotic pressure of the visceral pleural capillaries is equaled and pleural fluid reabsorption becomes dependent on lymphatic drainage. Thus, abnormal amounts of pleural fluid may accumulate: (1) when hydrostatic pressure is increased, such as in heart failure; (2) when capillary permeability is increased, as in inflammatory or neoplastic disease; or (3) when colloid osmotic pressure is decreased.
ANATOMY OF THE MEDIASTINUM
The mediastinum is the compartment between the pleural cavities. It extends anteriorly from the suprasternal notch to the xiphoid process and posteriorly from the first to the eleventh thoracic vertebrae. Superiorly, fascial planes in the neck are in direct communication; inferiorly, the mediastinum is limited by the diaphragm. Apertures through the inferior extent of the mediastinum are traversed by the aorta, inferior vena cava, esophagus, and vagus nerve.
The mediastinum may be divided into a number of compartments in several ways. Classically, it may be divided into the superior, anterior, middle, and posterior compartments. The superior compartment extends above a line drawn from the fourth thoracic vertebrae to the sternomanubrial junction (Angle of Louis.) In the three-compartment Burkell classification (Figure 18–6), the anterior mediastinum contains the thymus gland, the lymph nodes, the ascending aorta and transverse aorta, the great vessels, and areolar tissue. The middle mediastinum contains the heart, the pericardium, the trachea, the hila of the lungs, the phrenic nerves, lymph nodes, and areolar tissue. The posterior mediastinum contains the sympathetic chains, the vagus nerves, the esophagus, the thoracic duct, lymph nodes, and the descending aorta.
Figure 18–6. Divisions of the mediastinum (Burkell classification). Light screening: anterior mediastinum; lower dark screening: middle mediastinum; dotted area at right: posterior mediastinum.
Congenital abnormalities within the mediastinum are numerous. A defect in the anterior mediastinal pleura with communication of the right and left hemithorax is rare. This retrosternal part of the anterior mediastinum is normally thin, and overexpansion of one pleural space may cause “mediastinal herniation” or a bulge of mediastinal pleura toward the opposite side.
Displacements of the mediastinum occur from masses or from accumulations of air, fluid, blood, or chyle interfering with vital functions. Tracheal compression, vena caval obstruction, and esophageal obstructions cause clinical symptoms. The mediastinum can also be displaced laterally when pathologic processes of one hemithorax cause mediastinal shift. Fibrosis and lung volume loss can shift the mediastinum toward the affected side. Open pneumothorax and massive hemothorax shift the mediastinum away from the affected side. Open pneumothorax produces alternating paradoxic mediastinal shifts with respiration and will adversely affect ventilation. Acute mediastinal displacement may produce hypoxia or reduced venous return and cause dysrhythmias, hypotension, or cardiac arrest.
ANATOMY OF THE LUNG
The fundamental unit of lung anatomy is a bronchopulmonary segment (Figure 18–7). The right lung has three lobes: upper, middle, and lower. The left lung consists of two lobes: upper and lower. On the left, the lingular segments of the upper lobe are the homolog of the right middle lobe. Two fissures of varying completeness separate the lobes on the right side. The major, or oblique, fissure divides the upper and middle lobes from the lower lobe. The minor, or horizontal, fissure separates the middle from the upper lobe. On the left side, the single oblique fissure separates the upper and lower lobes. The parenchymal anatomy can be seen by studying the sequential division of the bronchopulmonary tree. The trachea and main stem bronchi and their branches contain a posterior membranous area and are prevented from collapsing by horseshoe-shaped anterior segments of cartilage in their walls. The cartilaginous reinforcement of the airway gradually becomes less complete as the branches become smaller, and reinforcement ceases with bronchi of 1-2 mm. The bronchopulmonary segmental anatomy is designated by numbers (Boyden) or by name (Jackson and Huber). There are typically 18 bronchopulmonary segments (right upper 3, right middle 2, right lower 5, left upper 4, left lower 4) as shown in Figure 18–7. The segmental bronchial anatomy is most constant with the pulmonary vascular structures showing more variability.
Figure 18–7. Segmental anatomy of the lungs.
The lungs have a dual blood supply: the pulmonary and the bronchial arterial systems. The pulmonary arteries transmit deoxygenated blood from the right ventricle for oxygenation. They closely accompany the bronchi. The bronchial arteries usually arise directly from the aorta or nearby intercostal arteries and are variable in number. They transmit oxygenated blood to the bronchial wall up to the level of the terminal bronchioles. The pulmonary veins travel in the interlobar septa and do not correspond to the distribution of the bronchi or the pulmonary arteries.
THE LYMPHATIC SYSTEM
The lymphatics travel in intersegmental septa centrally as well as to the parenchymal surface to form subpleural networks. Drainage continues toward the hilum in channels that follow the bronchi and pulmonary arteries. The lymphatics eventually enter lymph nodes in the major fissures of the lungs, the hilum, and the paratracheal regions.
The direction of lymphatic drainage—irrespective of the primary site—is cephalad and ipsilateral, but contralateral flow may occur from any lobe. The usual sequence of lymphatic spread of pulmonary cancer is first to the regional parabronchial nodes and then to the ipsilateral paratracheal, subcarinal, scalene, or inferior deep cervical nodes. The lymphatics from the left lower lobe may be almost equally distributed to the left and right. From the left upper lobe, distribution is often to the anterior mediastinal group (A-P window and para-aortic lymph nodes).
DIAGNOSTIC STUDIES
Skin Tests
Skin tests are used in the diagnosis of tuberculosis, histoplasmosis, and coccidioidomycosis. Tuberculin testing is usually done with purified protein derivative (PPD) injected intradermally. Intermediate-strength PPD should be used in patients who seem likely to have active disease. Induration of 10 mm or more at the injection site after 48-72 hours is positive and indicates either active or arrested disease. Because false-negative reactions are rare, a negative test fairly reliably rules out tuberculosis. Mumps antigen is usually placed on the opposite forearm to test for anergy. Skin tests for histoplasmosis and coccidioidomycosis are performed in a similar way, but skin tests for fungal infections are unreliable and serologic tests should be performed instead.
Endoscopy
Indirect laryngoscopy is used to assess vocal cord mobility in patients suspected of having lung carcinoma when there has been a voice change. It should also be performed to search for an otherwise occult source for malignant cells in sputum or metastases in cervical lymph nodes.
Roentgenographic evidence of bronchial obstruction, unresolved pneumonia, foreign body, suspected carcinoma, hemoptysis, aspiration pneumonia, and lung abscess are only a few of the indications for bronchoscopy. Depending on the indication, either flexible or rigid bronchoscopy may be performed. Rigid bronchoscopy must be done under general anesthesia and is most often used for clearing major airways of bulky obstructing lesions such as tumors, foreign bodies, or blood clots. Tumor ablation may be done via multiple techniques, including the use of Nd:YAG laser.
Flexible bronchoscopy is a highly effective diagnostic and therapeutic tool. It can be performed under local and intravenous sedation. Washings are usually obtained for bacterial or fungal culture and cytologic examination. Visible lesions are biopsied directly and brush biopsies are obtained from specific bronchopulmonary segments. Occasionally, transcarinal needle biopsy of a subcarinal node is obtained.
Bronchoscopically, 30%-50% of lung tumors are visible. Brushing, random biopsies, and sputum cytology may still yield a positive diagnosis of cancer or tuberculosis in the absence of a visible lesion. The yield is influenced by size, location, and histologic cell type of the lesion.
Additional techniques available during bronchoscopy include the use of endo-bronchial ultrasound (EBUS) and electromagnetic navigational bronchoscopy. EBUS enables visualization of masses and lymph nodes from the central airways, and facilitates fine needle aspiration of these lesions. Navigational bronchoscopy integrates use of a virtual bronchoscopy obtained from cross-sectional imaging (usually CT scan) and a tracking system based on three dimensional feedback from electromagnetic signals to allow access to lesions deep within the lung parenchyma.
Mediastinoscopy
Cervical mediastinoscopy remains a mainstay of evaluation of the mediastinum despite advances in imaging. Properly performed mediastinoscopy samples nodes from at least three stations, including ipsilateral and contralateral paratracheal levels 2 and 4 and subcarinal level 7. Cervical mediastinoscopy is performed through a 3- to 4-cm incision one fingerbreadth above the sternal notch. Dissection proceeds beneath the pretracheal fascia, allowing safe access to mediastinal nodes and avoiding major vascular structures. After palpation, the mediastinoscope can be inserted and nodes biopsied under direct vision. Unclear structures care aspirated prior to attempted biopsy.
Enlarged lymph nodes in the aorticopulmonary window are technically inaccessible by means of standard cervical mediastinoscopy. Extended cervical mediastinoscopy provides access to these aorticopulmonary window nodes. It is performed through the same neck incision as standard mediastinoscopy except the dissection is carried laterally beside the left carotid artery toward and then over the aorta into the aorticopulmonary space. Because of the surrounding structures, this procedure carries significant risks and in patients with dilated or calcific aortas or previous cardiac operations, is contraindicated.
In experienced hands, the complications of mediastinoscopy are minimal (< 1%-2%). Major bleeding complications requiring sternotomy or thoracotomy for repair are infrequent (1%-2%). Other possible complications include pneumothorax, recurrent nerve injury, infection, and esophageal injury.
Mediastinoscopy is almost invariably accurate in the diagnosis of sarcoidosis. It is also useful to diagnose tuberculosis, histoplasmosis, Castleman silicosis, metastatic carcinoma, lymphoma, and carcinoma of the esophagus. It should not be used in the investigation of primary mediastinal tumors, which should be approached by an incision permitting definitive excision.
Chamberlain Procedure
Anterior mediastinotomy (the Chamberlain procedure) is used to sample nodes and biopsy tissue in the anterior mediastinum, most commonly in the aortopulmonary window. A small (3-4 cm) incision is made over the second or third interspace on the appropriate side of the lesion. Alternatively, the procedure can be performed with videoscopic guidance (video-assisted thoracoscopic surgery [VATS]). The mediastinum is approached through the interspace directly or after excising the costochondral cartilage using either the mediastinoscope or an open technique. Careful attention is paid to preserving the mammary vessels encountered in the dissection. The mediastinum is approached extrapleurally unless lesions specifically within the thorax—effusions, tumors invading the hilum or chest wall—need to be investigated. Furthermore, if additional access is required to facilitate the dissection or to treat a complication, the incision can be converted to a larger anterior thoracotomy.
Complications resulting from anterior mediastinotomy include bleeding, recurrent nerve injury, and infection. Major morbidity is less than 1%-2%.
Scalene lymph node biopsy has been largely replaced by mediastinoscopy although remains important particularly for evaluation of suspicious supracervical lymphadenopathy.
Video-Assisted Thoracoscopic Surgery
VATS plays an important role in the diagnosis and staging of thoracic malignancies as well as in the resection of isolated peripheral pulmonary nodules and bullous lung disease. Furthermore, it has been an advance in lung biopsy and pleurodesis procedures. Although some oncologic concerns persist, thoracoscopic procedures are the standard of care for many resections, although they have not entirely supplanted open resection. As instruments and techniques have evolved, complications from VATS procedures (persistent air leaks, hemorrhage, tumor seeding, etc) have decreased. Overall, major complication rates of 1%-2% are reported. Faster patient recovery, shorter hospital stays, decreased pain are major advantages of VATS, although long-term differences between videoscopic and formal thoracotomy using muscle-sparing incisions are yet to be demonstrated.
Pleural Biopsy
Biopsies of the pleura can be performed either using percutaneous needle techniques, VATS, or open surgical approaches. It is indicated when the cause of a pleural effusion cannot be determined by analysis of the fluid or when tuberculosis is suspected. A definitive diagnosis can be obtained in 60%-80% of cases of tuberculosis or cancer. The principal complication is pneumothorax. Five percent to 10% of biopsy specimens are inadequate for diagnosis. Biopsy of the pleura can be performed via videoscopic or open technique with minimal morbidity, providing the pathologist with a specimen superior to that of needle biopsy.
Kużdżał J et al: Current evidence on transcervical mediastinal lymph nodes dissection. Eur J Cardiothorac Surg 2011;40(6):1470.
Yasufuku K et al: A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg 2011;142(6):1393.
Lung Biopsy
The most common indication for the use of transthoracic needle biopsy of the lung is the evaluation of a solitary pulmonary nodule. It may also be used to confirm the presence of metastatic disease. Lung biopsy may also be indicated in diffuse parenchymal disease and in some patients with localized lesions. Most commonly, lung biopsies are now performed under CT guidance. Complications following percutaneous needle biopsy include pneumothorax (5%-30%), hemothorax, hemoptysis, and air embolism. Pulmonary hypertension or cysts and bullae are contraindications. Several deaths have been reported. There is about a 60% chance of obtaining useful information. Additionally, there is controversy concerning the risks of spreading the tumor by needle biopsy in localized disease.
Thoracoscopy is the standard approach for open lung biopsy in patients who can tolerate single lung ventilation. Techniques for port placement vary, but all allow introduction of a stapler and operating thoracoscope. In addition to allowing smaller incisions, thoracoscopy allows for the visualization of multiple segments and taking multiple biopsies in diffuse diseases. For open biopsies a limited intercostal or anterior parasternal incision is used to remove a 3- to 4-cm wedge of lung tissue in diffuse parenchymal lung disease. The site of incision is selected for accessibility and potential diagnostic value. The incision is generally made at the fifth interspace on the right at the anterior axillary line to allow for access to all three lobes for biopsy. The middle lobe and lingula are selected in specific cases when pathology exists only in these areas, as they generally yield results of the poorest quality. Open lung biopsy is associated with a lower death rate, fewer complications, and greater diagnostic yield than needle biopsy. It is especially useful in critically ill, immunosuppressed patients for differentiation of infectious infiltrative lesions from neoplastic infiltrative lesions. Peripheral lesions are totally excised by wedge or segmental resection, and deeply placed lesions are removed by lobectomy in suitable candidates.
Sputum Analysis
Sputum cytology can be valuable for detecting lung cancer. Specimens are obtained by deep coughing or by abrasion with a brush, or bronchial washings are obtained by either bronchoscopic or percutaneous transtracheal washing techniques. Specimens should be collected in the morning and delivered to the laboratory promptly. Centrifugation or filtration can be used to concentrate the cellular elements.
In primary lung cancer, sputum cytology is positive in 30%-60% of cases. Repeated sputum examination improves the diagnostic return. Examination of the first bronchoscopic washing material yields a diagnosis in 60% of cases. Postbronchoscopy sputum analysis should always be made at 6-12 and 24 hours, as findings may be positive at these times when previous tests were negative. Cytologic analysis using immunohistochemistry to molecular markers (cytokeratins, hnRNP, etc) has improved accuracy and sensitivity and the ability to detect premalignant lesions.
Computed Tomography Scan
Computed tomography (CT) is a cornerstone of evaluation of chest pathology. CT scanning is critical in the staging of carcinoma, and has value in defining the extent of metastatic disease.
Magnetic Resonance Imaging
Although the major value of magnetic resonance imaging (MRI) in the thorax has been in cardiovascular imaging, it can also show invasion of lung cancer into the chest wall, vertebrae, and spinal cord as well as mediastinal structures. MRI has a particular niche in the evaluation of superior sulcus (Pancoast) tumors to establish involvement of the brachial plexus, subclavian vessel, or bony chest wall.
Positron Emission Tomography
Positron emission tomography (PET) is an important tool in staging and workup of the cancer patient. PET scanners are widely available. PET scanning may identify unsuspected regional or distant disease in up to 20%-30% of patients with lung cancer or esophageal cancer compared with conventional imaging methods (CT, bone scan). PET scanning is more accurate than CT scan in detection of cancer spread to mediastinal lymph nodes. Because of the high negative predictive value of PET scanning, a negative PET scan in the mediastinum permits direct progression to thoracotomy. The presence of a positive PET scan in the mediastinum mandates either mediastinoscopy or, more recently, endoscopic evaluation of mediastinal lymph nodes because of false-positive PET scan results.
The combined PET/CT is highly accurate (> 90%), but by itself it has a 10%-20% false-positive rate in the mediastinum. Therefore, interpretations of PET results must be accepted with caution and must be confirmed by surgical staging when inconsistent with the overall clinical picture.
DISEASES OF THE CHEST WALL
LUNG HERNIA
A lung hernia results from a defect in the chest wall may be congenital or acquired as the result of trauma or a surgical operation. Most lung hernias are thoracic in location, but cervical (defects of Sibson fascia) or diaphragmatic herniation may occur occasionally. Lung hernias may present as a tender subcutaneous mass that enlarges with cough or Valsalva. Other than this mass, they are usually asymptomatic. Once diagnosed, these hernias should be repaired, with repair of the skeletal defect and prosthetic mesh reinforcement. This may be done open or with VATS techniques.
CHEST WALL INFECTIONS
Infections of the chest wall or pleural spaces may pose complex challenges in medical management. Infections that appear to involve only the skin and soft tissues may actually represent outward extensions of deeper infection of the ribs, cartilage, sternum, or even the pleural space (empyema necessitatis). Inadequate drainage of superficial infection can lead to inward extension into the pleural space, causing empyema.
Subpectoral abscess is caused by suppurative adenitis of the axillary lymph nodes, rib or pleural infection, or posterior extension of a breast abscess. It may also occur as a complication of chest wall surgery (eg, mastectomy, pacemaker placement). Symptoms include erythema, induration of the pectoral region, and obliteration of the normal infraclavicular depression and may progress to systemic sepsis. Shoulder movement is painful. Organisms most commonly involved include hemolytic streptococci and Staphylococcus aureus. Treatment involves incisional drainage along the lateral border of the pectoralis major muscle and administration of systemic antibiotics.
Subscapular abscess may arise from osteomyelitis of the scapula but most commonly follows thoracic operations such as thoracotomy or thoracoplasty. Winging of the scapula or paravertebral induration of the trapezius muscle is usually present. A pleural communication is suggested if a cough impulse is present or if the size of the mass varies with position or direct pressure. The diagnosis is established by needle aspiration. Open drainage is indicated for pyogenic infections not involving the pleural space. Tubercular lesions should be treated by chemotherapy and needle aspiration, if possible.
Osteomyelitis of the Ribs
In the past, osteomyelitis of the ribs was often caused by typhoid fever and tuberculosis. Except in children, hematogenous osteomyelitis is a rare problem today. Thoracotomy incisions may result in osteomyelitis.
Sternal Osteomyelitis
Infection of the sternum most commonly follows median sternotomy incisions, particularly in diabetics. It presents as a postoperative wound infection or mediastinitis with drainage, fever, leukocytosis, and instability of the sternal closure. Treatment consists of control of systemic sepsis with appropriate antibiotics, open drainage, resection of the involved sternum, and reconstruction of the defect with pectoralis muscle, serratus muscle, or omental coverage. Occasionally, sternal osteomyelitis will be due to tuberculosis.
Infection of the Costal Cartilages & Xiphoid
Costal cartilage infections are relatively unresponsive to antibiotic therapy. Once devascularized, perichondral tissue necroses and acts as a foreign body to perpetuate the infection and favor sinus tract formation. The most common cause is direct extension of other surgical infections (eg, wound infection, subphrenic abscess). Surgical division of costal cartilages, as in a thoracoabdominal incision, may predispose to cartilage infection postoperatively if local sepsis develops. A wide variety of organisms have been implicated.
Erythema and induration with fluctuance and often spontaneous drainage can occur. The course can be fulminant or may be indolent over months or years, with periodic exacerbations. Associated osteomyelitis of the sternum, ribs, or clavicle may occur.
The treatment of choice includes resection of the involved cartilage and adjacent involved bony structures. Recurrence is due to underestimation of the extent of disease and inadequate resection.
Reconstruction of the Chest Wall
Chest wall reconstruction may be necessary following trauma, surgical resection, or infection resulting in destruction of chest wall structures. Rigid reconstruction of the chest wall is generally recommended for defects greater than 5 cm, although posterior resections covered by the scapula will not necessarily need rigid mesh reconstruction. Advances in the use of musculocutaneous flaps and the supportive use of methyl methacrylate and Marlex mesh to produce solidity below these muscular flaps have facilitated repairs. In massive chest wall defects, vascularization of the area is essential and can be accomplished by use of omental flaps as well as pectoralis, latissimus dorsi, and rectus flaps. Microsurgical techniques for repair of such defects have greatly expanded the ability of plastic surgeons to deal with extensive resectional and infective processes.
Mahabir RC, Butler CE: Stabilization of the chest wall: autologous and alloplastic reconstructions. Semin Plast Surg 2011; 25: 34-42.
TIETZE SYNDROME (COSTOCHONDRITIS)
Tietze syndrome is a painful, nonsuppurative inflammation of the costochondral cartilages and is of unknown cause. Recent evidence suggests that costochondritis may represent a manifestation of seronegative rheumatic disease. Local swelling and tenderness are the only symptoms; they usually disappear without therapy. The syndrome may recur.
Several reports have suggested the use of bone scintigraphy and chest CT for diagnosis of infected costochondritis. Bone scanning was effective in localizing and identifying inflamed costochondral junctions. Treatment is symptomatic and may include analgesics (NSAIDs) and local or systemic corticosteroids. When symptoms persist longer than 3 weeks and tumefaction suggests neoplasm, excision of the involved cartilage may be indicated and is usually curative.
Stochendahl MJ, Christe.nsen HW: Chest pain in focal musculoskeletal disorders. Medical Clin North Am 2010;94(2):259-273.
MONDOR DISEASE (THROMBOPHLEBITIS OF THE THORACOEPIGASTRIC VEIN)
Mondor disease consists of localized thrombophlebitis of the anterolateral chest wall. It is more prominent in women than in men and occasionally follows mastectomy. There are few symptoms other than the presence of a localized tender, cordlike structure in the subcutaneous tissues of the abdomen, thorax, or axilla. The disease is self-limited and does not pose a risk of thromboembolism. The possibility of an infective origin or stasis of the interrupted venous return due to neoplasm must be ruled out.
CHEST WALL TUMORS
Chest wall tumors may be simulated by enlarged costal cartilages, chest wall infection, fractures, rickets, scurvy, hyperparathyroidism, and other conditions. Most commonly, chest wall lesions present as a mass with localized or referred pain; less than 25% are asymptomatic. Approximately 60% of all chest wall masses prove to be malignant. Lesions arise from one of the three components of the chest wall, including soft tissues (eg, muscle, nerve, fascia), bone, and cartilage.
The majority of tumors arise from either bone or cartilage. Rib involvement is more common than sternal presentation. Chest CT offers the most information for diagnosis and staging. Chest wall sarcomas are associated with pulmonary metastasis. Simple chest x-rays may initially identify a mass, especially if it is calcified. Bone scans should be obtained in all cases.
Initial diagnosis is obtained by limited incisional biopsy (transverse) if the mass is large (> 4 cm). Smaller lesions are excised en bloc, ensuring negative margins, with full knowledge that a malignancy is present in many cases. Classic teaching has been to perform en bloc wide local excisions with immediate reconstruction for all lesions at initial presentations. Progress with adjuvant multimodality therapy, however, for tumors such as rhabdomyosarcomas and Ewing sarcoma supports the use of initial limited biopsy for tissue diagnosis to guide treatment planning.
Specific Neoplasms
Roughly 50% of all chest wall masses are sarcomas, yet overall they represent only a small percentage (5%) of all malignant soft tissue sarcomas. Survival is determined by the histologic grade, the completeness of resection, and the presence and development of metastases (synchronous or metachronous). Low-grade tumors have 5-year and 10-year survivals approaching 90% and 82%, respectively. With high-grade lesions, however, 5-year survival rates are only 30%-50%. The development of metastasis greatly reduces the chances of survival.
Treatment is directed at a complete resection with emphasis on achieving negative margins (1-2 cm). En bloc resection techniques include raising skin flaps and reconstruction with soft tissue flaps, Marlex mesh, and methyl methacrylate to correct chest wall deformity and prevent paradoxic chest movement.
There are many histologic subtypes of soft tissue sarcoma. Typically, low-grade sarcomas include desmoids or liposarcomas with low-grade features. Next most frequently seen are malignant fibrosarcoma, rhabdomyosarcoma, and malignant fibrous histiocytoma, which are usually high-grade lesions.
Individual histologic subtype is not by itself a significant prognostic variable, but histologic grade is significant. Metastases—either synchronous or metachronous—are most commonly to the lungs (75%) and should be resected if negative margins can be achieved and adequate lung function preserved. Therapy for low-grade lesions should consist of a complete resection. Incompletely resected lesions should be treated with external beam radiation therapy. High-grade lesions should be resected and patients enrolled in clinical trials evaluating the efficacy of systemic adjuvant chemotherapy. Postoperative radiotherapy is often helpful in the setting of close margins or tumor spillage.
Although a complete resection can often be curative, local recurrence portends future metastatic disease and poor survival. Therefore, even in the setting of large tumors (> 15–20 cm), resection should be considered even if it necessitates removal of more than eight ribs. With epidural pain control and immediate reconstruction techniques, most patients will do well. Despite large chest wall resections, most patients can be immediately extubated and will not suffer drastic changes in pulmonary function or chest wall dynamics.
Diagnosis can usually be made by fine-needle aspirate or incisional biopsy. Histologically, these tumors are unique and consist of broad sheets of small polyhedral cells with pale cytoplasm and small hyperchromatic nuclei. They stain periodic acid-Schiff-positive.
Ewing sarcoma is commonly a disease of childhood and adolescence. The most important prognostic indicator for survival is development of distant metastases. Current therapy consists of neoadjuvant chemotherapy (including cyclophosphamide, dactinomycin, doxorubicin, and vincristine) surgical resection if the tumor is well demarcated and can be completely resected. Radiotherapy may be indicated as postoperative adjuvant treatment, or in the case of tumors that are not completely resectable. Overall, 5-year survivals range from 15% to 60%. Long-term survivals (10 years) are achievable in patients who do not develop metastases.
Osteogenic sarcoma differs from chondrosarcoma in that it is usually sensitive to chemotherapy. They are treated with neoadjuvant chemotherapy followed by surgical resection. Even with neoadjuvant treatment, however overall 5-year survival after complete resection and postoperative chemotherapy may only be 15%.
Metastases to bones of the thorax are often multiple and are usually from tumors of the kidney, thyroid, lung, breast, prostate, stomach, uterus, or colon. Renal cell and thyroid malignancies have a high propensity for metastasizing to the sternum. Occasionally, they present as a pulsatile mass due to the excessive vascularity of the metastasis. An aneurysm of the ascending thoracic aorta, while rare, must be considered in the differential diagnosis and ruled out prior to attempts at excisional biopsy. Involvement by direct extension occurs in carcinoma of the breast and lung. Primary lung cancer with direct extension to chest wall without nodal involvement (T3 N0) carries a reasonable 5-year survival (40%-50%) when treated with radical en bloc resection. Lung metastasis with direct chest wall extension should be treated with radical en bloc resection of the chest wall and underlying lung.
Ferraro P et al: Principles of chest wall resection and reconstruction. Thorac Surg Clin 2010;20(4):465.
Hemmati SH et al: The prognostic factors of chest wall metastasis resection. Eur J Cardiothorac Surg. 2011;40(2):328.
Smith SE, Keshavjee S: Primary chest wall tumors. Thoracic Surg Clin 2010;20(4):495.
DISEASES OF THE PLEURA
Diseases of the pleura may be benign or malignant and may represent primary pleural processes, localized extrapleural diseases, or systemic illnesses. The most common pleural problem is the presence of air (pneumothorax) within the pleural space. Pleural effusions—accumulations of fluid—result from benign sterile fluid, malignant fluid, pus, chyle, or blood. Primary pleural tumors are uncommon, but involvement of the pleura with metastatic cancer is common.
The most common symptoms of pleural disease are pain and dyspnea. The pain is sharp, and it is characteristically worsened by respiratory movements, often inhibiting inspiration. Pleural pain is mediated through somatic intercostal nerves of the chest wall (cervical and costal pleura) and through the phrenic nerve (diaphragmatic and mediastinal pleura), causing chest wall or back pain and pain referred to the shoulder, respectively. The visceral pleura contains only sympathetic and parasympathetic nerve fibers and therefore is insensate; however, extension of visceral processes to involve the parietal pleura can produce typical pleuritic chest pain.
PLEURAL EFFUSION
Pleural effusion is the presence of fluid within the pleural space. More specific terminology may be used when the nature of the fluid is known. Hydrothorax is a collection of serous (most often transudative but also exudative) fluid, while pus in the pleural cavity is referred to as a pyothorax or empyema. Additional terms are used for blood (hemothorax) and chyle (chylothorax). Abnormal pleural fluid accumulates as a result of one or more of the following mechanisms: (1) increase in the pulmonary vascular hydrostatic pressure (congestive heart failure, mitral stenosis); (2) decrease in the vascular colloid oncotic pressure (hypoproteinemia); (3) increase in the capillary permeability due to inflammation (eg, pneumonia, pancreatitis, sepsis); (4) decrease in the intrapleural pressure (atelectasis); (5) decrease in the lymphatic drainage (carcinomatosis); (6) transdiaphragmatic movement of abdominal fluid through lymphatics or physical defects (ascites, pancreatic pseudocyst rupture); and (7) rupture of a vascular or lymphatic structure (traumatic injury).
Decreased respiratory excursion, diminished breath sounds, dullness to percussion, a pleural friction rub, and local tenderness are signs that indicate the presence of pleural effusion. With long-standing and advanced disease, contraction of the hemithorax with narrowed intercostal spaces and localized bulging, swelling, or redness may occur. Chest radiographs demonstrate varying degrees of opacification of the ipsilateral hemithorax. Accumulation of 300-500 mL fluid causes blunting of the costophrenic angle on x-ray. If the entire hemithorax is opacified, 2000-2500 mL may be present. The mediastinum may be shifted to the contralateral side in the presence of a large effusion, or it may remain in the midline—particularly if proximal bronchial obstruction results in lobar or total lung atelectasis, if the mediastinum is fixed from fibrosis or tumor infiltration, if the ipsilateral lung is infiltrated with tumor, or if malignant mesothelioma is present. CT scanning may be required to evaluate complex, loculated, or recurrent pleural fluid collections. Interventional radiology services are useful for loculated pleural effusions that may be managed by percutaneous drain placement under CT guidance.
Generally, serous effusions are separated into two broad categories—transudates and exudates—based on the physical and cellular characteristics of the pleural fluid. Identification of the specific type of effusion aids in determination of the cause and most often depends on examination of at least 20 mL of fluid obtained by thoracentesis. Basic tests should include total protein, lactate dehydrogenase (LDH), total and differential cell counts, glucose, pH, cytology, and Gram stain with culture. Furthermore, simultaneous serum total protein, LDH, and glucose should be measured. Effusions with total protein content less than 3 g/dL (or a fluid-serum ratio lower than 0.5), an LDH level less than 200 units/dL (or a fluid-serum ratio < 0.6), and a specific gravity below 1.016 represent transudates, while all other effusions are classified as exudates. The results of these basic tests frequently allow the underlying pathologic process to be elucidated (Table 18–1).
Table 18–1. Differential diagnosis of pleural effusions.1
Malignancy
More than 25% of all pleural effusions are secondary to cancer, and 35% of patients with lung cancer, 23% of patients with breast cancer, and 10% of patients with lymphoma develop malignant pleural effusions during the course of their disease. Approximately 10% of malignant effusions are secondary to primary pleural tumors, mostly mesothelioma. The mechanism is primarily through lymphatic obstruction in either the peripheral lung or central lymph node channels of the mediastinum. Malignant pleural effusions can be serous, serosanguineous, or bloody and are diagnosed primarily by demonstrating malignant cells in the fluid. Cytologic confirmation is successful 50%, 65%, and 70% of the time after one, two, or three thoracenteses, respectively. Closed pleural biopsy alone is successful in only 50% of cases, but coupled with thoracentesis it can increase the diagnostic yield to 80%. Thoracoscopy with direct pleural biopsy, however, is successful in 97% of patients and should be considered in any patient with a suspicious effusion after two negative thoracenteses.
Treatment of malignant effusions is strictly palliative: Most patients die within 3-6 months of developing a malignant pleural effusion, so prompt diagnosis and therapy are essential. The goals of treatment are lung reexpansion and pleural symphysis. This is most readily accomplished with placement of a chest tube (2028F) and closed-tube drainage for 24-48 hours. Generally, no more than 1 L is allowed to drain initially. Subsequently, 200-500 mL is allowed to drain every 1-2 hours until the effusion is fully drained. This controlled draining avoids the rare complication of reexpansion pulmonary edema. Once full lung expansion is obtained pleurodesis should be performed with an appropriate agent before loculations have formed. Different chemical, radioactive, and infectious agents have been used in the past with varying success rates, but most commonly used are talc (87%-100% insufflation; 83%-100% slurry), or doxycycline. Finally, mechanical pleurectomy without chemical instillation can control pleural effusions in over 99% of patients, but this requires an operative procedure. Talc is inexpensive, highly effective, and easily administered either as a powder insufflated into the open chest or as a slurry instilled through a chest tube.
Complications following pleurodesis include pneumothorax, loculated hydrothorax, fever, infection (empyema), acute respiratory distress syndrome (particularly following bilateral simultaneous pleurodesis, which for this reason alone are contraindicated), and recurrence. Problems are uncommon, and most patients can have their chest tubes removed within 48-72 hours following talc pleurodesis.
Cardiovascular Disease
Pleural effusions are common findings in patients with moderate to severe congestive heart failure. Heart failure may be secondary to ischemia, valvular heart disease, viral myocarditis, congenital heart disease, and other less common lesions. The effusion may be bilateral or unilateral. When unilateral, the right hemithorax is most often affected. Fluid frequently involves the interlobar fissures (most commonly the minor fissure on the right) and can form localized collections simulating mass lesions known as “pseudotumors.” Other cardiovascular causes of pleural effusions include constrictive pericarditis and pulmonary venous obstruction.
Renal Disease
Hydronephrosis, nephrotic syndrome, and acute glomerulonephritis are on occasion associated with pleural effusions. Rupture of the collecting system into the pleural space can also produce a hydrothorax. In this latter case, the pleural fluid creatinine will be elevated (fluid-serum creatinine ratio significantly > 1.0).
Pancreatitis
Moderate to severe pancreatitis is associated with a pleural effusion that characteristically occurs on the left and contains fluid with an amylase concentration substantially higher than that in the serum. Rarely pseudocysts of the capsule of the pancreas may communicate with the pleural space, resulting in high-volume pleural effusions.
Cirrhosis
Approximately 5% of patients with cirrhosis and ascites will develop a pleural effusion. In contrast to pancreatitis, nearly all of these effusions occur on the right side.
Thromboembolism
Pulmonary thromboemboli are sometimes accompanied by a pleural effusion. These effusions are typically serosanguineous and small, but they may be frankly bloody and massive. Characteristic x-ray findings are almost always present in the lung. Since the fluid is usually reabsorbed in a short period of time, drainage is seldom necessary.
Pyothorax (empyema thoracis) is the accumulation of pus within the pleural cavity. The pus is usually thick, creamy, and malodorous. If empyema occurs in the setting of underlying suppurative lung disease (ie, pneumonia, lung abscess, or bronchiectasis), it is referred to as a parapneumonic empyema (60% of cases). Other causes of thoracic empyema are surgery (20%), trauma (10%), esophageal rupture, other chest wall or mediastinal infections, bronchopleural fistula, extension of a subphrenic or hepatic abscess, instrumentation of the pleural space (thoracentesis, chest tube placement, etc), and, rarely, hematogenous seeding from a distant site of infection.
Empyemas are divided into three phases based on their natural history: acute exudative, fibrinopurulent, and chronic organizing. The acute exudative phase is characterized by the outpouring of sterile pleural fluid (incited by pleural inflammation), with a low viscosity, white blood cell count, and LDH concentration as well as normal glucose level and normal pH. The pleura remains mobile during this phase. The fibrinopurulent phase develops at approximately 2-7 days, marked by an increase in the turbidity, white blood cell count, and LDH levels in the fluid. Glucose levels and pH of the fluid decrease and fibrin is deposited on pleural surfaces, limiting the empyema but also fixing (trapping) the lung. The chronic organizing phase begins 7-28 days after the onset of the disease and is characterized by a pleural fluid glucose level less than 40 mg/dL and a pH less than 7.0. The pleural exudate becomes thick, and the pleural fibrin deposits thicken and begin to organize, further immobilizing the lung. In patients with inadequately treated chronic empyema, erosion through the chest wall (empyema necessitatis), chondritis, osteomyelitis of the ribs or vertebral bodies, pericarditis, and mediastinal abscesses may occur.
The bacteriology of thoracic empyema has evolved over the years. Prior to the discovery of penicillin in the 1940s, most empyemas were caused by pneumococci and streptococci. With modern antibiotics and improved anaerobic culture techniques, however, the most common isolates from adult empyemas are now anaerobic bacteria, particularly bacteroides species as well as fusobacterium andPeptococcus species.
Staphylococcus is the most common organism causing empyema (92% in children under 2 years), and staphylococcal empyema is one of the most common complications of staphylococcal pneumonias in both adults and children (Table 18–2). Gram-negative bacteria also continue to be significant pathogens, particularly in parapneumonic empyemas. Escherichia coli and pseudomonas species account for 66% of aerobic gram-negative empyemas, and other organisms include Klebsiella pneumoniae, Proteus species, Enterobacter aerogenes, and Salmonella. Rarely, fungi (Aspergillus, Coccidioides immitis,Blastomyces, and Histoplasma capsulatum) and parasites such as Entamoeba histolytica can cause empyemas. In a review, empyemas were found to contain anaerobic bacteria in only 35% of cases, aerobic bacteria in only 24%, and a combination in 41%. In addition, the average number of bacterial species isolated was 3.2 per patient.
Table 18–2. Incidence of various complications of staphylococcal pneumonia in adults and children (in %).
Aspiration of oropharyngeal flora may represent a source of polymicrobial infection. Although patients may rarely be completely asymptomatic, most patients with thoracic empyemas present with varying symptoms depending on the underlying disease process, the extent of the pleural involvement, and the immunologic state of the patient. Patients typically complain of fever, pleuritic chest pain or a sense of chest heaviness, dyspnea, hemoptysis, and a cough usually productive of purulent sputum. Signs of thoracic empyema include anemia, tachycardia, tachypnea, diminished breath sounds with dullness to percussion on the involved side, clubbing of fingertips, and occasionally pulmonary osteoarthropathy.
Although the medical history and physical examination often suggest the presence of thoracic empyema, the plain chest radiograph is the most important noninvasive diagnostic test. Empyemas may be associated with an underlying pneumonia, lung abscess, or pleural effusion and appear as posterolateral D-shaped densities on x-ray. In large empyemas, the mediastinum may be shifted away from the affected side. Bronchoscopy should be performed on all patients to exclude the presence of endobronchial obstruction. CT scanning provides critical anatomic detail regarding loculations and can assist in differentiation of empyema from lung abscess.
Thoracentesis is the procedure of choice for the diagnosis of thoracic empyema. Aspiration of pus establishes the diagnosis, permitting identification of the offending organisms. In early empyemas—particularly those partially treated with antibiotics—the pleural fluid may not be frankly purulent. In these cases, a pleural fluid pH less than 7.0, glucose less than 40 mg/dL, and an LDH level greater than 1000 units/L strongly suggest an evolving empyema even if Gram stain and cultures fail to identify organisms.
Goals for the treatment of thoracic empyemas include: (1) control of the infection; (2) removal of the purulent material with obliteration and sterilization of the pleural space and reexpansion of the lung; and (3) elimination of the underlying disease process.
Options for treatment include repeated thoracentesis, closed tube thoracostomy, rib resection and open drainage, decortication and empyemectomy, thoracoplasty, and muscle flap closure. Adjunctive maneuvers reported to aid in the disruption and drainage of loculated empyemas include instillation of fibrinolytic enzymes (such as tPA) and video-assisted thoracoscopic debridement. A rational approach to empyema management is outlined in Figure 18–8. Initially, an intercostal catheter of adequate size is carefully inserted into the most dependent portion of the empyema cavity. If after 24-72 hours sepsis persists—or if there is any question as to the adequacy of drainage—a CT scan should be obtained. If, on the other hand, complete drainage and reexpansion of the lung are achieved, no further drainage procedures are necessary.
Figure 18–8. Management of empyema. (Modified and reproduced with permission from Shields TW. General Thoracic Surgery, 3rd ed. Williams & Wilkins, Baltimore, 1989.)
Patients with residual spaces that are inadequately drained, patients with continued sepsis, and patients thought to require prolonged tube drainage are candidates for open drainage procedures. These can usually be safely performed 10-14 days after closed-tube drainage, since the pleurae fuse by that time and the risk of pneumothorax and lung collapse is eliminated. Options for an open drainage include simple rib resection and open flap drainage (Eloesser procedure). Simple rib resection involves the removal of short segments (3-6 cm) of one, two, or three ribs at the most dependent portion of the empyema cavity (at or anterior to the posterior axillary line). A tube can be placed through this opening and effective drainage established. A second approach involves the creation of a U-shaped flap of chest wall that is sewn to the parietal pleura after resection of short segments (3-6 cm) of one, two, or three ribs. This creates an epithelialized tract for long-term tubeless drainage of empyema cavities. This type of an open drainage allows the empyema cavity to drain reliably and to be easily debrided, irrigated, and cleaned. Ultimately, through lung reexpansion, wound contraction, and granulation, the cavity often completely disappears.
Another option is early decortication and empyemectomy. This is especially useful for good-risk patients with early loculated empyemas and inadequate tube drainage or lung expansion. Furthermore, if performed early in the course of the process, resection of both parietal and visceral pleural peels (decortication) can be performed as a thoracoscopic procedure. More advanced or chronic disease involves a thoracotomy with decortication with resection of the intact empyema itself (empyemectomy), if possible. The best results with this approach are obtained when the underlying lung is entirely normal and reexpands fully. Posttraumatic empyema, in particular, has been amenable to this treatment.
Empyemas that occur following pulmonary resection may be difficult to manage. If residual lung is present (resections less than pneumonectomy), the general principles outlined above still apply, although a complicating bronchopleural fistula is often present (Figure 18–9). Simple tube drainage is instituted initially followed by open drainage if necessary. Empyemas following pneumonectomy, however, pose a special problem because there is no longer any lung to obliterate the infected space. In addition, postpneumonectomy empyemas frequently are associated with bronchopleural fistulas. In these patients, specific surgical procedures designed to obliterate residual intrathoracic spaces and in many cases close remaining bronchopleural fistulas may be required (Figure 18–10). In the absence of a bronchopleural fistula, sterilization and closure of a postpneumonectomy space (without obliteration) may be attempted using an irrigation catheter inserted into the apex of the chest cavity. An antibiotic solution specific for the organisms present is then infused into the chest. The solution is allowed to drain through a dependent tube or opening created by simple rib resection. After 2-8 weeks, the catheters are removed and the cavity is closed. The success rate with this technique is quite variable and is reported to be 20%-88%. For patients who fail this approach and for those patients with bronchopleural fistulas, the main goal of therapy is to obliterate the residual space and close any bronchopleural fistulas. This is most readily accomplished by the transposition of muscle with or without omentum into the empyema cavity. Multiple muscles may be required, including pectoralis major, latissimus dorsi, serratus anterior, intercostal muscle, and rectus abdominis (Figure 18–11). Use of these muscles is highly successful in closing any remaining bronchopleural fistulas and in completely obliterating the remaining intrathoracic space. The success of muscle flap closure of empyema spaces has made thoracoplasty (once a common procedure for reducing empyema spaces) a rare operation.
Figure 18–9. Postlobectomy empyema. (Modified and reproduced with permission from Shields TW. General Thoracic Surgery, 3rd ed. Williams & Wilkins, Baltimore, 1989.)
Figure 18–10. Postpneumonectomy empyema. (Modified and reproduced with permission from Shields TW. General Thoracic Surgery, 3rd ed. Williams & Wilkins, Baltimore, 1989.)
Figure 18–11. Extrathoracic muscle flap closure of a postpneumonectomy empyema cavity.
Antibiotics are an important adjunct in the treatment of empyemas, but it must be emphasized that drainage is the primary treatment modality. Although antibiotic therapy is always instituted early in the course of therapy when signs of systemic infection generally are present, they need not be continued once effective drainage is established. In fact, overuse of antibiotics may lead to the generation of resistant bacteria and therefore compromise the success of any subsequent procedures designed to obliterate residual intrathoracic space.
Krassas A et al: Current indications and results for thoracoplasty and intrathoracic muscle transposition. Eur J Cardiothorac Surg 2010;37(5):1215.
Blood in the pleural space usually occurs secondary to trauma, surgery, diagnostic or therapeutic procedures, neoplasms, pulmonary infarction, and infections (tuberculosis). Most hemothoraces can be treated effectively with large-bore (32-36F) closed chest tube drainage, particularly since small amounts of blood (occupying less than one-third of the hemithorax) are readily reabsorbed by the body. However, if significant blood clot has formed (occupying more than one-third of the hemithorax) or if secondary infection occurs, further measures must be taken to avoid the development of an empyema or fibrothorax with pulmonary compromise. Many hemothoraces requiring more than simple tube drainage can be managed with VATS procedures. Rarely, open thoracotomy may be required for complete decortication and evacuation.
Accumulation of chyle within the pleural space is most often due to surgical procedures, particularly cardiothoracic and esophageal operations. Trauma, malignancy, central venous catheterization, congenital lymphatic malformations, thoracic aortic aneurysms, filariasis, and cirrhosis may also rarely cause chylothorax. Penetrating thoracic trauma can lacerate the thoracic duct at any level, but blunt thoracic trauma usually causes a shearing of the duct at the right crus of the diaphragm. This may also occur with violent coughing or hyperextension of the spine. The initial treatment of chylothorax is similar to that of a malignant pleural effusion. Closed chest tube drainage is instituted; the lung is fully reexpanded; and a low-fat diet is started. In some cases, intravenous hyperalimentation (either peripheral or central) may greatly improve the patient’s condition. Some evidence supports the use of somatostatin to decrease the output from chylous effusions. The irritating nature of chyle promotes pleurodesis, and in half of patients the leak will stop spontaneously. The instillation of sclerosing agents (see section on pleural effusion, above) has also been advocated to increase the chances of success. If chyle continues to drain for more than 7 days or if significant drainage continues for even a shorter period of time, serious consideration should be given to operation since patients quickly become malnourished from the large associated protein losses. Video-assisted thoracoscopic techniques are usually ideal, making open thoracotomy rarely necessary. The standard approach is via the right chest, where the thoracic duct may be identified as it emerges from beneath the diaphragm between the aorta and the azygos vein. Ligation of the tissues in this area is usually all that is needed.
PNEUMOTHORAX
Air in the pleural space (pneumothorax) can occur as a result of a breach in either the parietal (trauma, esophageal perforation, surgery, etc) or visceral pleura (bulla, fine-needle aspirations, etc). Rarely, infections of the pleural space with gas-forming organisms may produce a pneumothorax. Since a chest radiograph is only a two-dimensional representation of a three-dimensional space, a relatively small separation of the pleural surfaces (eg, 1 cm) on a chest x-ray can translate into a relatively large pneumothorax. A large amount of intrapleural air that causes a shift of the mediastinum toward the contralateral lung is referred to as a tension pneumothorax. A pneumothorax associated with an open chest wound may be termed an open pneumothorax or sometimes a “sucking chest wound.” Tension and open pneumothoraces are surgical emergencies because both ventilation and venous return of blood to the heart are compromised. Intrapleural air may mix with blood, as frequently occurs after trauma (hemopneumothorax) or esophageal perforation (pyopneumothorax).
Pneumothoraces usually are classified as either spontaneous or acquired (those caused by a specific event such as trauma, invasive procedures, etc). Spontaneous pneumothoraces sometimes are divided into “primary” and “secondary” categories; however, all spontaneous pneumothoraces are secondary to some underlying pathologic process, and such a division is therefore strictly artificial. Most commonly, spontaneous pneumothoraces are caused by rupture of small subpleural blebs due to increased transpulmonary pressure most pronounced at the apex of the lung (apex of the upper lobe and superior segment of the lower lobe). Coughing, rapid falls in atmospheric pressure (> 10 millibars/24 h), rapid decompression (scuba divers), and high altitudes (jet pilots) all are associated with increased transpulmonary pressures and spontaneous pneumothorax. In addition, normal transpulmonary pressures can cause rupture of blebs in patients with connective tissue disorders such as Marfan syndrome. Other causes of spontaneous pneumothorax include apical bullae (patients with chronic obstructive pulmonary disease [COPD]), Pneumocystis pneumonia (patients with AIDS), metastatic cancer (particularly sarcomas), lymphangioleiomyomatosis, eosinophilic granuloma, rupture of the esophagus or of a lung abscess, cystic fibrosis, and menstruation (catamenial pneumothorax). Classically, however, spontaneous pneumothoraces occur in asthenic males (male-to-female ratio 6:1) between the ages of 16 and 24, often with a history of smoking. The true incidence is unknown, since up to 20% of patients remain asymptomatic and do not seek medical attention.
Patients with pneumothoraces complain of pleuritic chest pain and dyspnea. If severe underlying cardiopulmonary disease exists or if a tension pneumothorax develops, symptoms become much more dramatic and include diaphoresis, cyanosis, weakness, and symptoms of hypotension and cardiovascular collapse. Physical examination reveals tachypnea, tachycardia, deviation of the trachea away from the involved side (tension pneumothorax), decreased breath sounds, hyperresonance, and diminished vocal fremitus on the involved side. Arterial blood gases may demonstrate hypoxia and occasionally hypocapnia from hyperventilation, and the EKG may show axis deviations, nonspecific ST segment changes, and T wave inversion. The standard test for the diagnosis of pneumothoraces is the posteroanterior (PA) and lateral chest radiograph. Exhalation accentuates the contrast between the collapsed lung and the intrapleural air as well as the magnitude of the collapse. Rarely, a CT scan may be necessary to differentiate a pneumothorax from a large bulla in patients with severe emphysema. In 5%-10% of patients, a small pleural effusion may be present and can be hemorrhagic.
The treatment of spontaneous pneumothoraces varies depending on the patient’s symptoms and condition, the degree of collapse, the cause, and the estimate of the chance of recurrence. Small (< 20%-25%), stable, asymptomatic pneumothoraces in otherwise healthy patients can be followed (often on an outpatient basis) with the expectation of complete resolution within several weeks, since air is normally reabsorbed at a rate of 1%-1.25% per day. Larger asymptomatic pneumothoraces taking longer than 2-3 weeks to resolve place the patient at risk for developing trapped lung as a result of deposition of fibrin on the visceral pleura. These patients—as well as patients with symptoms, increasing pneumothoraces, or pneumothoraces associated with pleural effusions—should have them evacuated. In highly selected patients, this can be accomplished with simple aspiration as long as the immediate and 2-hour delayed chest radiographs document reexpansion. It should be emphasized, however, that some small breaks in the visceral pleural seal once the lung collapses and can reopen with reexpansion. The chance of recurrence is 20%-50% with this method, and follow-up x-ray is therefore mandatory after 24 hours.
Most patients with significant pneumothoraces (> 30%) require placement of a closed-chest catheter (8-20F) for acceptable reexpansion. This catheter then can be placed either to underwater suction drainage or to a Heimlich (one-way) valve. If a Heimlich valve maintains full expansion, the patient may be treated as an outpatient; however, if a Heimlich valve fails to reexpand the lung fully or if the patient’s condition is not optimal, admission to hospital and underwater chest tube suction drainage is required. Unless some contraindication exists, chest tubes should be placed in the midaxillary line at the level of the fifth intercostal space (nipple line). In women, the breast tissue should be retracted medially and avoided in the dissection to the chest wall. Placement with the use of blunt clamp dissection avoids the dangers of trocar insertion and should almost always be used. Following resolution of any air leakage, the tube may be taken off suction (water seal) and removed if the lung remains fully inflated. In patients with classic spontaneous pneumothoraces, the chance of recurrence increases with each episode. Following a single episode, the risk of a recurrent pneumothorax is 40%-50%. After two episodes, the risk increases to 50%-75%, and with three previous episodes, the risk is in excess of 80%. Currently, most first-time patients are treated initially with simple chest tube drainage; however, with subsequent recurrences, additional therapy generally is indicated. Furthermore, with the development of VATS, some feel that a more aggressive approach should be taken even for first-time pneumothoraces.
Patients with air leaks lasting longer than 7 days, patients who do not fully reexpand their lungs, patients in high-risk occupations (scuba divers, airline pilots, etc), patients with large bullae or poor pulmonary function, and patients with bilateral or recurrent pneumothoraces are candidates for additional medical (pleurodesis) or surgical intervention. Furthermore, patients who frequently travel to places distant from medical care are offered early surgical intervention. Previously, tetracycline pleurodesis was used to decrease the incidence of recurrent pneumothoraces. The use of this substance, however, was associated with significant pain and controversy. It is currently no longer available. The use of talc slurry or powder in this setting is also controversial due to the potential for long-term fibrothorax and restrictive lung disease but has been shown to reduce the recurrence rate to as low as 2%. Many other chemical agents have been used in the past, including mechlorethamine, doxycycline, iodoform, guaiacol, urea, and hypertonic glucose, with varying success rates. Since pleurodesis can make subsequent surgical procedures more difficult, the use of this treatment option continues to generate controversy.
Medically fit patients who are candidates for pleurodesis are also candidates for operation. The procedures used to prevent recurrent pneumothoraces include: (1) axillary thoracotomy with apical bullectomy, mechanical pleurodesis, and partial pleurectomy; and (2) complete parietal pleurectomy. Both procedures can be performed with either open or VATS techniques. Complete parietal pleurectomy generally is avoided, since some patients may require future thoracic surgical procedures that are extremely difficult in the face of total parietal pleurectomy. Apical bullectomy, mechanical pleurodesis, and partial apical pleurectomy have been shown to reduce the recurrence rate to near zero. In addition, this procedure is easily accomplished either with VATS techniques or through a small transaxillary thoracotomy, both of which are well tolerated.
Several special situations exist that require particular expertise in treatment decisions. Patients with cystic fibrosis and severe COPD may be candidates for lung transplantation, and both pleurodesis and operation may make subsequent transplantation more dangerous. Therefore, consultation with a transplant surgeon is advisable prior to considering these therapies. AIDS patients with Pneumocystispneumonia and pneumothorax are extremely difficult to manage, having a high rate of persistent bronchopleural fistula, treatment failure, and death. For optimal management, the pulmonary surgeon should have extensive experience in the management of chest catheters.
PRIMARY PLEURAL TUMORS
Primary pleural tumors are uncommon neoplasms of two main types: diffuse malignant pleural mesotheliomas and localized fibrous tumors of the pleura (previously referred to as localized mesotheliomas). Although diffuse malignant pleural mesothelioma is the most common primary pleural tumor, involvement of the pleura with metastatic disease is more frequent and represents the most likely cause of any newly diagnosed pleural malignancy.
Localized fibrous tumors of the pleura arise from subpleural fibroblasts than produce an array of lesions varying from peripheral pulmonary nodules to sessile subpleural masses to the more typical large pedunculated neoplasms. The visceral pleura is involved more often than the parietal pleural, and both benign (70%) and malignant (30%) variations exist. Histologically, benign tumors can exhibit three patterns—fibrous, cellular, and mixed—while malignant ones also have three distinct appearances: tubulopapillary, fibrous, and dimorphic. These tumors behave more like sarcomas of the pleura than diffuse malignant mesotheliomas. Most localized fibrous tumors of the pleura are asymptomatic, discovered only incidentally on chest radiography. Extremely large tumors, however, may produce symptoms of bronchial compression with dyspnea, cough, and chest heaviness—and, rarely, symptoms of hypoglycemia from the production of an insulin-like peptide (4% of patients). On physical examination, signs of clubbing and hypertrophic pulmonary osteoarthropathy (20%-35%) may be present. Chest radiography most often demonstrates a well-circumscribed mass that may move with changes in position if the tumor is pedunculated. A pleural effusion is present in 15% of cases and can be bloody, though this does not indicate unresectability. Fine-needle aspiration cytology may be suggestive; however, the diagnosis generally can be established with certainty only at surgery.
The treatment of these lesions is a complete resection. Although lobectomy is usually not required for lesions involving the visceral pleura, wedge resection of the pulmonary parenchyma in the area of the tumor is recommended. For neoplasms arising from the parietal pleura, chest wall resection is prudent. Following complete surgical excision, no further therapy is indicated and the prognosis is good, with some patients surviving for over 10 years without recurrence; however, if the resection is incomplete, radiation therapy should be contemplated because the prognosis is poor, with a median survival of only 7 months.
Diffuse malignant pleural mesothelioma is the most common primary tumor of the pleura. Since 1960, the disorder has been strongly linked to the use of asbestos. Thick serpentine asbestos fibers (chrysotile) generally are deposited in the proximal airways and are easily cleared with less risk of the development of tumors; however, thin needle-like amphibole fibers (crocidolite, amosite, actinolite, anthophyllite, and tremolite) and the soil silicate zeolite, found in the Anatolia region of Turkey, usually lodge in the terminal airways and migrate to the pleura, thereby increasing the risk of diffuse malignant pleural mesothelioma to more than 300 times that of the general population. The increased incidence of mesothelioma in shipbuilders exposed to asbestos-laden insulation from World War II-era ships further implicates asbestosis in the pathophysiology of the disease. The latency period after exposure ranges from 15 to 50 years. Recent research suggests that the generation of free radicals (including nitric oxide), depression of the immune system (both cellular and humoral), induction of cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1α, IL-1β, and IL-6), and the production of genetic defects, such as abnormalities of chromosomes 1, 3, 4, 6, 7, 9, 11, 17 (p53), and 22 (involves c-sis, which encodes for one chain of platelet-derived growth factor) all may play a role in the mechanism of asbestos-related disease.
Histologically, diffuse malignant pleural mesotheliomas are divided into four categories: (1) epithelial or tubopapillary (35%-40%), which are associated with pleural effusions and a slightly better prognosis; (2) fibrosarcomatous or mesenchymal (20%), which are often “dry” mesotheliomas; (3) mixed (35%-40%); and (4) undifferentiated (5%-10%). The right hemithorax (60%) is affected more often than the left (35%) and 5% are bilateral.
Most patients with diffuse malignant pleural mesotheliomas complain of dyspnea on exertion and chest wall discomfort, but other symptoms, such as cough, fever (paraneoplastic), malaise, weight loss, and dysphagia, also occur. Complaints of severe chest wall pain, abdominal distention, pericardial tamponade, and superior vena cava syndrome suggest advanced disease. Although most patients develop distant metastases at some time during the course of their disease, these lesions rarely become symptomatic. Chest radiographs are distinctly abnormal, showing pleural thickening, effusion (75%), and narrowing of intercostal spaces. CT often suggests the diagnosis because of diffuse irregular pleural thickening. The diagnosis generally requires substantial tissue samples and is not generally obtainable from fine-needle aspiration cytology. Tissue can be easily acquired with VATS techniques.
Immunohistochemical stains for carcinoembryonic antigen, LeuM1, B72.3, and BerEP4 are usually negative, while those for vimentin and keratin are generally positive. Calretinin stain, which is specific for cells of mesothelial origin, has recently become available. This immunohistochemical marker can with near certainty determine whether an epithelial malignant tumor is either metastatic to pleura, for example, an adenocarcinoma (calretinin-negative) or a primary malignant mesothelioma (calretinin-positive). This stain has become an important clinical tool and should be performed on all suspected cases of diffuse malignant pleural mesothelioma. Electron microscopy may also be helpful in distinguishing this disorder from metastatic adenocarcinoma, with which it is often confused. Pathologic staging of diffuse malignant pleural mesothelioma, like its treatment (see below), has been controversial. The original Butchart staging system and a more recently promulgated tumor, node, metastases (TNM) staging system are set forth in the Table 18–3; however, neither is widely accepted or utilized.
Table 18–3. Staging systems for malignant mesothelioma.
The treatment of diffuse malignant pleural mesothelioma also remains variable. Owing to the low incidence of this disease, its natural history has not been carefully defined with regard to various prognostic factors, and few randomized trials have been conducted to compare treatment strategies. The reported median survival for all patients ranges from 7 months to 16 months. Recent randomized prospective trials have demonstrated benefit of platinum-based chemotherapy in combination with the antifolates pemetrexed or raltitrexed. Vogelzang and co-workers randomized 448 patients with unresectable pleural mesothelioma to receive cisplatin versus cisplatin in combination with pemetrexed. Patients treated with pemetrexed in addition to cisplatin demonstrated improved median survival (12.1 vs 9.3 months) and progression-free survival. The improved survival came at a cost of increased bone marrow–related toxicity (neutropenia and leukopenia). van Meerbeeck and co-workers demonstrated similar findings in a randomized sample of patients comparing cisplatin and combination cisplatin and raltitrexed. Mean survival in the cohort receiving combination cisplatinum andraltitrexed was 11.2 months versus 8.8 months in patients receiving cisplatin alone. Newer chemotherapeutic agents under active investigation include ranpirnase, intrapleural IL-2, and vascular endothelial-derived growth factor antagonists (bevacizumab).
Surgery alone has also been used in attempts to improve survival, and two major approaches have been utilized: radical pleuropneumonectomy or parietal pleurectomy with decortication. The initial experience with radical pleuropneumonectomy demonstrated only a higher associated morbidity but not better long-term survival when compared to less radical pleurectomy and decortication. When combined with postoperative chest wall irradiation, the latter procedure results in a median survival of up to 25 months. Other approaches have combined preoperative chemotherapy (MD Anderson), intraoperative and postoperative chemotherapy (Lung Cancer Study Group, Cleveland Clinic), photodynamic therapy (NCI), and immunotherapy with TNF-α as well as interferon (IFN)-α and IFN-Γ (NCI, SWOG) with limited success. Currently, the use of intraoperative radiation therapy (UCSF, MSKCC) and gene therapy are also being investigated. Although the general impression is that multimodality therapy is superior to any one therapy alone, the exact combination of treatment options for this disease is yet to be defined. It is clear, however, that new therapies are needed.
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Kadota K et al: Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma. J Thorac Oncol 2011;6(5):896.
Rusch V et al: The role of surgical cytoreduction in the treatment of malignant pleural mesothelioma: meeting summary of the International Mesothelioma Interest Group Congress, September 11-14, 2012, Boston, Mass. J Thorac Cardiovasc Surg 2013;145(4):909.
DISEASES OF THE MEDIASTINUM
MEDIASTINITIS
Mediastinitis may be acute or chronic. There are four sources of mediastinal infection: direct contamination, hematogenous or lymphatic spread, extension of infection from the neck or retroperitoneum, and extension from the lung or pleura. The most common direct contamination is esophageal perforation. Acute mediastinitis may follow esophageal, cardiac, and other mediastinal operations. Rarely, the mediastinum is directly infected by suppurative conditions involving the ribs or vertebrae. Most direct mediastinal infections are caused by pyogenic organisms. Most mediastinal infections that invade via the hematogenous and lymphatic routes are granulomatous. Contiguous involvement of the mediastinum along fascial planes from cervical infection is frequent; this occurs less commonly from the retroperitoneum because of the influence of the diaphragm. Empyema often loculates to form a paramediastinal abscess, but extension to form a true mediastinal abscess is uncommon. Extension of mediastinal infections to involve the pleura is common.
Esophageal perforation, the source of 90% of acute mediastinal infections, can be caused by vomiting (Boerhaave syndrome), iatrogenic trauma (endoscopy, dilation, operation), external trauma (penetrating or blunt), cuffed endotracheal tubes, ingestion of corrosives, carcinoma, or other esophageal disease. Mediastinal infection secondary to cervical disease may follow oral surgery; cellulitis; external trauma involving the pharynx, esophagus, or trachea; and cervical operative procedures such as tracheostomy, mediastinoscopy, and thyroidectomy.
Clinical Findings
Emetogenic esophageal perforation (Boerhaave syndrome) is usually associated with a history of vomiting but in some cases is insidious in onset. Severe boring pain located in the substernal, left or right chest, or epigastric regions is the chief complaint in over 90% of cases. One-third of patients have radiation to the back, and in some cases pain in the back may predominate. Low thoracic mediastinitis can sometimes be confused with acute abdominal diseases or pericarditis. Acute mediastinitis is often associated with chills, fever, or shock. If pleural extension develops, breathing may aggravate the pain or cause radiation to the shoulder. Swallowing increases the pain, and dysphagia may be present. The patient is febrile, and tachycardia is noted. About 60% of patients have subcutaneous emphysema or pneumomediastinum. A pericardial crunching sound with systole (Hamman sign) is often a late sign. Fifty percent of patients with esophageal perforation have pleural effusion or hydropneumothorax. Pneumomediastinum or pneumothorax following esophageal endoscopy is sine qua non of esophageal perforation. Neck tenderness and crepitation are more often found in cervical perforations.
The diagnosis may be confirmed by contrast x-ray examination of the esophagus, preferably using thin barium. If no esophageal leak is evident then the study is completed using standard concentration barium. The use of water-soluble media is to be avoided to prevent consequences of water- soluble contrast aspiration in this population that is at increased risk for repiratory complication. Endoscopic visualization of the perforation is not recommended as an initial diagnostic maneuver as this may inadvertently extend the perforation. Chest CT scan with oral and intravenous contrast is helpful in determining the level of the perforation and the degree of mediastinal soilage as well as possible underlying esophageal or pulmonary pathology. The patient, however, must be clinically stable to be subjected to the rigors of these tests. For more critically ill patients, simple oral administration (or administration through a proximally placed nasogastric tube) of contrast and a simultaneous portable chest x-ray in an intensive care setting can often confirm the diagnosis. Myocardial infarction is sometimes mistakenly diagnosed in patients with esophageal perforation when a predisposing cause of pneumomediastinum is not apparent.
Treatment
Surgical management of intrathoracic esophageal perforation depends on the underlying cause (iatrogenic, tumor, stricture, etc) and the amount of elapsed time from leak to diagnosis. All intrathoracic leaks should be surgically explored. Initial management includes immediate drainage of associated pleural contamination by large-bore chest tubes and decompression of the occasional pneumothorax. Broad-spectrum antibiotics, including antifungal therapy, are initiated and vigorous fluid hydration administered.
Typically, a right thoracotomy offers the most access to the intrathoracic esophagus and should be used through the sixth interspace. Even distal left-sided perforations can be managed from the right side. A left thoracotomy, however, is useful when a perforated esophagus from a distal esophageal stricture is encountered.
Treatment of an immediately recognized (< 24 h) iatrogenic esophageal perforation in an otherwise normal esophagus includes primary two-layer closure with careful attention to complete mucosal closure by interrupted absorbable sutures or surgical staplers. Esophageal muscle is then closed over the mucosal injury and buttressed with either a flap of parietal pleura, diaphragm, or intercostal muscle. Copious irrigation and wide drainage is performed. Occasionally, closure over a T-tube drain has been successful.
Esophageal perforations more than 48 hours old are widely drained and the esophagus either defunctionalized or resected. This depends on the degree of mediastinal soilage discovered upon exploration, the extent of sepsis, and the patient’s performance status. When perforation occurs secondary to esophageal cancer or manipulation for severe reflux stricture, achalasia, or an otherwise abnormal esophagus, different surgical options exist. If the perforation is recognized immediately and the patient is not floridly septic, esophageal resection is preferred. Reconstruction (usually using a gastric conduit) can be done at the same setting but only if the patient is stable and the degree of contamination minimal. Otherwise, reconstruction is performed at a later date when the patient has fully recovered from the septic event. Esophageal stent placement and adequate drainage of the mediastinal and pleural spaces also can be considered.
The mortality associated with esophageal perforation remains high (30%-60%) despite advances in critical care, nutritional support, and operative management. The specific surgical approach—repair, resection, or endoscopic—must be tailored to the individual circumstances (mechanism of perforation, underlying pathology, time to diagnosis, and patient performance status) in order to achieve optimal results.
Chronic mediastinitis usually involves specific granulomatous processes with associated mediastinal fibrosis and chronic abscesses. Histoplasmosis, tuberculosis, actinomycosis, nocardiosis, blastomycosis, and syphilis have been incriminated. Amebic abscesses and parasitic disease such as echinococcal cysts are rare causes. The infectious process is usually due to histoplasmosis or tuberculosis and involves the mediastinal lymph nodes. Esophageal obstructions may occur. Adjacent mediastinal structures may become secondarily infected. Granulomatous mediastinitis and fibrosing mediastinitis are different manifestations of the same disease. Mediastinal fibrosis is a term used synonymously with idiopathic, fibrous, collagenous, or sclerosing mediastinitis. Eighty or more cases of mediastinal fibrosis have been reported, but the cause has been determined in only 16%, and of these over 90% were due to histoplasmosis. In only 25% of 103 cases of granulomatous mediastinitis has the cause been identified. Histoplasmosis was the most common known cause (60%) and tuberculosis the second-most common (25%).
About 85% of patients with mediastinal fibrosis have symptoms from entrapment of mediastinal structures as follows: superior vena caval obstruction in 82%; tracheobronchial obstruction, 9%; pulmonary vein obstruction, 6%; pulmonary artery occlusion, 6%; and esophageal obstruction, 3%. Rarely, inferior vena caval obstruction or involvement of the thoracic duct, atrium, recurrent laryngeal nerve, or stellate ganglion is found. Multiple structures may be simultaneously involved.
Seventy-five percent of patients with granulomatous mediastinitis have no symptoms, and disease is discovered by chest x-ray, which shows a mediastinal mass. The mass is in the right paratracheal region in 75% of cases. In the 25% of patients with symptoms, about half have superior vena caval obstruction and one-third have esophageal obstruction. Occasional patients have bronchial obstruction, bronchoesophageal fistula, or pulmonary venous obstruction.
A mediastinal tuberculous or fungal abscess occasionally dissects long distances to present on the chest wall paravertebrally or parasternally. Secondary rib or costal cartilage infections with multiple draining sinus tracts occur.
Clinical Findings
Granulomatous and fibrosing mediastinitis affects women two to three times more commonly than men. Women aged 20-30 years are most typically affected, though the disorder may present in the fourth to fifth decades. Esophageal involvement results in dysphagia or hematemesis. Tracheobronchial involvement may cause severe cough, hemoptysis, dyspnea, wheezing, and episodes of obstructive pneumonitis. Pulmonary vein obstruction—the most common serious manifestation—produces congestive heart failure resembling advanced mitral stenosis and is usually fatal. Although not diagnostic, the respective skin tests in cases due to histoplasmosis or tuberculosis are strongly positive.
X-ray findings demonstrate a right paratracheal or anterior mediastinal mass. There may be spotty or subcapsular calcifications. Classically, histoplasmosis presents with hilar node calcification or so-called popcorn granuloma appearance. Calcification can also occur in thymoma or teratoma located in the anterior mediastinum. Chest CT (with intravenous and oral contrast) is most effective in defining the extent of mediastinal fibrosis and impingement on vital structures.
Treatment
Specific antimicrobial therapy is indicated when an infecting organism is identified. Patients with symptomatic mediastinal masses and fibrosis can require resection for relief of obstruction.
Prognosis
The prognosis following surgical excision of granulomatous mediastinal masses is good. Operative procedures do not appear to activate fibrosing mediastinitis, but success in treatment has been unpredictable. Most patients with fibrosing mediastinitis—whether treated or not—survive but have persistent symptoms.
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SUPERIOR VENA CAVAL SYNDROME
Superior vena caval obstruction produces a distinctive clinical syndrome. Malignant tumors are the cause in 80%-90% of cases; lung cancer accounts for about 90%. The incidence of superior vena caval syndrome in lung cancer patients is 3%-5%. The male-to-female ratio is about 5:1. Other primary mediastinal tumors that may cause superior vena caval obstruction include thymoma, Hodgkin disease, and lymphosarcoma. Metastatic tumors from the breast or thyroid or from melanoma also occasionally cause superior vena caval obstruction. Benign tumors are an unusual cause, but substernal goiter, any large benign mediastinal masses, and atrial myxoma have been implicated. Thrombotic conditions, either idiopathic or associated with polycythemia, mediastinal infection, or indwelling catheters, are unusual causes. The association of superior vena caval obstruction with chronic mediastinitis is discussed in the preceding section. Trauma may produce acute venous obstruction (eg, traumatic asphyxia, mediastinal hematoma).
The clinical manifestations depend on the abruptness of onset, the location of the obstruction, the completeness of occlusion, and the availability of collateral pathways.
Venous pressure measured in the arms or head varies from 200 to 500 mm H2O, and severity of symptoms is correlated with the pressure. Fatal cerebral edema can occur within minutes of an acute complete obstruction, whereas a slowly evolving one permits development of collaterals and may be only mildly symptomatic. Symptoms are milder when the azygos vein is patent. Azygous blood flow—normally about 11% of the total venous return—can increase to 35% of the venous return from the head, neck, and upper extremities. Thus, the most severe cases occur when occlusion is complete and the azygos vein is involved. The thrombus may propagate proximally to occlude the innominate and axillary veins.
Clinical Findings
Symptoms include puffiness of the face, arms, and shoulders and a blue or purple discoloration of the skin. Central nervous system symptoms include headache, nausea, dizziness, vomiting, distortion of vision, drowsiness, stupor, and convulsions. Respiratory symptoms include cough, hoarseness, and dyspnea, often due to edema of the vocal cords or trachea. Nasal congestion is often an early presenting symptom. These symptoms are made worse when the patient lies flat or bends over. In long-standing cases, esophageal varices may develop and produce gastrointestinal bleeding. The veins of the neck and upper extremities are visibly distended, and in long-standing cases there are marked collateral venous channels over the anterior chest and abdomen. Chronic pleural effusions may develop as a result of impaired lymphatic drainage. Onset of symptoms in fibrosing mediastinitis may be insidious, consisting initially of early morning edema of the face and hands. Occasionally, symptoms and findings are localized to one side when the level of obstruction is above the vena cava and only the innominate vein is blocked. In this situation, symptoms are mild because communicating veins in the neck usually decompress the affected side.
The diagnosis can be confirmed by measuring upper extremity venous pressure; in patients with severe symptoms, a pressure of 350 mm H2O or more is usual. Of patients with malignant vena caval obstruction studied by venography, 35% have thrombosis involving the innominate or axillary veins, 15% have complete caval obstruction without thrombosis, and 50% have partial superior vena caval obstruction. If patency of the azygos vein is in question, interosseous azygography may be useful. Chest x-ray may show a right upper lobe lung lesion or right paratracheal mass. Aortography is occasionally required to exclude aortic aneurysm. CT or MRI scan with contrast enhancement provides sufficient anatomic detail, supplanting the need for arteriography or venography as a diagnostic modality for this syndrome. The differential diagnosis may include angioneurotic edema, congestive heart failure, constrictive pericarditis, and fibrosing mediastinitis. Effort thrombosis of the axillary vein and innominate vein obstruction from elongation and buckling of the innominate artery can be considered in unilateral cases.
Complications
In patients with partial superior vena caval obstruction, thrombosis may suddenly change mild symptoms to marked venous distention, cyanotic swelling, vocal cord edema, and impaired cerebration. Bleeding from esophageal varices is rare except in severe long-standing cases.
Treatment
Superior vena caval obstruction caused by cancer should be treated with diuretics, restriction, avoidance of upper extremity intravenous lines, head elevation, and prompt radiation therapy. Cases of superior vena cava obstruction due to tumor begin to subside by 7-10 days of treatment. Because of the possibility of thrombosis in malignant cases, the use of fibrinolytic agents has been suggested. Caution must be advised in using anticoagulants, however, because many patients have advanced disease and may harbor occult cerebral metastases. Therefore, before starting therapy, patients should undergo CT or MRI brain scanning to prevent the occurrence of intracerebral hemorrhage. Recently, the use of intravascular expansile stents has been pioneered. Limited early experience suggests that the lumen can be reopened and that good venous drainage and decompression can be achieved by minimally invasive interventional radiologic techniques. Long-term results have not been reported, and disadvantages include the need for anticoagulation to prevent recurrent thrombosis. Chemotherapy is sometimes used alone or with radiotherapy. Most cases of malignant superior vena caval obstruction are not remediable by operation. Tissue diagnosis is important for diagnosis and for guiding therapy. Invasive procedures, however, must be tailored to the individual patient and the severity of the caval obstruction. Patients with new, severe, or rapidly progressive symptoms should receive immediate palliative radiation therapy. Patients with subacute presentations can better tolerate the time required to make the diagnosis.
Fine-needle aspiration, bronchoscopy, cervical mediastinoscopy, and anterior mediastinotomy—and even, occasionally, thoracotomy—offer possible approaches for obtaining tissue. Caution must be advised, however, in the setting of acute fulminant superior vena caval obstruction because any invasive procedure will carry a significantly higher morbidity due to bleeding from venous obstruction. In this case, attempts at invasive techniques for tissue diagnosis should be avoided. Most frequently, the disease process has been previously histologically confirmed because superior vena caval obstruction presents typically as a complication of locally advanced disease. In benign incomplete superior vena caval obstruction, surgical excision of the compressing mass can provide an excellent result. In total obstruction, such as occurs in fibrosing mediastinitis, most patients will gradually improve without treatment. There are numerous surgical procedures designed to bypass caval obstruction, replace the superior vena cava, or recanalize the vena caval lumen. These procedures have been dramatically effective in some cases, but only recently have they been sufficiently successful to warrant consideration.
Prognosis
Radiotherapy is most effective when superior vena caval obstruction is incomplete. Mean survival of patients with malignant caval obstruction from lung cancer is 6-8 months. The death rate from causes related to vena caval obstruction itself is only 1%-2%.
MEDIASTINAL MASS LESIONS
Lesions within the mediastinum include a variety of masses, both malignant and benign, that arise from the diverse organs and tissues which occupy the central thorax. Overall, the incidence of all mediastinal masses is low, especially compared with the frequency of lesions arising within the lung (bronchogenic cancer, etc). Mediastinal malignancies constitute less than 20% of all thoracic tumors.
Mediastinal masses arise from specific structures that reside in relatively constant anatomic arrangement. The mediastinum itself is defined laterally by the mediastinal pleura of each lung; superiorly and inferiorly by the thoracic inlet and diaphragm, respectively; anteriorly by the sternum; and posteriorly by the vertebral bodies. For purposes of definition, the mediastinum is divided loosely into three main compartments: anterior (or anterosuperior), middle, and posterior. The anterior mediastinum contains the thymus, fat, and lymph nodes while the middle mediastinum contains the heart, pericardium, ascending and transverse aorta, brachiocephalic veins, trachea, bronchi, and lymph nodes. The posterior mediastinum consists of the descending thoracic aorta, esophagus, azygous vein, autonomic ganglia and nerves, lymph nodes, and fat. This has important implications for diagnosing suspected masses. The likelihood of malignancy is influenced primarily by three main factors: anatomic location, age, and the presence or absence of symptoms. Although two-thirds of mediastinal tumors are benign, masses in the anterior compartment are more likely to be malignant. Age is an important predictor as well with many lymphomas and germ cell tumors presenting between the second and fourth decade of life. Symptomatic patients are more likely to have a malignancy. Although classically in adults the majority of mediastinal masses tend to be benign (cysts, neurogenic tumors, etc), recent series have demonstrated a shift toward malignant processes being more prevalent.
An anterior mediastinal mass can indicate the following: thymoma (the most common), thymic hyperplasia, thymolipoma, thymic cyst, thymic carcinoid, thymic carcinoma, germ cell tumor (teratoma, seminoma, and nonseminomatous germ cell tumor), lymphoma, parathyroid adenoma, substernal thyroid, and lymphangioma. A middle mediastinal mass can include lymphoma, pericardial cyst, bronchogenic cyst, aneurysm, and lymphadenopathy. A posterior mediastinal mass can include neurogenic tumor, enteric cyst, bronchogenic cyst, meningocele, diaphragmatic or hiatus hernia, and paravertebral abscess. The most common mediastinal masses in children are neurogenic tumors (50%-60%). In young children (< 4 years of age), they are invariably malignant (neuroblastomas). In the adults, a neurogenic tumor is the most common mediastinal mass. This arises in the posterior compartment (typically from a peripheral nerve sheath) and is usually benign, occasionally calcified, and well circumscribed.
An extensive workup of a mediastinal lesion is usually not required for diagnosis since surgery is usually required both to establish the diagnosis and provide effective treatment. Standard PA and especially lateral chest films will often provide much useful information; however, contrast CT scanning has become the diagnostic test of choice. MRI, while helpful for assessing vascular or spinal cord extension, has not proved to be more effective than dynamic CT scanning.
Fluoroscopy may show pulsation or variation of shape or location with change of position and respiration. Tomography may reveal calcification or air-fluid levels. Barium swallow is used to evaluate intrinsic esophageal lesions or esophageal displacement by extrinsic masses. Contrast studies of the intestinal tract may reveal the stomach, colon, or small bowel in a hernia. Myelography can be of crucial importance in neurogenic tumors to explain symptoms or to plan operative management. CT angiography can identify aneurysms or displacement. Pulmonary arteriography may be useful to distinguish mediastinal and pulmonary tumors.
Scintigraphy scanning is important in evaluating possible substernal goiter in anterior mediastinal lesions, since goiters can generally be removed by the standard cervical approach. Skin tests and serologic studies may be used in suspected granulomatous disease. Bone marrow examination, hormone assays, and serum tumor markers (α-fetoprotein [AFP], β-human chorionic gonadotropin [β-HCG], and LDH) are important adjuncts to evaluate a suspected germ cell tumor.
Bronchoscopy and esophagoscopy are occasionally useful to identify primary lung lesions or lesions of the esophagus. Mediastinoscopy and mediastinal biopsy must be used cautiously in mediastinal tumors that are potentially curable. Excisional biopsy is imperative in lesions (eg, thymomas) that are histologically difficult to evaluate since a curable but locally invasive malignancy might be dispersed. Mediastinoscopy is useful for the diagnosis of sarcoidosis, Castleman disease, or disseminated lymphoma.
Clinical Findings
Symptoms are more frequent among patients with malignant rather than benign lesions. About one-third of patients have no symptoms. Those patients who become symptomatic can present with cough (60%), chest pain (30%), fevers/chills (20%), or dyspnea (16%). Hemoptysis and, rarely, expectoration of cyst contents may occur. Weight loss and dysphagia are found each in about 10% of patients. Myasthenia gravis (MG) (15%-20% with thymoma), fever, and superior vena caval obstruction are each found in about 5% of patients.
Symptoms can be categorized into two groups: localizing symptoms and systemic symptoms. Localizing symptoms are secondary to tumor invasion and include respiratory compromise, dysphagia, paralysis of the limbs, diaphragm, and vocal cords, Horner syndrome, and superior vena cava syndrome. These findings are concerning for a malignant process. Malignant tumors, especially lymphomas, may produce chylothorax. Systemic symptoms are typically due to the release of excess hormones, antibodies, or cytokines. Thymoma has been associated with myasthenia, hypogammaglobulinemia, Whipple disease, red blood cell aplasia, and Cushing disease. Hypoglycemia is a rare complication of mesothelioma, teratoma, and fibroma. Hypertension and diarrhea occur with pheochromocytoma and ganglioneuroma. Neurogenic tumors may produce specific neurologic findings from cord pressure or may be associated with hypertrophic osteoarthropathy and peptic ulcer disease.
Neurogenic tumors are derived from tissue of the neural crest, including cells of the peripheral, autonomic, and paraganglionic nervous systems. Neurogenic tumors almost always occur in the posterior mediastinum—often the superior portion—arising from intercostal or sympathetic nerves. Rarely, the vagus or phrenic nerve is involved. Seventy to eighty percent of all neurogenic tumors are benign. The most common tumor (40%-65%) arises from the nerve sheath (schwannoma and neurofibroma) and is usually benign. Malignant tumors occur more frequently in children. Most malignant tumors (neuroblastoma, etc) arise from the nerve cells. Neurogenic tumors may be multiple or dumbbell in type, with widening of the intervertebral foramen. In these cases, MRI is necessary to determine if the mass extends within the spinal canal. Dumbbell tumors have been removed in the past by a two-stage approach, though a single-stage approach is now more widespread. 123I metaiodobenzylguanidine scintigraphy can be applicable particularly for patients with middle metastinal tumor suspected to be a pheochromocytoma.
Cysts of the mediastinum may arise from the pericardium, bronchi, esophagus, or thymus. Pericardial cysts are also called “springwater” or mesothelial cysts. Seventy-five percent are located near the cardiophrenic angles and 75% of these are on the right side. Ten percent are actually diverticula of the pericardial sac that communicate with the pericardial space. Bronchogenic cysts arise close to the main stem bronchus or trachea, often just below the carina. Histologically, these contain elements found in bronchi, such as cartilage, and are lined by respiratory epithelium. Enterogenous cysts are known by several names, including esophageal cyst, enteric cyst, or duplication of the alimentary tract. They arise along the surface of the esophagus and may be embedded within its wall. They may be lined by squamous epithelium similar to the esophagus or gastric mucosa. Enterogenous cysts are occasionally associated with congenital abnormalities of the vertebrae. About 10% of cysts in the mediastinum are nonspecific, without a recognizable lining.
Germ cell tumors are common mass lesions found in young adults and represent 15% of anterior mediastinal mass lesions. Malignant germ cell tumors are more common in men (>90%). Historically, they are both solid and cystic, and the more differentiated tumors can contain hair or teeth. Microscopically, ectodermal, endodermal, and mesodermal elements are present. These tumors occasionally rupture into the pleural space, lung, pericardium, or vascular structures. Most germ cell tumors of the mediastinum are metastatic and present with concomitant retroperitoneal disease.
Primary mediastinal extragonadal germ cell malignancies are rare, representing less than 5% of all mediastinal germ cell cancers and less than 5% of all primary mediastinal tumors. As pluripotent cells, germ cell tumors (GCTs) can give rise to several histologically distinct malignancies, including seminoma (40%), embryonal carcinomas and nongestational choriocarcinomas (20%), and yolk sac tumors (20%). Teratomas (20%) can have both benign and malignant components. Almost all such tumors (> 90%) produce tumor markers, including β-HCG and AFP. LDH—a nonspecific tumor marker—is produced by most bulky mediastinal germ cell tumors and is often an effective indicator of tumor burden.
Much progress in treating these tumors has been made with multi-modality therapy (surgery, radiation therapy, and chemotherapy). Currently, over 50% 5-year survival is achievable for nonseminomatous GCT, and over 90% 5-year survival is typical for seminomatous mediastinal GCT. Patients should be screened and followed with AFP, β-HCG, and LDH markers. Resection should be offered after combination chemotherapy has been administered and only after all elevated tumor markers have normalized.
Residual mediastinal masses following chemotherapy and normalization of tumor markers should be resected. At surgery, approximately 40% will be mature teratomas (with the potential for malignant degeneration), 40% necrotic tumors, and 20% residual tumors (requiring postoperative salvage chemotherapy). Rarely is palliative debulking surgery indicated if tumor markers remain elevated after several cycles of chemotherapy. Instead, alternative chemotherapy or investigational therapy should be offered.
Lymphoma is usually associated with disseminated disease metastatic to the mediastinum. It is typically identified in the anterior compartment but can present anywhere through the mediastinum. This is the second-most common mass in the anterior mediastinum. Occasionally, lymphosarcoma, Hodgkin disease, or reticulum cell sarcoma arises as a primary mediastinal lesion.
Treatment
Treatment is tailored to the specific disease process causing the mediastinal mass. In almost all cases, tissue diagnosis is imperative for guiding appropriate therapy. Minimally invasive techniques (fine-needle aspiration or core-needle biopsy) or mediastinoscopy and mediastinotomy are appropriate for diagnosis of a mediastinal mass that is secondary to metastatic disease (eg, lymphomas and germ cell tumors). Mediastinal masses that represent primary malignancies (thymoma, neurogenic tumors, etc) are treated usually with initial resection. Percutaneous biopsy of primary malignancies should be reserved for patients with locally advanced disease, considered either unresectable or suitable for preoperative systemic therapy and/or radiation therapy prior to attempted resection.
Surgical approaches include median sternotomy (anterior masses), posterolateral thoracotomy (posterior and middle mediastinal masses) as well as VATS or bilateral anterior thoracotomy (all mediastinal compartments). Adjuvant chemotherapy is important for malignant germ cell lesions, malignant neurogenic tumors, and bulky or advanced thymomas. Postoperative radiation therapy decreases local recurrence in higher stage thymoma and in other incompletely resected lesions. Radiation and chemotherapy constitutes the principal therapy for primary mediastinal lymphoma.
Complete resection is the treatment of choice for all neurogenic tumors. A standard posterolateral thoracotomy offers optimal exposure; however, more limited incisions, including thoracoscopy, can be effective for resection of clinically benign small (< 6 cm) lesions. Dumbbell lesions involving the spinal canal warrant a neurosurgical consultation. For lesions that cannot be completely excised, postoperative radiation may decrease local recurrence and symptoms. Incompletely excised or especially large or infiltrative neuroblastomas should receive combination radiation and chemotherapy in conjunction with surgery.
Prognosis
Overall, the outlook for patients with mediastinal masses has improved, with advances in combined chemotherapy and multimodality therapy. Surgical morbidity and mortality remain low (1%-4%). Patients with benign mediastinal lesions do significantly better (> 95% cure rates) than those who have malignant mediastinal masses (< 50% overall survival).
Albany C et al: Extragonadal germ cell tumors: clinical presentation and management. Curr Opin Oncol 2013;225(3):261-265.
Boateng et al: Vascular lesions of the mediastinum. Thorac Surg Clin 2009;19:91-105.
TUMORS OF THE THYMUS & MYASTHENIA GRAVIS
The thymic gland is the site of a variety of neoplasms that include thymoma, lymphoma, (eg, Hodgkin disease), granuloma, and other less common tumors. Cell types of the thymus include epithelial cells, myoid cells, thymic lymphocytes, and B lymphocytes. Tumors of the thymus can arise from any of these cell types with thymic epithelial tumors (thymoma, thymic carcinoma, and neuroendocrine tumor) being the most common. Lymphoid or hematopoietic neoplasms and mesenchymal tumors occur less frequently. Thymoma is a primary neoplasm of the thymus gland arising from thymic epithelial cells without cytologic or histologic signs of malignancy. A well-differentiated thymic carcinoma has some cytologic features of atypia, and thymic cancer cells are cytologically malignant. Thymoma is the most common tumor of the anterior mediastinum composing approximately 50% of all tumors of the anterior mediastinum and 15%-20% of all mediastinal tumors.
Thymoma may be classified according to predominant cell type into lymphocytic (25%), epithelial (25%), and lymphoepithelial (50%) varieties. Spindle cell tumor, which is sometimes associated with red cell aplasia, is considered among the epithelial tumors. The histologic subtypes have not been associated with prognostic significance. The World Health Organization (WHO) consensus guidelines provide a histologic classification system for thymoma and thymic carcinoma based on both morphology and lymphocyte-to-epithelial cell ratio. The WHO classification system classifies thymoma and thymic carcinoma in categories ranging from type A (bland spindle cells and limited lymphocytes) to type C (grossly atypical cells that are indicative of thymic carcinoma). The identification of a single pathologic subtype is difficult however, since there is considerable histologic heterogeneity. The Masaoka staging system, originally described in 1981 and revised in 1994, is the most frequently used staging method of thymoma and thymic carcinoma. This staging system classifies thymoma into four stages based on the presence of invasion and anatomic extent of involvement observed both clinically and histopathologically. The Masaoka staging system has been shown to be a significant independent factor for survival, with 5-year survival rates by stage approaching 98%-100% for stage I and II diseases, 88% in stage III disease, and 70% for patients with stage IVa and 52% for IVb, respectively. The WHO classification system as well as the Masaoka staging system is set forth in Table 18–4.
Table 18–4. Staging system for malignant thymoma.
MG is a neuromuscular disorder characterized by weakness and fatigability of voluntary muscles owing to decreased numbers of acetylcholine receptors at neuromuscular junctions. Because of the high incidence of thymic abnormalities, improvement after thymectomy, association with other autoimmune disorders, and presence in the serum of 90% of patients of an antibody against acetylcholine receptors, MG is thought to be of autoimmune etiology. About 30% of patients with thymoma have MG, and about 15% of patients with myasthenia develop a thymoma. Thymic carcinoma, which carries a worse prognosis than other thymomas, is rarely associated with MG. About 85% of patients with MG have thymic abnormalities consisting of germinal center formation in 70% and thymoma in 15%. MG can occur in association with tumors of any cell type but is more common with the lymphocytic variety. The mean age of patients with thymoma-associated MG is between 44 and 49 years of age without significant differences between males and females. Patients with thymoma-associated MG tend to be younger than those with non-MG thymoma.
Clinical Findings
Fifty percent of thymomas are first identified in an asymptomatic patient on a chest x-ray obtained for another purpose. Symptomatic patients may present with chest pain, dysphagia, myesthenic symptoms, dyspnea, or superior vena caval syndrome. Paraneoplastic symptoms are fairly common in the setting of thymoma and account for approximately 60% of all presentations of thymoma.
CT with intravenous contrast of the chest provides information on the size, density, and relationship of the tumor to the surrounding intrathoracic organs and vessels. It may also reveal any pleural metastases. MRI is occasionally helpful to assess vascular invasion.
The diagnosis of MG can be made from the patient’s history of easy fatigability and associated decremental response in muscular contraction to repeated stimulation of the motor nerve or from improvement in these abnormalities in response to edrophonium (Tensilon), a short-acting anticholinesterase drug.
Level of clinical suspicion for thymoma may dictate the need for biopsy prior to resection. In patients with a high likelihood of thymoma, excision without biopsy may be both diagnostic and therapeutic. CT-guided core needle biopsy is a useful and less invasive technique for determining histology of an anterior mediastinal mass, but should be considered only if there is evidence for local invasion such that a greater extent of resection might be necessary. Definitive diagnosis of thymoma is based on histologic study of a tissue sample usually after excisional biopsy or a complete resection has been performed. Small, well-encapsulated anterior mediastinal masses should not be biopsied, as the procedure penetrates the tumor capsule and can lead to tumor seeding and recurrence, thus jeopardizing the opportunity for cure of an early-stage thymoma.
Treatment
The surgical approaches to thymectomy are varied and reflect the balance between complete, curative resection and the magnitude and morbidity of a procedure. All approaches enable a complete resection of the capsular thymus with the extent of peri-thymic mediastinal and cervical tissue resection distinguishing each of the procedures. The goal of the operation is total thymectomy. Transsternal thymectomy with en bloc resection of the anterior mediastinal fat tissue from phrenic to phrenic laterally and the diaphragm to the thyroid gland is considered the standard, classical operative approach. Alternative approaches include transcervical thymectomy and minimally invasive approaches such as VATS thymectomy and robotic-assisted thymectomy. The latter approaches, while useful for thymectomy for benign conditions (myasthenia, etc), arguably have a limited role in the surgical treatment of malignant thymoma.
Despite a paucity of randomized controlled trials, summary treatment guidelines for each stage of the disease have been established by consensus in the literature. Multidisciplinary discussion is encouraged to assure appropriate therapy is recommended and provided. For disease stages I and II (see Table 18-4), complete resection alone is the standard of care. Radiotherapy may be considered for patients at risk for recurrence. Risk factors for recurrence include invasion through the capsule, close surgical margins, WHO grade B type, and a tumor adherent to the pericardium. Patients presenting with resectable or potentially resectable stage III disease should be evaluated for multimodality therapy. Surgical resection can be considered either initially or following neoadjuvant therapy if complete resection is not initially feasible. Neoadjuvant or induction chemotherapy may decrease the volume of the tumor, thereby facilitating complete resection. If resection is not appropriate then chemotherapy, either concurrent or sequential, with radiotherapy can be considered. For patients with stage IVA disease, operation can be considered only if pleural or pericardial metastases are resectable.
Anticholinesterase drugs (eg, neostigmine bromide) are given as initial treatment to patients with MG. Corticosteroids may be given in selected cases, but a high incidence of side effects makes them unsuitable for more liberal use. Early thymectomy is now recommended for all patients with symptomatic MG whether or not a thymoma is suspected. The course of the disease is usually improved, and subsequent development of a malignant thymoma is eliminated. Thymectomy can be postponed in the occasional patient with mild disease well controlled by anticholinesterase therapy.
Following thymectomy, about 75% of patients with MG are improved and 30% achieve complete remission. Younger patients benefit more from thymectomy than do those over the age of 40 years, but a positive effect also accrues to the latter group. Recently, minimally invasive approaches to thymectomy for myasthenia patients has resulted in reduced length of stay, decreased blood loss, and decreased pain in comparison with more traditional partial sternal splitting procedures.
Prognosis
The rates of complication and death with thymectomy are low except in the setting of locally advanced disease. Respiratory care of patients with MG in the immediate postoperative period now presents little difficulty because of the availability of anticholinesterase drugs. Recent evidence including a retrospective review by Okereke et al suggests that neither MG nor paraneoplastic syndromes are associated with a poor prognosis and there are no differences in survival between those with and without MG.
The Masaoka staging system has been widely accepted as the best predictor of survival in thymoma patients. Although in general the WHO histologic classification of thymoma has been considered reproducible, issues have been raised regarding interobserver variability which may impact its prognostic ability. Completeness of resection has been shown to be an important independent predictor of survival.
Overall survival rates are extremely good for early-stage thymomas, and 10-year survival rates are excellent. Stage I lesions approach 100% 10-year survival rates. Stage II tumors with resection and postoperative radiation therapy have approximately 75% 10-year survival rates. Patients with locally advanced stage III thymoma, however, have long-term survival rates of less than 25%. Outcomes with multimodality therapy (neoadjuvant chemotherapy, surgery followed by chemotherapy and radiation therapy) are improving, as marked by significant tumor responses and enhanced resectability rates. Long-term disease specific survival can be expected not only after surgery for early-stage thymoma but also after surgery for advanced disease, including select patients with pleural metastases. However, patients who undergo surgery for stage IVa disease have reduced disease-free survival.
THYMIC CARCINOMA
This tumor is a rare variant (< 15%) of thymic lesions and is histologically and biologically quite different from invasive or malignant thymoma. A large number of histologic types of thymic carcinoma have been described and range from low-grade, well-differentiated neoplasms to high-grade, poorly differentiated malignancies. The most common type of thymic carcinoma in Western patients is poorly differentiated, nonkeratinizing squamous cell carcinoma. Thymic carcinomas tend to be very invasive and difficult to resect completely. Unfortunately, even in the setting of a complete resection, recurrence is common both locally and at distant sites. Still, when at all possible, an aggressive combined-modality approach (induction chemotherapy, resection, and postoperative chemoradiotherapy) should be employed. Typically, these are young men (< age 50 years) with an otherwise excellent performance status. While a good response to induction therapy and a complete resection will provide a significant disease-free interval, long-term survival is still unlikely. Better systemic agents and a molecular understanding of this cancer holds hope for significant improvements in cure rates.
Casey EM et al: Clinical management of thymoma patients. Hematol Oncol Clin N Am 2008;22(3):457.
Falkson CB et al: The management of thymoma: a systematic review and practice guidelines. J Thorac Oncol 2009;4(7):911.
Moran CA, Suster S: Thymic carcinoma: current concepts and histologic features. Hematol Oncol Clin N Am 2008:22(3): 393.
Okereke IC et al: Prognostic indicators after surgery for thymoma. Ann Thorac Surg 2010;89(4):1071.
DISEASES OF THE LUNGS
CONGENITAL CYSTIC ANOMALIES OF THE LUNG
Congenital lesions of the lung include primarily tracheobronchial atresia, bronchogenic cysts, pulmonary dysplasia, pulmonary sequestration, congenital cystic adenomatoid malformations (CCAM), and congenital lobar emphysema (CLE). Although many of these lesions present early in life with dramatic symptoms and physical findings, most remain occult until late childhood and even into adult life. These uncommon lesions arise from aberrations in normal aerodigestive tract development, which begins during the fourth week of fetal life when the lung bud forms at the caudal end of a groove in the primordial pharynx. An initial phase of sequential airway branching occurs until as many as 20-25 generations are reached by the sixteenth week of fetal life. These branches are divided into three zones: a proximal conductive zone (branches 1-16), an intermediate transitional zone (branches 17-19), and a distal respiratory zone (branches 20-25). A second canalicular phase is then entered as capillaries develop in the distal air passages. Finally, the alveolar phase begins at approximately 26 weeks of fetal life as prototype alveolar air sacs appear complete with both type I and type II pneumocytes. The number and size of alveoli continue to increase until the total alveolar surface reaches the adult size of nearly 100 m2.
Atresia of the tracheobronchial tree can occur at any level and may involve an isolated segment or multiple diffuse areas of the airway. Tracheal atresia is associated with polyhydramnios, prematurity, esophageal atresia, and tracheoesophageal fistula. Typically, neonates present with intractable cyanosis and despite a normal-appearing larynx are unable to be intubated. Emergency tracheostomy can be life-sustaining in babies with isolated subglottic atresia; in other infants with more diffuse disease, mask ventilation can achieve some palliation through anomalous esophagobronchial connections. Diffuse airway involvement, however, is invariably fatal.
Isolated bronchial atresia results in a bronchus that ends in a blind pouch. A mucocele develops distal to the obstruction and, as a result of compression of neighboring normal bronchial structures, causes emphysematous changes in the surrounding lung. Since children frequently develop wheezing, stridor, and pulmonary infections in the involved segments, resection is almost always indicated. Like bronchial atresia, true congenital bronchial stenosis is rare, although right main stem bronchial stenosis occurs not infrequently from iatrogenic airway trauma in chronically ventilated patients.
Related anomalies of the tracheobronchial tree include anomalous tracheal or esophageal bronchi and tracheal diverticula. These rare lesions often present with symptoms of bronchial obstruction and in many cases require resection of involved lung tissue due to chronic infection and the development of bronchiectasis (see section on Bronchiectasis). Similar to pulmonary sequestration, these lesions can have a dominant systemic arterial blood supply that must be kept in mind if operation is contemplated.
Bronchogenic cysts are the most common cystic lesions of the mediastinum and arise from abnormal budding of the foregut during development. The cyst wall consists of fibroelastic tissue, smooth muscle, and cartilage, whereas the cyst itself is lined with respiratory tract epithelia. It may also contain mucus-producing cuboidal cells, which contribute to enlargement of the cyst with mucus. They may occur anywhere along the tracheobronchial tree but occur most commonly in the vicinity of the right pulmonary hilum and subcarinal region. Less frequently, they present in the neck, lower lobes of the lung, pleura, pericardium, or below the diaphragm. When large, cysts can compress surrounding vital structures, including the aerodigestive tract causing dysphagia, pneumothorax, cough, or hemoptysis or become infected. The diagnosis is confirmed by CT as a spherical fluid- or mucus-filled nonenhancing mass. An air-fluid level may be present thus suggesting communication with the airway. Cysts within the pulmonary parenchyma more commonly communicate with a bronchus, as opposed to those in the mediastinum. In general, mediastinal bronchogenic cysts present with airway compression and parenchymal cysts are manifested by pulmonary infection. Some cysts have been noted to enlarge rapidly and rupture into the pleural space, causing tension pneumothorax. Rare cases of malignant transformation have been reported. All bronchogenic cysts—regardless of location—are best treated with either simple or segmental resection by VATS or thoracotomy. Rarely, lobectomy is required.
Correia-Pinto J, et al. Congenital lung lesions underlying molecular mechanisms. Semin Pediatr Surg 2010;19(3):171.
Masters IB: Congenital airway lesions and lung disease. Pediatr Clin North Am 2009;56(1):227.
Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that occurs in infants, usually in preterm infants receiving respiratory support with mechanical ventilation or prolonged oxygen supplementation. With the introduction of positive pressure ventilation in newborn infants Northway et al originally described a pattern of lung injury characterized by airway injury, inflammation, and parenchymal fibrosis in preterm infants who had received mechanical ventilation. Since the introduction and implementation of antenatal corticosteroids and postnatal surfactant replacement BPD now more commonly affects those of extremely low birth weight and born less than 26 weeks of gestation. BPD nowadays is fundamentally viewed as the result of abnormal reparative processes in response to injury and inflammation occurring in an immature lung of a genetically susceptible infant. The pathogenesis of BPD begins with a very immature lung complicated by iatrogenic damage from therapy with oxygen and volume ventilation with superimposed infection and inflammation as well as pulmonary edema complicated by poor nutrition. Treatment is supportive combining new approaches to ventilation (nasal CPAP and inhaled nitric oxide) with vitamin A. The American Thoracic Society has recently published a position paper on the care of the child with chronic lung disease of infancy and childhood that addresses many of these issues.
Pulmonary hypoplasia is a relatively common abnormality of lung development and is defined pathologically as an abnormally low radial alveolus count and low ratio of lung weight to body weight. Pulmonary hypoplasia is termed primary pulmonary hypoplasia when no inciting cause is identified and is likely caused by abnormalities of the transcription factors that regulate early lung morphogenesis. These neonates present with tachypnea and hypoxemia resistant to administration of supplemental oxygen due to abnormal thickening of the pulmonary arteriolar wall. Persistent fetal circulation, hypoxemia, hypercapnia, and acidosis lead to early death in over 75% of patients. Secondary pulmonary hypoplasia is associated with a restriction of lung growth or the absence of fetal breathing. Any reduction of the chest cavity by a mass, effusion, or external compression can impact lung growth. The most common of these abnormalities is congenital diaphragmatic hernia (see Chapter 43). Other conditions associated with secondary pulmonary hypoplasia include those that produce oligohydramnios and direct chest compression (eg, bilateral renal agenesis [Potter syndrome], renal dysplasia, and amniotic fluid leaks); those with abnormal bone development and small rigid chest walls (eg, achondroplasia, chondrodystrophia fetalis calcificans, osteogenesis imperfecta, and spondyloepiphyseal dysplasia); those with decreased fetal respiratory movements (eg, phrenic nerve agenesis, abdominal masses or ascites with elevation of the diaphragm, arthrogryposis multiplex congenita, camptodactyly, and congenial myotonic dystrophy); those with intrathoracic mass lesions (eg, CCAM, cystic hygroma, esophageal duplication cysts); and those with pulmonary vascular abnormalities (eg, scimitar syndrome, pulmonary artery agenesis).
Unilateral pulmonary agenesis occurs when one lung and the associated vascular structures fail to develop. Neonates with pulmonary agenesis may present with tachypnea and cyanosis, particularly if associated cardiac anomalies exist (50% of cases). Some patients, however, remain asymptomatic until childhood, when they complain of dyspnea and wheezing suggestive of asthma. Physical examination in these patients reveals marked tracheal deviation toward the side of the agenesis, and chest x-ray, barium esophagography, and chest CT may be required to exclude other diagnostic possibilities such as total lung atelectasis from foreign body aspiration, total lung sequestration, and esophageal bronchus.
Pulmonary sequestration describes a mass of lung parenchyma that arises through abnormal budding of the caudal embryonic foregut and consequently has no bronchial communication with the otherwise normal tracheobronchial tree. Sequestration may occur either within normal lung tissue, termed intralobar sequestration, or as separate masses with their own visceral pleura, referred to as extralobar sequestration. The majority (85%) of sequestrations are of the intralobar type. Intralobar sequestrations receive their blood supply from the thoracic or abdominal aorta and splenic artery and their venous drainage from the pulmonary veins. In some cases this may be associated with anomalous venous drainage of the normal lung. Intralobar sequestrations are most commonly found on the left side in the lower lobe. Extralobar sequestrations are less common and receive their blood supply from the thoracic or abdominal aorta and the venous drainage via the systemic veins such as the hemiazygos or azygous veins or inferior vena cava. Both are associated with foregut communications but more commonly in extralobar sequestrations.
Intralobar sequestrations are usually diagnosed later in childhood or adolescence with multiple episodes of pneumonia. Common symptoms include a chronic or recurrent cough. Extralobar sequestrations usually present in infancy with respiratory distress and chronic cough or manifest as gastrointestinal symptoms if a communication with the gastrointestinal tract exists. In rare instances, patients may present with hemoptysis or congestive heart failure from large left-to-right shunts through the sequestration. The diagnosis is usually suspected on chest x-ray and confirmed with a CT scan of the chest delineating the arterial and venous drainage. Angiography can be used to confirm the diagnosis and elucidate aberrant vascular anatomy. Treatment consists of segmental resection or, if necessary, lobectomy via thoracotomy or video-assisted procedure. Great care must be taken to identify the nature of both the arterial blood supply and the venous drainage to avoid exsanguinating hemorrhage from division of an unrecognized systemic artery or venous infarction of the normal lung from ligation of the common draining vein. Following successful resection, the prognosis is favorable.
CCAM is the second most common cause of newborn respiratory distress, secondary to structural problems. CCAM is a discrete, space-occupying intrapulmonary mass that contain variable-sized cysts. These lesions do not function in normal gas exchange yet airspaces within these masses communicate with the tracheobronchial tree. Histologically, CCAM is distinguished from other lesions and normal lung by polypoid projections of the mucosa, an increase in smooth muscle and elastic tissue within cyst walls, an absence of cartilage, the presence of mucus-secreting cells, and the absence of inflammation. The classification system described by Stocker organizes these lesions on pathologic appearance and clinical outcome. Class I consists of large cysts greater than 2 cm; class II consists of small cysts less than 2 cm; class III consists of solid lesions without cysts. Children will present either at birth or in early childhood with recurrent respiratory infections. The growth of CCAMs usually plateaus between 25 and 28 weeks, at which time the fetus appears to grow around the lesion. The vast majority of small- to moderate-sized CCAMs remain asymptomatic during fetal life. Approximately 15% of CCAMs will shrink significantly before birth. However, large lesions represent 5%-10% of CCAMs and may produce significant mass effect, which can lead to pulmonary hypoplasia, impaired fetal swallowing and polyhydramnios, and impaired venous return and heart failure. Fetal hydrops can result and appears to depend on the size and rate of growth of the mass, and result from compression of the superior vena cava and impaired venous return. As therapeutic fetal interventions have become feasible, the ability to predict which infants will progress to hydrops has become critical. High-resolution fetal MRI can calculate a cyst volume ratio which is useful in predicting progression to hydrops. Fetal interventions including a short course of maternal betamethasone for microcystic CCAM and minimally invasive in utero thoracoamniotic shunting for macrocystic CCAM have been shown to be successful. If fetal development is uncomplicated, early delivery is not encouraged. At birth, the infants are stratified based on symptoms. Critically ill infants require immediate resection of the involved lobe. An asymptomatic neonate should be initially evaluated with chest radiography. While surgery can be delayed in those patients with small lesions, any patient with known CCAM should undergo elective resection due to possible future complications including pneumonia and malignant transformation.
CLE is the cause of half of the episodes of newborn respiratory distress due to structural abnormalities and is defined as an overdistended lobe resulting from the obstruction of a lobar bronchus. Obstruction can arise from abnormal cartilage development or an ischemic event during bronchial development. CLE also can develop as the result of meconium aspiration, lobar torsion, or an extrinsic cause such as obstructing lymph nodes. The left upper lobe is most commonly involved, and with the right middle lobe next in prevalence. In addition, neonates who require prolonged mechanical ventilation (eg, those with hyaline membrane disease) can develop lobar emphysema from a combination of suction catheter trauma and barotrauma. The right lower lobe is most frequently affected in such patients. Most infants present within the first 6 months of life with respiratory distress. In some patients, severe respiratory distress may occur in the neonatal period, requiring emergency evaluation and treatment. Almost all infants present with tracheal and mediastinal deviation away from the affected side, hyperresonance and decreased breath sounds on the affected side, and a chest radiograph demonstrating hyperlucency in the area of the affected lobe with compression of adjacent lung. A chest radiograph often is sufficient before proceeding with operation. Occasional patients, particularly older children, may require chest CT scans to exclude other pathology (eg, bronchogenic cysts, anomalous pulmonary vessels, and hilar lymphadenopathy). Bronchoscopy also may be necessary to rule out the presence of a foreign body causing ball-valve airway obstruction. Successful therapy in all patients requires pulmonary resection, which almost uniformly consists of lobectomy. Great care is necessary with airway management at the time of induction of general anesthesia in these patients as positive-pressure ventilation can result in further shifting of the mediastinum resulting in impaired venous return and cardiovascular collapse. If such a situation arises, an emergent thoracotomy should be preformed to allow for the affected lobe to “herniate out” of the incision decompressing mediastinal pressure. Even after lung resection, patients may have bronchomalacia and a tendency toward bronchospasm.
CONGENITAL VASCULAR LESIONS OF THE LUNG
Vascular diseases of the lung include two main processes: arteriovenous malformations and vascular rings. Arteriovenous malformations are uncommon congenital lesions that develop as a result of abnormal capillary formation during the canalicular phase of development. Most arise from the pulmonary artery, but occasionally a systemic arterial source can be involved similar to that in pulmonary sequestration. Rarely, an arteriovenous malformation can arise from a coronary artery, with the right coronary artery involved 55% of the time. Coronary arteriovenous fistulas drain into the right ventricle (40%), right atrium (25%), pulmonary artery (20%), coronary sinus (7%), superior vena cava (1%), or left-sided heart chambers (7%). Patients are either asymptomatic or develop signs of congestive heart failure. Myocardial infarction is rare. A continuous murmur and signs of reduced left ventricular afterload may be present. Although the diagnosis often can be established with echocardiography and color Doppler imaging, the definitive diagnosis, shunt fraction, and complete preoperative planning require catheterization and angiography. Operation is indicated for symptomatic patients and for those asymptomatic patients with large shunts.
Vascular rings occur from abnormal development of the aortic arches and major branches, with resulting compression of the trachea and esophagus. In normal fetal development, a dual system of six aortic arches regresses in such a way that the left fourth arch becomes the main left-sided aorta, the left sixth arch develops as the ductus arteriosus, and the right fourth arch persists as the right innominate artery and subclavian artery. Most vascular rings, however, are associated with a right-sided aortic arch and are classified as complete vascular rings or incomplete rings (arterial slings). Complete vascular rings include a double aortic arch (67%, the most common complete ring), a right aortic arch with a left subclavian and left ductus arteriosus (30%), a right aortic arch with mirror-image branching and a left ductus arteriosus (rare), and a left aortic arch with an aberrant right subclavian and right ductus arteriosus (very rare). Incomplete rings consist of an aberrant right subclavian artery that originates on the left side and passes posterior to the esophagus (most common incomplete ring) and an anomalous left pulmonary artery arising from the right pulmonary artery and passing between the trachea and the esophagus (pulmonary artery sling).
Most patients present with symptoms of tracheal or esophageal compression. Patients with an anomalous right subclavian artery may present later in life with obstructive symptoms (dysphagia lusoria), while those with complete vascular rings and pulmonary artery slings typically present early in life (within 6 months) with symptoms of respiratory distress (often frank stridor), particularly with neck flexion and poor feeding. The diagnosis is often suggested by characteristic findings on barium esophagogram. Bilateral indentations imply double aortic arch. A posterior indentation suggests an aberrant right subclavian artery, large right-sided indentations suggest complete rings associated with a right aortic arch, and an anterior impression is typical of a pulmonary artery sling. Often, the diagnosis can be confirmed by echocardiography. MRI/MRA often provides useful anatomic details. Surgical repair of these lesions is indicated once the diagnosis is established and is accomplished by dividing the vascular ring usually through a left thoracotomy. With double aortic arches, the smaller of the two arches is divided distal to the subclavian artery, while other complete rings generally are treated by division of the ligamentum arteriosum. Aberrant right subclavian arteries may be simply divided or, if necessary, divided and transposed to the right side. Pulmonary artery slings require reimplantation of the left pulmonary artery and often resection of the compressed trachea, which often has severe tracheomalacia and stenosis. Rarely, tracheomalacia secondary to vascular ring compression necessitates suspension of the aortic arch from the sternum.
SUPPURATIVE DISEASES OF THE LUNG
A lung abscess usually begins as a necrotizing pneumonia progessing to liquefactive necrosis of the lung parenchyma. The liquefied necrotic material eventually empties into a draining bronchus, forming a necrotic cavity of pus containing an air-fluid level. With rupture, the infection can extend into the pleural space, producing an empyema. Arbitrarily, abscesses are termed acute if the duration is less than 6 weeks and chronic if more than 6 weeks. Although the incidence of lung abscesses fell dramatically following the introduction of effective antibiotics in the 1940s and 1950s, a recent increase in the number of immunocompromised individuals secondary to organ transplantation, chemotherapy, and AIDS has resulted in a resurgence in the numbers of lung abscesses requiring treatment.
Lung abscesses can be divided into two major categories based on etiology: primary and secondary. Lung abscesses are termed primary when they arise in a previously healthy individual or secondary to an underlying cause. Most commonly a primary abscess occurs as a result of aspiration owing to impaired consciousness or swallowing dysfunction due to neuromuscular or esophageal diseases. Sixty to seventy percent of lung abscesses present in the right lung in the dependent posterior segment of the right-upper lobe and superior segment of the lower lobe. They are most commonly polymicrobial with a predominance of anaerobic organisms including Peptostreptococcus, Bacteroides fragilis, and Fusobacterium. Conditions that predispose to aspiration include anesthesia (both general and monitored), neurologic disorders (cerebrovascular accidents, seizures, diabetic coma, head trauma, etc), drug ingestion (alcohol, narcotics, etc), normal sleep, poor oral hygiene (increases bacterial load), and esophageal disease (gastroesophageal reflux, achalasia, cancer, tracheoesophageal fistula). Secondary causes include bronchial obstruction (tumor, foreign body, hilar lymphadenopathy), necrotizing pneumonia (S auerus, K pneumoniae), chronic pneumonia (due to fungi, tubercle bacilli), and opportunistic infection in an immunodeficient host. Over the years the incidence of secondary lung abscess arising in the setting of an immunocompromised state has increased. As a result, virulent aerobic species such as Klebsiella, Pseudomonas, Proteus, Enterobacter, and S aureus now comprise the majority of these infections as opposed to anaerobic species. Gram-negative lung abscess occurs in elderly and immunocompromised patients with nosocomial pneumonia. Cavitating lesions may arise in the setting of a malignancy or pulmonary infarct. Direct extension of a localized infection such as amebiasis or subphrenic abscess may also progress to a secondary lung abscess. Blood-borne infections can give rise to multiple lung abscesses in the periphery of the lung and are the result of septic emboli from bacteria, endocarditis, septic thrombophlebitis, or subphrenic infection. It should be noted that secondary infections of congenital or acquired cystic lesions, such as bronchogenic cysts, bullae, tuberculous cavities, and hydatid cysts, are not true pulmonary abscesses because they occur in a preformed space.
Clinical Findings & Diagnosis
Patients with lung abscesses typically reports symptoms of cough, fever, putrid sputum, hemoptysis, dyspnea, pleuritic chest pain, and weight loss. Symptoms are often insidious in onset and associated with malaise and weight loss if chronic. Complications include rupture into a bronchus, with initial hemoptysis followed by the production of foul-smelling, purulent sputum (and the potential for life-threatening pneumonia from aspiration of pus into normal lung); rupture into the pleural space with resulting pyopneumothorax, sepsis, and possibly empyema necessitatis; and, rarely, massive hemoptysis requiring emergent pulmonary resection. On physical examination, signs of lobar consolidation predominate; but clubbing, signs of pleural effusion, cachexia, and rarely a draining chest wound (empyema necessitatis) can be present. Laboratory studies should include a differential white blood cell count and sputum culture. Chest radiography and CT scan of the thorax are usually sufficient to aid diagnosis and differentiate between empyema and abscess. Cavitation is generally apparent on chest radiographs 2 weeks after the onset of symptoms. Radiological resolution lags behind clinical and biochemical improvement, taking up to 3 months to resolve in up to 70%. In cases of suspected bronchial obstruction or in all patients with unexplained lung abscesses, bronchoscopy is indicated. Fine-needle aspiration of the abscess cavity for diagnostic culture has been shown to isolate the offending pathogens in 94% of patients compared with only 11% and 3% from sputum culture and bronchoalveolar lavage, respectively. Early fine-needle aspiration can prompt a change of the antibiotic regimen in 43% of cases and can be life-saving in immunocompromised patients with unusual organisms.
Treatment
Antibiotic administration has been the mainstay of therapy following general resuscitation measures. First-line treatment should include aerobic and anaerobic coverage for a period of 4-6 weeks. Once the acute sepsis subsides (after up to 2 weeks), therapy can frequently be changed to an oral outpatient regimen and continued until complete resolution of the abscess occurs (3-5 months). Important adjuncts to antibiotic administration include chest physiotherapy, postural drainage, bronchoscopy (may require repeated examinations to maintain bronchial drainage), and health maintenance measures (general nutrition, dental hygiene, etc).
In patients who do not respond to this initial regimen and who do not have surgical indications (see below), early percutaneous drainage has been shown to be a safe and effective procedure (mortality rate, 1.5%; morbidity rate, 10%). Specific proposed indications for percutaneous drainage include: (1) an abscess under tension as evidenced by mediastinal shift, displacement of fissures, or downward displacement of the diaphragm; (2) radiographic verification of contralateral lung contamination; (3) unremitting signs of sepsis after 72 hours of adequate antibiotic therapy; (4) abscess size larger than 4 cm or increasing abscess size; (5) rising fluid level; and (6) persistent ventilatory dependency.
In addition to drainage, intervention permits microbiological analysis of the aspirate. In up to 47% of patients, initial antibiotic regimens require adjustment based on microbial speciation and sensitivity analyses. Tube thoracostomy carries risk of parenchymal injury with resulting chronic air leak and/or bronchopleural fistula (BPF). Operative intervention is rarely indicated in the management of lung abscess but should be considered in patients with failure of clinical or radiological improvement after 4-6 weeks of antibiotic therapy, abscesses larger than 6 cm, massive or life-threatening hemoptysis (4%), empyema or BPF (4%), and bronchial obstruction (particularly if secondary to resectable cancer). Furthermore, acute rupture into the pleural space (pyopneumothorax) is still a surgical emergency. When surgery is indicated, either thoracoscopic or open lobectomy generally is the preferred procedure and can be accomplished with low morality (0%-2%) and morbidity. A double-lumen tube is mandatory to protect the airway due to the high risk of spillage of abscess into the contralateral lung. Routine buttressing of the bronchial stump with a vascularized pedicle (intercostal muscle or pericardial fat) is recommended to prevent BPF.
Prognosis
Antibiotics given over 4-6 weeks with percutaneous drainage is effective in 85%-95% of patients. Mortality for lung abscess has decreased from 30% to 40% in the preantibiotic era to 10% in the present era, but remains greater for elderly individuals, immunocompromised patients, or those who have abscess larger than 6 cm, bronchial obstruction, multiple abscesses, necrotizing pneumonia, or gram-negative pneumonia.
Agasthian T. Results of surgery for bronchiectasis and pulmonary abscesses. Thorac Surg Clin 2012;22:333.
Bronchiectasis is defined as irreversible dilation of the peripheral airways secondary to damage of the structural components of the bronchial wall (elastin, muscles, and cartilage). Mechanisms of damage include bronchial wall injury, bronchial lumen obstruction, and traction from adjacent fibrosis seen in end-stage lung fibrosis. Cole’s “vicious cycle” hypothesizes that initial infection, in a background of genetic susceptibility or impaired mucosal clearance, results in retention of microorganisms in the bronchial tree. Overproduction of thick inflammatory mucus in the setting of persistent microbial colonization of dilated airways, together with impairment of mucociliary clearance mechanisms causes a vicious cycle of repeated and prolonged episodes of chronic inflammation resulting in progressive airway and lung damage.
The clinical syndrome manifests as chronic dilation of bronchi, a paroxysmal cough that produces variable amounts of fetid, mucopurulent sputum, and recurrent pulmonary infections. Aspirated foreign bodies, endobronchial neoplasms, and hilar lymphadenopathy (see section on Middle Lobe Syndrome, later) also can cause retention of secretions, infections, and progressive bronchiectasis. The presence of true established bronchiectasis, however, must be distinguished from pseudobronchiectasis, which is a cylindric bronchial dilation that is associated with acute bronchopneumonia. When left untreated, true bronchiectasis progresses, while pseudobronchiectasis reverses completely after weeks to months.
Most cases are related to acquired disorders and are caused by two factors: infection and bronchial obstruction. Acquired viral and bacterial infections in infancy and childhood (eg, pertussis, measles, influenza, tuberculosis, bronchopneumonia) were common predisposing conditions that led to bronchiectasis in the past and are still common in developing countries. With the reemergence of tuberculosis postinfectious bronchiectasis is also becoming more prevalent, and is seen 11% of patients. In developed countries, immune deficiency syndromes (hypogammaglobulinemia and leukocyte dysfunction), metabolic defects (cystic fibrosis, alspha-1 antitrypsin deficiency), ultrastructural defects (primary ciliary dyskinesia, Young syndrome, Kartagener syndrome, congenital defects of cartilage), and pulmonary sequestration are more common causes.
Reid categorized bronchiectasis into three main types based on pathologic appearance: (1) tubular or cylindrical, characterized by smooth dilation of the bronchi; (2) varicose, in which the bronchi are dilated with multiple indentations; and (3) cystic or saccular, in which dilated bronchi terminate in blind ending sacs of pus with no communication with the rest of the lung. Saccular bronchiectasis follows severe infections and cases of bronchial obstruction, while the cylindrical variant is associated with tuberculosis and immune disorders. Varicose consists of alternating areas of cylindrical and saccular types.
Bronchiectasis can be classified also as perfused or nonperfused types according to functional hemodynamic perfusion studies as described by Ashour. The perfused type has cylindrical bronchiectatic changes with intact pulmonary artery flow, whereas the nonperfused type involves cystic bronchiectasis with absent pulmonary artery flow and retrograde filling of the pulmonary artery through the systemic circulation.
Taken together, tubular or cylindric bronchiectasis tends to have better prognosis than cystic/varicose varieties, as the lung areas affected by the former tend to have good function and perfusion. Cystic bronchiectasis tends to indicate a completely destroyed, nonfunctional, and nonperfused lung. Additionally, all parameters of respiratory function are worse in the saccular type as compared with the tubular type. Saccular type bronchiectasis also is associated with higher bacterial loads with virulent strains, such as Pseudomonas.
In general, bronchiectasis involves the second-order to fourth-order branches of the segmental bronchi, and its distribution is largely characteristic of the underlying pathology. The left lung tends to be more involved than the right lung in 55%-80% of cases. This may be because the left mainstem bronchus is narrower and longer than the right and subject to greater compression pressures, especially by the aortic arch. The lower lobes are commonly affected owing to gravity-dependent retention of infected secretions. Congenital disorders, for example, are associated with diffuse bilateral bronchiectasis, while tuberculosis and granulomatous diseases are characterized by unilateral or bilateral disease, most commonly limited to the upper lobes and superior segments of the lower lobes. Furthermore, bronchiectasis following pyogenic and viral pneumonias usually involves only the lower lobes, middle lobe, and lingula, and postobstructive bronchiectasis is generally limited to the obstructed segments (see also Middle Lobe Syndrome, later). Common pathogens in patients with bronchiectasis include H influenzae, S aureus, K pneumoniae, E coli, and, in the chronic setting, Pseudomonas species. Mycobacteria, fungi, andLegionella should also be cultured.
Clinical Findings & Diagnosis
Patients with a history of recurrent febrile episodes often complain of a chronic or intermittent cough that produces variable amounts of foul-smelling sputum (up to 500 mL/d). Hemoptysis occurs in 41%-66%, but rarely is it massive. Bronchiectasis associated with granulomatous disease may not be associated with a productive cough (so-called dry bronchiectasis). Exacerbations and advanced disease are manifested by increased sputum production, fever, dyspnea, anorexia, fatigue, and weight loss. A history of sinus problems, infertility, or a family history of similar problems suggests the presence of an inherited disorder associated with bronchiectasis. Physical examination may reveal cyanosis, clubbing, pulmonary osteoarthropathy, evidence of malnutrition, and, in advanced disease, signs of cor pulmonale. Although bronchiectasis is suspected, an imaging study is usually required for confirmation. Bronchograms were at one time required, but high-resolution chest CT scans are now the imaging procedure of choice to document bronchial dilation, particularly with saccular disease. Even with the diagnosis of bronchiectasis, however, endobronchial neoplasm or foreign body must be excluded by flexible fiberoptic bronchoscopy.
Treatment
In nearly all patients, conservative medical therapy is indicated and generally is sufficient. This includes broad-spectrum antibiotics, bronchodilators, humidification, expectorants, mucolytics, and effective routine postural drainage. In patients with continued infection, bronchoscopy with bronchoalveolar lavage should be considered to obtain more accurate culture results. Other adjunctive therapies include influenza and pneumococcal vaccines and, in some patients, chronic “prophylactic” antibiotic administration with trimethoprim-sulfamethoxazole, erythromycin, or ciprofloxacin. A recent advance in controlling underlying bacterial (especially pseudomonas) infection and symptoms associated with bronchiectasis has been the use of inhaled antibiotics. In the cystic fibrosis and chronic bronchiectasis population, nebulized tobramycin or gentamicin has proven effective in controlling infection, sputum production, and symptoms in a significant proportion of patients.
Patients who fail intensive medical therapy may be candidates for surgical resection if the following criteria are met: (1) the disease must be localized and completely resectable; (2) pulmonary reserve must be adequate; (3) the process must be irreversible (ie, not pseudobronchiectasis, bronchial stricture, foreign body, etc); and (4) significant symptoms must persist. Preoperative assessment requires a high-resolution chest CT scan, although some surgeons still prefer a bronchogram as a “road map.” Pulmonary function studies generally are not necessary, since the involved segments do not function.
The goals of surgery are to remove all active disease and to preserve as much functioning lung parenchyma as possible. The surgical approach includes complete segmental resection of the involved areas. Partial resection almost always ends in recurrence. Resection most commonly involves all basal segments (unilaterally or bilaterally) along with the middle lobe or lingula. With tuberculosis, however, removal of the upper lobe or lobes with or without the superior segment of the lower lobes is more likely. During operation, meticulous maintenance of a clear airway devoid of mucopurulent secretions and blood is essential. Careful dissection of the bronchovascular structures is difficult in patients with chronic inflammation and scarring but is essential to avoid complications.
Prognosis
Although most patients are successfully treated with medical therapy, some require operation. The results of pulmonary resection depend on the cause and type of parenchymal involvement. Success with elimination of symptoms occurs in up to 80% of patients with limited localized disease but only 36% of those with diffuse disease. Prognostic factors include: (1) unilateral disease restricted to the basal segments; (2) young age; (3) absence of sinusitis and rhinitis; (4) history of pneumonia; and (5) no major airway obstruction. Overall morbidity and mortality rates are surprisingly low at 3%-5% and less than 1%, respectively.
Middle lobe syndrome (MLS) is characterized by recurrent or chronic collapse of the middle lobe of the right lung but can also involve the lingula of the left lung. There are two forms of MLS: obstructive and nonobstructive. Obstructive MLS occurs as a result of an endobronchial lesion or extrinsic compression of the middle lobe bronchus from hilar lymphadenopathy or tumor causing postobstructive atelectasis and pneumonitis. The most common cause of extrinsic compression of the right-middle lobe bronchus is enlargement of peribronchial lymph nodes due to fungal infections such as histoplasmosis or atypical mycobacterial infections. Adenopathy due to sarcoidosis or lymph node metastases has also been described in obstructive MLS. Less common causes include aspirated foreign objects, broncholiths, inspissated mucus (associated with cystic fibrosis), and endoluminal granulomas associated with sarcoidosis.
Nonobstructive MLS is characterized by the absence of a mechanical obstruction of the middle lobe bronchus on bronchoscopy and/or CT of the chest. Though poorly understood the narrow diameter and long length of the middle lobe bronchus, combined with an acute angle at its origin, create poor conditions for adequate drainage. This form of MLS is the most common cause and commonly occurs in adults and children with recurrent pneumonia. It is often related to asthma, bronchitis, and cystic fibrosis.
The diagnosis of MLS should be entertained in a patient with repeated episodes of right-sided pneumonia, only after other causes of obstruction (bronchogenic cancer, foreign body, etc), have been ruled out. Evaluation includes chest radiography, bronchoscopy and CT of the chest. Most patients respond to intensive medical therapy including bronchodilators, mucolytics, and broad spectrum antibiotics in addition to therapeutic bronchoscopy. Those who do not respond should be offered resection of the right-middle lobe and/or debulking lymphadenopathy, which is associated with a low mortality rate and favorable outcome. Other indications for surgery include bronchiectasis, fibrosis (bronchial stenosis), abscess, unresolved or intractable recurrent pneumonia, hemoptysis, and suspicion of neoplasm.
Gudbjartsson T et al: Middle lobe syndrome: a review of clinicopathological features, diagnosis and treatment. Respiration 2012;84:80.
Broncholithiasis is defined as the presence of calculi (broncholiths) within the tracheobronchial tree. In most cases, a broncholith is formed by erosion and extrusion of a calcified adjacent lymph node into the bronchial lumen and is usually associated with long-standing foci of necrotizing granulomatous lymphadenitis. Calcified lymph nodes can remain attached to the bronchial wall, lodge in a bronchus, or be expectorated (lithoptysis). The most common cause of broncholithiasis in the United States is histoplasmosis. Tuberculosis is another frequent cause in some parts of the world.
Patients with broncholithiasis often complain of hemoptysis, lithoptysis (30%), cough, sputum production, fever, chills, and pleuritic chest pain. The hemoptysis is characteristically sudden and self-limited, though rarely it may be massive. Symptoms of pneumonia may indicate bronchial obstruction from an impacted broncholith. Signs suggesting broncholithiasis include localized wheezing on physical examination, evidence of hilar calcifications or segmental atelectasis and pneumonia on chest x-ray, and bronchoscopic evidence of peribronchial disease. The diagnosis is confirmed by documentation of lithoptysis or the presence of an endobronchial “lung stone.”
The complications of broncholithiasis include hemoptysis, which on occasion can be massive and life threatening; suppurative lung diseases (eg, pneumonia and bronchiectasis); midesophageal traction diverticula; and, rarely, tracheobronchoesophageal fistula.
In addition to instituting appropriate therapy for underlying pulmonary diseases, treatment is primarily directed at removal of endobronchial stones. This can be accomplished at the time of bronchoscopy if the broncholith is freely floating within the tracheobronchial tree or if it extends well into the bronchial lumen and can be removed without excessive force or traction (20% of cases). The main danger of transbronchoscopic removal of broncholiths is the risk for massive hemorrhage. This results during inappropriate removal of broncholiths that remain substantially attached to the parabronchial tissues. Because of intense peribronchial fibrosis in this situation, the broncholith not infrequently becomes adherent to vascular structures such as the pulmonary artery, which may be torn with vigorous attempts at broncholith removal.
Nearly 80% of patients with broncholiths that remain in situ require surgical removal. The goal of surgery in this disease is preservation of lung function. The broncholith may be removed safely with bronchotomy; however, most patients require segmentectomy or lobectomy, particularly if destruction of lung parenchyma has occurred from postobstruction suppurative lung disease. Fistulas between the airway and the esophagus should be repaired with interposition of normal tissue (intercostal muscle flap, etc) between the two structures to prevent recurrence. Following surgery, the prognosis is excellent.
Cerfolio R et al: Rigid bronchoscopy and surgical resection for broncholithiasis and calcified mediastinal lymph nodes. J Thorac Cardiovasc Surg 2008;136:186.
Cystic fibrosis is an autosomal recessive multisystem congenital disorder that is characterized by chronic airway obstruction and infection and by exocrine pancreatic insufficiency and gastrointestinal tract dysfunction with consequent effects on nutrition, growth, and maturation. The disorder is the result of several characterized mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, most commonly the ΔF508 mutation. Such mutations cause abnormalities of chloride and likely sodium transport leading to abnormal regulation and reduction of airway surface liquid volume. The result is a viscous and tenacious mucus that adheres to the airway surface epithelium resulting in airflow obstruction and bacterial infection (S auerus, P aeruginosa, and Burkholderia cepacia). Once established, infection of the CF lung is rarely eradicated. Pulmonary manifestations of the disorder include mucoid impaction, bronchitis, bronchiectasis, pulmonary fibrosis, emphysema, and lung abscess. Mucoid plugs are rubbery, semisolid, gray to greenish-yellow in color, and round, oval, or elongated in shape. There is often a history of recurrent upper respiratory infection, fever, and chest pain. Expectoration of hard mucus plugs or hemoptysis may occur.
The earliest manifestation of CF lung disease is a cough that progressively worsens to becoming a daily event and productive. It often becomes paroxymal and associated with gagging and emesis. Sputum is usually tenacious, purulent, and often green, reflecting bacterial infection. Hyperinflation of the lungs due to airway obstruction is noted early in the progression of lung disease. Asthmatic or bronchiolitic-type wheezing is common. CF patients typically have mild bronchitis symptoms for long periods of time punctuated by increasingly frequent acute exacerbations of symptoms that include increased intensity of cough, tachypnea, shortness of breath, decreased activity and appetite, and weight loss. Intense antibiotic therapy and assistance with clearance of mucus are usually required to reduce lung symptoms and improve lung function. End-stage lung disease is characterized by substantial hypoxemia, pulmonary hypertension, cor pulmonale, and death.
The primary objectives of CF treatment are to control infection, promote mucus clearance, and improve nutrition. Therapy includes postural drainage with chest percussion, expectorants, detergents, bronchodilators, antibiotics, and aerosol inhalation. More novel therapies include inhaled hypertonic saline which osmotically draws water onto the airway surface thereby “rehydrating” the airway mucus allowing for easier expectoration, aerosolized rhDNase which lyses the viscous DNA contained within airway mucus and ibuprofen which has been shown to slow the decline in lung function. Surgery including partial lung resection is indicated for apparently localized disease (lung abscess and bronchiectasis) and recurrent severe exacerbations. Lobectomy is occasionally indicated for massive hemoptysis that is refractory to bronchial artery embolization.
Double lung transplantation has become an accepted therapy for respiratory failure secondary to CF. Patients should be referred when their prognosis is about equal to the waiting time for donor lungs, currently about 2 years after acceptance as a lung transplant candidate. Relative contraindications to transplant include severe malnutrition (ideal body weight < 70%), chronic steroid use greater than 20 mg of prednisone daily and mechanical ventilation (center dependent). Multiresistant P aeruginosa infection is not a contraindication for transplantation although pan-resistant P aeruginosa is considered, at some centers, to be a contraindication. Burkholderia cepacia is viewed by some to be a contraindication to lung transplantation. The transplanted lungs remain free of CF, but are subject to secondary infection, acute rejection, and chronic rejection (bronchiolitis obliterans syndrome). The 5-year survival following lung transplantation is 48%. The median survival in all CF patients now exceeds 31 years.
O’Sullivan BP et al: Cystic fibrosis. Lancet 2009;373:1891.
Tuberculosis markedly declined as a cause of death between 1953 and 1984, but since 1985, this disease has experienced resurgence due to increased immigration of infected individuals and HIV infection. A reservoir of about 5000-8000 clinical cases exists, and an additional 25,000 new cases occur annually. Multidrug-resistant tuberculosis (MDR-TB) and, most recently, extensively drug-resistant tuberculosis (XDR-TB) have emerged over the last 20 years. MDR-TB is defined as those strains resistant to at least isoniazid and rifampicin. XDR-TB strains are defined as those resistant to rifampicin, isoniazid, flurooquinolones, and any of capreomycin, kanamycin, or amikacin. Resistance to these antituberclar drugs is the result of spontaneous mutations in the genome and is due to a myriad of factors most commonly inadequate treatment of active pulmonary tuberculosis. Less than 20% of the United States population is tuberculin-positive, but tuberculosis remains a common infectious cause of death worldwide. It is estimated that there are 440,000 new MDR-TB cases identified each year worldwide, many of these arising in previously treated patients. Nearly 50% of cases occur in India and China. The prognosis of treatment of MDR-TB or XDR-TB is significantly worse than for drug-susceptible disease.
Several species of the genus mycobacterium may cause lung disease, but 95% of cases of lung disease are due to Mycobacterium tuberculosis. Several “atypical” species of Mycobacterium, such asMycobacterium bovis and Mycobacterium avium, that are chiefly soil-dwellers, have become clinically more important in recent years because they are less responsive to preventive and therapeutic measures. Mycobacteria are nonmotile, nonsporulating, weakly gram-positive rods classified in the order Actinomycetales. Dormant organisms remain alive for the life of the host.
The initial infection often involves pulmonary parenchyma in the midzone of the lungs. When hypersensitivity develops after several weeks, the typical caseation appears. Regional hilar lymph nodes become enlarged. Most cases arrest spontaneously at this stage. Should the infection progress, caseation necrosis develops and giant cells produce a typical tubercle. A cause of latent disease in the elderly or debilitated patient is dormant reactivation tubercles. Sites in the apical and posterior segments of the upper lobes and superior segments of the lower lobes are the usual areas of infection.
Clinical Findings
Patients may present with minimal symptoms, including fever, cough, anorexia, weight loss, night sweats, excessive perspiration, chest pain, lethargy, and dyspnea. Extrapulmonary disease may be associated with more severe symptoms, such as involvement of the pericardium, bones, joints, urinary tract, meninges, lymph nodes, or pleural space. Erythema nodosum is seen occasionally in patients with active disease.
False-negative tests with intermediate-strength PPD are usually due to anergy, improper testing, or outdated tuberculin. Anergy is sometimes associated with disseminated tuberculosis, measles, sarcoidosis, lymphomas, or recent vaccination with live viruses (eg, poliomyelitis, measles, rubella, mumps, influenza, or yellow fever). Immunosuppressive drugs (eg, corticosteroids, azathioprine) and disease states (eg, AIDS, organ transplantation) may also cause false-negative responses. Mumps skin tests are negative in patients taking immunosuppressive drugs. Culture of sputum, gastric aspirates, and tracheal washings as well as pleural fluid and pleural and lung biopsies may establish the diagnosis.
Radiographic findings include involvement of the apical and posterior segments of the upper lobes (85%) or the superior segments of the lower lobes (10%). Seldom is the anterior segment of the upper lobe solely involved, as in other granulomatous diseases such as histoplasmosis. Involvement of the basal segments of the lower lobes is uncommon except in women, blacks, and diabetics, but endobronchial disease usually involves the lower lobes, producing atelectasis or consolidation. Differing x-ray patterns correspond to the pathologic variations of the disease: the local exudative lesion, the local productive lesion, cavitation, acute tuberculous pneumonia, miliary tuberculosis, Rasmussen aneurysm, bronchiectasis, bronchostenosis, and tuberculoma.
Differential Diagnosis
It is critical to distinguish the x-ray findings from bronchogenic carcinoma, particularly when there is tuberculoma without calcification.
Treatment
Active disease should be treated with one of the chemotherapeutic regimens that have recently been shown to shorten the period of treatment while maintaining their potency. Such drugs include isoniazid, streptomycin, rifampin, and ethambutol.
Treatment of MDR-TB and XDR-TB is less well defined. The World Health Organization (WHO) recently updated and put forth recommendations for treating MDR-TB. This includes:
The success of MDR-TB therapy ranges from 36% to 79% with a mortality rate of 11%. It is estimated that less than 10% of people with MDR-TB are receiving appropriate treatment according to international guidelines.
The role of surgery in treatment of tuberculosis has diminished dramatically since chemotherapy became available. It is now confined to the following indications: (1) failure of chemotherapy; (2) performance of diagnostic procedures; (3) destroyed lung; (4) postsurgical complications; (5) persistent bronchopleural fistula; and (6) intractable hemorrhage. The most common parenchymal resections include lobectomy, followed by pneumonectomy. Muscle flap coverage is strongly recommended. The infectious process often involves the pleural space and it is useful to perform an extrapleural dissection to minimize contamination or bacterial superinfection of the resection cavity.
Pulmonary resection is adjunctive to chemotherapy. The rationale for lung resection of parenchyma affected by MDR-TB is to remove a large focal burden of organisms present in destroyed nonviable lung tissue. The destroyed lung parenchyma and associated cavities are an ideal environment for the bacillus to grow due to its isolation from the circulation and therefore the host’s defenses. Surgery is recommended in MDR-TB patients with extensive drug resistance—those with localized disease amenable to resection and those with high drug activity. Pretreatment with chemotherapeutic regimens for at least 2 months is required before operation to reduce the bacterial burden, followed by 12-24 months of treatment after surgery.
Diagnostic lung resection may be necessary to rule out other diseases, such as cancer, or to obtain material for cultures. Patients with destroyed lobes or cavitary tuberculosis of the right-upper lobe containing large infected foci may sometimes be candidates for resection.
The disease can become reactivated in some patients who have had thoracoplasty, plombage, or resection, and a few will require reoperation. The most common indications for surgery after plombage therapy are pleural infection (pyogenic or tuberculous) and migration of the plombage material, causing pain or compression of other organs. Following pulmonary resection, tuberculous empyema may develop in the postpneumonectomy space, sometimes associated with a bronchopleural fistula or bony sequestration. Persistent bronchopleural fistula after chemotherapy and closed tube drainage may require direct operative closure. Use of muscle flaps (intercostal, etc) is highly recommended to cover any bronchial stumps, especially in the setting of pneumonectomy.
Tuberculous empyema poses unique problems of management. Treatment depends on whether the empyema is: (1) associated with parenchymal disease; (2) mixed tuberculous and pyogenic or purely tuberculous; and (3) associated with bronchopleural fistula. The ultimate objective is complete expansion of the lung and obliteration of the empyema space. Pulmonary decortication or resection may be used for tuberculosis, but open or closed drainage is necessary when the process is complicated by pyogenic infection or bronchopleural fistula.
Prognosis
The prognosis is excellent in most cases treated medically; the death rate decreased from 25% in 1945 to less than 10% currently. Perioperative mortality for pulmonary resections for tuberculosis ranges from 10% for pneumonectomy to 3% for lobectomy and 1% for segmentectomy and subsegmental resections.
The morbidity of surgical resection ranges from 12% to 39% with the most common complications being bleeding, empyema, wound complications, and bronchopleural fistula. The rate of sputum sterilization ranges from 78% to 96% in MDR-TB patients. Factors leading to poorer outcomes include retreatment cases, XDR-TB, bilateral disease, and low body mass index.
Falzon D et al: WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 2011;38:516-528.
Kang MW et al: Surgical treatment for multidrug-resistant and extensive drug-resistant tuberculosis. Ann Thorac Surg 2010;89:1597-1602.
Kempker RR et al: Surgical treatment of drug-resistant tuberculosis. Lancet Infect Dis 2012;12(2):157-166.
Massard G et al: Surgery for the sequelae of postprimary tuberculosis. Thorac Surg Clin 2012;22(3):287-300.
FUNGAL INFECTIONS OF THE LUNG
Pulmonary fungal infections are increasing due to the widespread use of broad-spectrum antibiotics, the use of corticosteroids and other immunosuppressive drugs, and the spread of HIV infection. However, infection can occur in immunocompetent hosts. Fungal infections frequently involve the respiratory tract and include histoplasmosis, coccidioidomycosis, blastomycosis, cryptococcosis, aspergillosis, mucormycosis, and candidiasis. Fungal infections, though ubiquitous, are notable for several characteristic endemic areas. Candidiasis rarely if ever requires operative treatment and thus will not be discussed here.
Histoplasma capsulatum is a dimorphic soil fungus found in soil enriched by the nitrogen contained in bird and bat guano. Abandoned buildings, attics, lofts, and areas under trees that serve as bird and bat roosts and caves are especially likely to contain high concentrations. In endemic areas, exposure is common, and most infections are sporadic. Outbreaks have been traced to spelunking, demolition of buildings, and activities that disrupt contaminated soil. This organism is found primarily in the Ohio and Mississippi River valleys and in Central America. Mammals, including humans, inhale the organism and macrophages engulf the fungus. It then transforms into the budding yeast form, causing activation of inflammatory cytokines. Over several months the ongoing inflammation causes granuloma formation in lymph nodes with resulting caseation, necrosis, fibrosis, and calcification. The diagnosis of histoplasmosis is made definitively by growth of the organism from either sputum, BAL fluid, lung tissue, or mediastinal lymph nodes—though incubation periods of 4-6 weeks are required. Serology also plays an important role in the diagnosis. Both complement fixation and immunodiffusion tests should be ordered. Serology is not useful in immunosuppressed patients who are unable to mount an antibody response. The Histoplasma EIA has been under development as a diagnostic aid and detects the galactomannan component of the cell wall of H capsulatum. The original assay was marked by poor sensitivity; however, with modifications its sensitivity has increased to 65% in patients with acute pulmonary histoplasmosis.
Most infections in immunocompetent individuals are asymptomatic. Infections are classified as acute, chronic, or disseminated. Acute infections are manifested: (1) as a flu-like syndrome with fever, chills, dry cough, headache, retrosternal discomfort, arthralgias, and a rash suggesting erythema nodosum; (2) with symptoms similar to a flu-like syndrome but limited to the lungs and occasionally accompanied by a productive cough; or (3) as an acute diffuse nodular disease with mild symptoms. Radiographic findings in these three acute syndromes typically demonstrate ill-defined upper lobe nonsegmental opacities; nonsegmental areas of consolidation that tend to change; and diffuse, discrete 3- to 4-mm nodules, respectively. Hilar adenopathy on chest x-ray is common. Physical examination can be normal or may reveal signs of pneumonia.
In contrast, chronic infections include: (1) an asymptomatic solitary, discrete nodule less than 3 cm in diameter known as a histoplasmoma (most common), often with central and concentric calcifications (“target lesion”) and frequently located in the lower lobes; (2) chronic cavitary histoplasmosis, which typically occurs in patients with underlying obstructive disease, characteristically mild symptoms, fibronodular upper lobe infiltrates, and centrilobular emphysematous spaces; (3) mediastinal granulomas that may result in broncholithiasis, esophageal traction diverticula, superior vena cava compression, and tracheobronchoesophageal fistulas; and (4) fibrosing mediastinitis, which can produce compression of the superior vena cava, tracheobronchial tree, or esophagus.
Disseminated disease includes an acute, subacute, and chronic form. These infections occur in children (acute and subacute) as well as adults (subacute and chronic). Fever and abdominal pain are common. Other findings include hepatosplenomegaly, pancytopenia, meningitis, endocarditis, adrenocortical insufficiency, and oropharyngeal ulceration (chronic form).
Radiographic imaging in disseminated disease may demonstrate diffuse interstitial pneumonitis (25%) or minimal findings. The symptoms and roentgenographic findings of histoplasmosis resemble those of tuberculosis, although the disease appears to progress more slowly. There may be cough, malaise, hemoptysis, low-grade fever, and weight loss. As many as 30% of cases coexist with tuberculosis. Pulmonary fibrosis, bulla formation, and pulmonary insufficiency occur in advanced cases of histoplasmosis. Mediastinal involvement is quite frequent and may take the form of granuloma formation, or dysphagia. Furthermore, mediastinal fibrosis is among the most common benign causes of superior vena caval syndrome (discussed earlier in the chapter). Erosion of inflammatory lymph nodes into bronchi may cause expectoration of broncholiths, hemoptysis, wheezing, or bronchiectasis. Traction diverticula of the esophagus may lead to development of tracheoesophageal fistula. Pericardial involvement may lead to constrictive pericarditis.
In lesions that present as solitary pulmonary nodules, histoplasmosis is diagnosed in about 15%-20% of cases. Radiologically, early infections appear as diffuse mottled parenchymal infiltrations surrounding the hila, with enlargement of hilar lymph nodes. Cavitation indicates advanced infection and is the complication about which the surgeon is most often consulted. The diagnosis rests on finding a positive skin test or complement fixation test and culturing the fungus from sputum or a bronchial aspirate.
Medical therapy of histoplasmosis is indicated only in cavitary and severe disease and for most infections in immunocompromised hosts. Azoles are recommended as first-line treatment for patients who have mild to moderate pulmonary histoplasmosis. Itraconazole (200-400 mg/d for 6 months) is the drug of choice for cavitary disease, while amphotericin B (1-2 g total dose) is reserved for patients with more serious infections and infections in immunocompromised patients. Reflecting increasing use of corticosteroids for ARDS in the last decade, the current American Thoracic Society Guidelines recommend the use of intravenous methylprednisilone as adjunctive therapy for severe acute pulmonary histoplasmosis. Operative intervention is reserved for treatment of complications and to rule out neoplastic disease in the case of suspicious pulmonary nodules. Broncholithectomy via rigid bronchoscopy with or without pulmonary resection, repair of tracheobronchoesophageal fistulas, decompression of mediastinal granulomas, and spiral saphenous vein bypass of severe symptomatic superior vena cava obstruction are typical examples. The Infectious Diseases Society of America recommends pericardiectomy for recurrent pericardial effusions. In cases of vascular fibrosis of the superior vena cava and pulmonary vessels percutaneous intravascular dilation and stenting is recommended as first-line treatment.
Coccidioides immitis is a dimorphic soil fungus endemic to the Sonoran life zone (Utah, Arizona, California, Nevada, and New Mexico) and is associated with creosote brush. Dry heat with brief intense rain is essential for this fungus, which is spread by strong winds. Infection occurs through inhalation of as few as 1-10 arthrospores, which then germinate as parasitic spherules. Spherules have a double refractile cell wall and produce endospores that cause the spherule to rupture, spreading the infection to the surrounding tissues. Caseation, suppuration, abscess formation, and fibrosis follow. The diagnosis of coccidioidomycosis relies on the detection of acutely elevated titers of immunoglobulin M (IgM) antibodies (by latex agglutination and confirmed by immunodiffusion tube precipitin tests) or rising serum immunoglobulin G (IgG) antibody complement fixation titers (seroconversion or fourfold rise) in the appropriate clinical context. The coccidioidin and Spherulin skin tests, which become positive 3-21 days following infection, are generally useful only for epidemiologic studies and not for the diagnosis of acute disease. C immitis grows well in culture, but it is extremely hazardous to handle and requires a laminar flow hood due to the highly infectious nature of the arthrospores. Identification of the spherules in tissue, lavage samples, and fine-needle aspirates is helpful in making the diagnosis in some patients. Although many stains can be used, including routine fungal (potassium hydroxide, KOH) preparations, Pap staining is most sensitive. Gram stains, however, fail to demonstrate spherules.
Primary infection is asymptomatic in 60% of patients, while most others develop desert fever, with fever, productive cough, pleuritic chest pain, pneumonitis, and a rash typical of erythema nodosum or erythema multiforme. Disease that includes arthralgias is known as desert rheumatism. Radiographic findings demonstrate segmental or nonsegmental, homogeneous or mottled infiltrates with a predilection for the lower lobes. Physical examination is often unrevealing, but rales and rhonchi may be present. Other findings include eosinophilia (66%), hilar adenopathy (20%), and small exudative pleural effusions (2%-20%). Symptomatic persistent infection associated with chest x-ray findings 6-8 weeks after primary infection is classified as one of five types: persistent pneumonia, chronic progressive pneumonia, miliary coccidioidomycosis, coccidioidal nodules, or pulmonary cavities. Persistent pneumonia manifests with symptoms of fever, productive cough, and pleuritic chest pain in association with protracted infiltrates and consolidation on chest x-ray generally resolving within 8 months. Patients with chronic progressive pneumonia complain of fever, cough, dyspnea, hemoptysis, and weight loss, with bilateral apical nodular densities and multiple cavities lasting years. This presentation closely resembles tuberculosis and chronic histoplasmosis. Miliary coccidioidomycosis occurs early and rapidly, associated with bilateral diffuse infiltrates. This form of disease implies the presence of impaired immunity and has an associated mortality rate of 50%. Nearly half of patients with coccidioidal nodules are asymptomatic. These nodular densities (coccidiomas) appear in the middle and upper lung fields, often within 5 cm of the hilum; range from 1 to 4 cm in size; and do not calcify, making it hard to distinguish them from malignancy. In endemic areas, 30%-50% of all nodules are coccidiomas. Patients develop pulmonary cavities in 10%-15% of cases of coccidioidomycosis. Typically, these are solitary (90%), thin-walled, located in the upper lobes (70%), less than 6 cm in size (90%), and close spontaneously within 2 years (50%). Some cavities, however, cross fissures; cause hemoptysis (25%-50%), usually mild; rupture, producing a pyopneumothorax with a bronchopleural fistula; or become infected with Aspergillus. Uncommonly, dissemination can occur, particularly in immunocompromised individuals, in pregnancy (third trimester), and in non-Caucasian individuals. Although pulmonary symptoms in disseminated disease are mild, meningeal involvement is common and the mortality rate is high (50%).
Medical therapy is not indicated in asymptomatic, immunocompetent individuals. Patients with persistent or chronic pneumonia, miliary disease, and those at risk for dissemination should be treated with antifungal therapy. Amphotericin B (0.5-2.5 g intravenously as total dose) is the standard treatment, though the newer azole compounds (fluconazole, ketoconazole, and itraconazole) may be used for long-term maintenance therapy, since the relapse rate may be as high as 25%-50%. Surgery is reserved for patients with coccidiomas when cancer is a concern and in patients with cavities that have an associated radiographic abnormality suggesting carcinoma (ie, thick wall) or that develop a complication (eg, hemoptysis and pyopneumothorax from rupture). Resection should include all diseased tissue and most often requires lobectomy.
Blastomyces dermatitidis is a dimorphic soil fungus found in warm, wet, nitrogen-rich soil in an endemic area that extends east of a line from the Texas Gulf coast to the border between Minnesota and North Dakota (except Florida and New England). Infection occurs characteristically in males (male-to-female ratio 6:1-15:1) from 30-60 years of age through inhalation of conidia (asexual spores). At 37°C, the conidia germinate as yeasts, producing caseation in a manner similar to tuberculosis. Rarely, infection may develop through direct skin inoculation. Risk factors include poor hygiene, exposure to dust and wood, manual labor, and poor housing conditions. Since no accurate skin or serologic tests exist, the diagnosis depends on culture or histologic identification of the yeast form. Culture of the mycelial form can be hazardous. B dermatitidis grows as white to tan colonies of septate hyphae at room temperature but changes to budding yeast at 37°C. This temperature-dependent change reflects the uncoupling of oxidative phosphorylation. The yeast form can be found in sputum (33%), bronchoalveolar lavage specimens (38%), lung biopsies (21%), and fine-needle aspirates (7%) and can be demonstrated with standard KOH preparations or many other histologic stains (but not Gram stain). The yeast, however, does not have a large capsule (distinguishes it from Cryptococcus neoformans) and does not grow intracellularly (differentiates it from H capsulatum).
Manifestations of blastomycosis can occur in many organ systems, including the lungs, skin, bone, genitourinary tract (prostatitis and epididymo-orchitis), and central nervous system. Pulmonary infection can be asymptomatic or may present with flu-like symptoms, evidence of pneumonia, or pleurisy. Cough (36%), weight loss (20%), pleuritic pain (26%), fever (23%), hemoptysis (21%), erythema nodosum, and ulcerative bronchitis are common. Radiographic findings include homogeneous or patchy consolidation in a nonsegmental distribution with pleural effusions or thickening or cavitation (15%-35%). In some patients, the appearance of pulmonary masses may mimic carcinoma. A predilection for the upper lobes has been noted; however, unlike histoplasmosis and coccidioidomycosis, in blastomycosis, hilar and mediastinal adenopathy is unusual.
Limited disease in asymptomatic immunocompetent patients requires no specific therapy. Itraconazole, 100-200 mg/d orally for at least 2-3 months, is now the therapy of choice for nonmeningeal disease, with a response rate of over 80%. Amphotericin B (0.5-2 g), however, is indicated in patients with meningeal disease or failed therapy. Surgical resection is rarely necessary except when the possibility of malignancy cannot be excluded.
Cryptococcus neoformans is an encapsulated yeast-like budding fungus. It is a saprophyte existing on the skin, nasopharynx, gastrointestinal tract, and vagina of humans as well as in pigeon excreta, grasses, trees, plants, fruits, bees, wasps, insects (cockroaches), birds, milk products, pickle brine, and soil. Cryptococcal infection generally indicates the presence of an underlying debilitating disease in an immunocompromised host. Infection occurs from inhalation of the yeast form. The diagnosis can be established by the detection of serum antigen (via complement fixation tests) in patients with appropriate clinical and radiographic findings. More commonly, however, histologic identification with India ink stains is used; routine cultures are not performed because they are extremely time-consuming and require multiple biochemical tests for differentiation of cryptococcus from other fungi. No accurate skin test exists for cryptococcosis.
The most common sites of infection are the lungs and central nervous system. Pulmonary infection may remain asymptomatic, or patients may complain of cough, pleuritic chest pain, and fever. Radiographically, cryptococcus can appear as a localized, well-defined 3-10-cm pleural-based mass without smooth borders; as single or multiple areas of consolidation, usually within one lobe but in nonsegmental distribution; or as a disseminated miliary nodular infiltrate. A predilection for the lower lobes has been noted. Central nervous system infection usually follows an asymptomatic pulmonary infection. Central nervous system symptoms are highly variable, since many patients are severely immunocompromised and do not manifest the usual signs and symptoms of meningitis or cerebritis.
Medical therapy is indicated in most cases of pulmonary infection except for rare cases of limited localized disease. Amphotericin B (0.5-2 g) remains the treatment of choice and is often combined with flucytosine (150/mg/kg/d) for synergy. New azole compounds (eg, fluconazole, itraconazole, and voriconazole) have been used with increasing frequency as first-line therapy both as single agents and in combination. Surgery is rarely indicated and is useful only to exclude the possibility of malignancy or to determine the etiology of an undiagnosed diffuse pulmonary infiltrate by open lung biopsy.
Aspergillus species are ubiquitous dimorphic soil fungi found in soil and decaying organic matter. The most common pathogenic species include Aspergillus fumigatus (most common), Aspergillus niger, Aspergillus flavus, and Aspergillus glaucus. In culture, these fungi resemble an aspergillum, which is a brush used to sprinkle holy water. Aspergillosis represents the second-most common (after candidiasis) opportunistic fungal infection in immunocompromised hosts and the third-most common systemic fungal infection requiring hospital care. Infection occurs almost exclusively through inhalation of conidia into areas of lung with impaired mucociliary function (eg, tuberculous cavities). Although the diagnosis is supported by demonstrating immediate and delayed-type hypersensitivity skin reactions, by culturing uniform septate hyphae with dichotomous branching at 45 degrees, and by detecting specific IgG and IgE antibodies, a definitive diagnosis requires demonstration of hyphal tissue invasion or documentation of hyphae on methenamine silver stain in a suspected aspergilloma. Galactomannan enzyme-linked immunosorbent assays have recently become available and serve as a sensitive serum measure of invasive infection.
Infection with Aspergillus species usually takes one of three forms: allergic bronchopulmonary aspergillosis, invasive aspergillosis, and aspergilloma. Allergic bronchopulmonary aspergillosis occurs in patients who are atopic (asthmatics) and in patients with cystic fibrosis. Endobronchial fungal growth leads to dilated airways filled with mucus and fungus. Continuous exposure to fungal antigens results in precipitating antibodies, increased IgE levels (which correlate with disease activity), and both immediate and delayed-type hypersensitivity. Patients complain of cough, fever, wheezing, dyspnea, pleuritic pain, and hemoptysis. Chest x-ray shows homogeneous densities in a “gloved-finger,” inverted Y, or “cluster of grapes” pattern. Five stages have been defined depending on disease activity and steroid dependency: Stage 1 includes acute infection with characteristic x-ray and laboratory evidence of disease; stage 2 occurs with steroid-induced remission; stage 3 is characterized by asymptomatic exacerbations of laboratory and x-ray findings; steroid-dependent asthma with worsening laboratory tests (total IgE, precipitins, etc) is indicative of stage 4 disease; and end-stage fibrosis, bronchiectasis, and obstruction define stage 5.
Invasive aspergillosis is found exclusively in immunocompromised patients, particularly in patients with leukemia (50%-70% of cases). Dissemination occurs frequently, and three types of pulmonary disease have been described: tracheobronchitis (uncommon), necrotizing bronchopneumonia, and hemorrhagic infarction (most common). In tracheobronchitis, disease is usually limited to the larger airways (bronchus more so than trachea) with little parenchymal involvement. Focal or diffuse mucosal ulceration, pseudomembranes, and intraluminal fungal plugs are common. Patients often present with cough, dyspnea, wheezing, and hemoptysis. Occasionally, patchy areas of atelectasis secondary to bronchial obstruction can be seen on chest x-ray. Necrotizing bronchopneumonia should be suspected in patients with unremitting fever, dyspnea, tachypnea, radiologic evidence of bronchopneumonia, and a poor response to standard antibiotic therapy. Finally, hemorrhagic infarction due to vascular permeation with nonthrombotic occlusion of small- to medium-sized arteries and necrosis typically results in either a well-defined nodule or a wedge-shaped, pleura-based density. Symptoms are nonspecific and include fever, dyspnea, dry cough, pleuritic chest pain, and hemoptysis. Cavitation is common, and radiologic examination may reveal “round” pneumonia or “air crescents” of a mycotic lung sequestrum.
Aspergillomas (“fungus balls” or mycetomas) are divided into two types: simple, thin-walled cysts lined with ciliated epithelium and surrounded by normal parenchyma; and complex cavities associated with markedly abnormal surrounding lung tissue. Aspergillomas most often occur in the upper lobes and in the superior segments of the lower lobes. Although they may be multiple (22%), calcification and air-fluid levels are rare. Most aspergillomas—particularly complex ones—are associated with cavitary lung disease, that is, tuberculosis (most common), histoplasmosis, sarcoidosis, bronchiectasis, and others. Hemoptysis occurs in 50%-80% and can present with frequent minor episodes (30% subsequently have massive bleeding), repeated moderate episodes, or a single episode of massive hemoptysis. Chest x-ray may reveal a 3- to 6-cm round, mobile density with a crescent of air.
Corticosteroids are indicated in patients with allergic bronchopulmonary aspergillosis in addition to measures to relieve bronchospasm (inhaled β-agonists or anticholinergics). In invasive aspergillosis, amphotericin B (0.5-2 g intravenously as total dose) has been standard therapy despite a mortality of 90%. In addition, some patients with complex aspergillomas and severe pulmonary disease are not candidates for surgical resection, and intracavitary amphotericin has been used with modest success. Surgery is indicated for complications of Aspergillus infection. Hemoptysis due to aspergillomas is usually best treated by surgical resection. Furthermore, hemoptysis associated with localized invasive aspergillosis (particularly once cavitation has occurred) can be treated by resection and amphotericin B. Generally, wide excision (lobectomy) is required; however, in some high-risk patients with aspergillomas, cavernostomy, and muscle flap closure is an alternative.
Infection with Rhizopus arrhizus, Absidia species, and Rhizomucor species of the class Zygomycetes and the order Mucorales occurs in certain distinct immunosuppressed patient populations: people with poorly controlled diabetes and leukemia patients. These fungi are ubiquitous organisms that are found in decaying fruit, vegetable matter, soil, and manure. Infection occurs following inhalation of sporangiospores, which germinate in a hyphal form. The diagnosis is made by demonstrating the organism in symptomatic patients. No accurate skin or serologic tests exist. Although the fungi do grow in culture as broad, irregular nonseptate hyphae that branch at angles up to 90 degrees (occasionally being confused with Aspergillus species), most commonly the diagnosis is made on histologic examination. The sine qua non for mucormycosis is hyphal vascular invasion between the internal elastic membrane and the media of blood vessels, causing thrombosis, infarction, and necrosis.
In addition to pulmonary infections, mucormycosis manifests as distinct clinical syndromes such as rhinocerebral infection (direct extension into the central nervous system from paranasal sinus infection), cutaneous infection (burn patients), gastrointestinal infection (children with protein-calorie malnutrition), and disseminated infection (uremic patients receiving deferoxamine therapy). Patients with pulmonary infection complain of fever, cough, pleuritic chest pain, and hemoptysis. Frequently, this type of infection occurs in immunocompromised hosts and follows a fulminant course. Three patterns of infection are noted on chest x-ray: limited disease with involvement of a single lobe or segment, diffuse or disseminated disease with involvement of both lungs and the mediastinum, and endobronchial disease with bronchial obstruction and secondary bacterial infection. Characteristic CT findings include a halo sign (area of low attenuation around a dense infiltrate), ring enhancement, and an air-crescent sign (area of contrast between normal lung and a radiodense cavitating lesion). Amphotericin B is the standard treatment. In nonneutropenic patients, the newer azole compounds may be useful; however, infection with these fungi remains highly lethal, with a mortality of 90%. The cause of death in these patients is often fungal sepsis, progressive pulmonary dysfunction, and hemoptysis. In the small group of patients with limited disease, aggressive surgical resection in combination with amphotericin B has lowered the mortality to only 50%. In contrast, the endobronchial form can be effectively treated with transbronchoscopic resection (using the Nd:YAG laser) in a large proportion of patients.
Pneumocystis carinii is a fungal organism that has been found in the lungs of a variety of domesticated and wild mammals and is distributed worldwide in humans. Pulmonary involvement leads to progressive pneumonia and respiratory insufficiency. Disease has been seen with increasing frequency in recipients of organ transplants who are undergoing immunosuppressive therapy. Diagnosis is made by open lung biopsy. Without treatment with trimethoprim-sulfamethoxazole, pentamidine, or inhaled antimicrobial therapy, the course is one of relentless progression. With improved antiviral therapy for HIV infections, the incidence of pneumocystosis has been declining.
LoCicero J et al: Surgery for other pulmonary fungal infections, Actinomyces, and Nocardia. Thorac Surg Clin 2012;22:363-374.
Smith JA et al: Pulmonary fungal infections. Respirology 2012;17:913-926.
SARCOIDOSIS (BOECK SARCOID, BENIGN LYMPHOGRANULOMATOSIS)
Sarcoidosis is a noncaseating granulomatous disease of unknown cause involving the lungs, liver, spleen, lymph nodes, skin, and bones. The highest incidence is reported in Scandinavia, England, and the United States. The incidence in blacks is 10-17 times that in whites. Half of patients are between ages 20 and 40 years, with women more frequently affected than men.
Clinical Findings
Sarcoidosis may present with symptoms of pulmonary infection, but usually these are insidious and nonspecific. Erythema nodosum may herald the onset, and weight loss, fatigue, weakness, and malaise may appear later. Fever occurs in approximately 15% of cases. Pulmonary symptoms occur in 20%-30% and include dry cough and dyspnea. Hemoptysis is rare. One-fifth of patients with sarcoidosis have myocardial involvement, and heart block or failure may occur. Peripheral lymph nodes are enlarged in 75%, scalene lymph nodes are microscopically involved in 80% and mediastinal nodes in 90%, and cutaneous involvement is present in 30%. Hepatic and splenic involvement can be shown by biopsy in 70% of cases. There may be migratory or persistent polyarthritis, and central nervous involvement occurs in a few patients.
The x-ray findings in sarcoidosis are classified into five descriptive categories or stages (Table 18–5). Pulmonary disease can manifest as a reticulonodular infiltrate, an acinar pattern of opacities, or large nodules with or without mediastinal adenopathy. Mediastinal lymph node involvement characteristically includes bilateral symmetric hilar and paratracheal lymphadenopathy. Anterior or posterior mediastinal adenopathy or asymmetric hilar involvement should prompt a suspicion of other diseases, particularly Hodgkin disease and non-Hodgkin lymphomas. Pleural effusions and cavitation are rare and, if present, necessitate an evaluation for tuberculosis, congestive heart failure, and coincidental pneumonia.
Table 18–5. Radiographic stages of sarcoidosis.
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Stage 0: No x-ray abnormality Stage 1: Hilar and mediastinal lymph node enlargement without pulmonary abnormalities Stage 2: Hilar and mediastinal lymph node enlargement with pulmonary abnormalities Stage 3: Diffuse pulmonary disease without adenopathy Stage 4: Pulmonary fibrosis |
Although no single test exists to confirm absolutely the diagnosis of sarcoidosis (the diagnosis remains one of exclusion), it may be suggested by the characteristic radiographic appearance of bilateral hilar and mediastinal lymphadenopathy, by gallium 67 scanning, and by elevated serum and bronchoalveolar fluid levels of angiotensin-converting enzyme and lysozyme. Pathologic documentation of noncaseating granulomas should normally be obtained either via transbronchial biopsy or mediastinoscopy (more reliable, with > 95% success rate). Culture for mycobacteria, fungi, and other atypical infections must also be negative.
Asymptomatic patients and those with minimal clinical disease may require no therapy. Corticosteroids have been used in patients with pulmonary impairment and symptomatic disease with good success. Despite the indolent nature of the disease and steroid therapy, long-term mortality is reported as high as 10%. Lung transplantation has been utilized with success in patients refractory to medical management.
NEOPLASMS OF THE LUNG
PRIMARY LUNG CANCER
Lung cancer is the most common cause of cancer-related death in both men and women in the United States. In 2013, it is estimated that 228,190 new cases and 159,480 deaths will occur due to pulmonary malignancies. This represents 14% of all new cancer cases and 27% of all cancer-related deaths. Tobacco smoking accounts for 85% of all lung cancer cases. The effect is greatest for cigarettes and least for pipe smoking and is directly related to the amount of tobacco smoked. Following 5-6 years of smoking cessation, the risk exponentially declines, and after 15 years approaches, but never reaches, that of nonsmokers. “Passive” exposure to cigarette smoke, on the other hand, increases the risk in nonsmokers by two to three times. Exposure to all forms of asbestos (amosite, chrysotile, and crocidolite) has been implicated in as many as 23% of lung cancers, accounting for the high incidence among shipyard workers, insulators, cement makers, truck drivers, and plumbers. The effect is particularly pronounced in smokers and is most commonly associated with squamous cell and small cell carcinoma. Exposure to radon and its alpha-emitting daughter isotopes have been implicated in the increased incidence of lung cancer in both uranium miners and populations living in geographic areas naturally contaminated with high levels of radon gas. Although it has been known for some time that people with high activity of 4-debrisoquine hydroxylase, the so-called debrisoquine metabolic phenotype, have a 10-fold increased risk of lung cancer, only recently has the role of genetic factors been appreciated.
Chromosome deletions (particularly 11p, 13q, 17p, and 3p), tumor suppressor gene mutations (p53, Hap-1, ErbAb, etc), and constitutive, high-level expression of both growth factor genes (insulin-like and transferrin-like growth factors), epidermal growth factor receptors (HER2/neu, EGFR1, etc), and protooncogenes (c-, N-, and L-myc; H-, N-, and K-ras; and c-myb) have all been implicated in the pathogenesis of lung cancer. Other factors such as vitamin A deficiency, air pollution; exposure to arsenic, cadmium, chromium, ether, and formaldehyde; and employment as bakers, cooks, construction workers, cosmetologists, leather workers, pitchblende miners, printers, rubber workers, and pottery workers have also been incriminated. Finally, certain diseases (eg, progressive systemic sclerosis [scleroderma]) have a defined predisposition for the development of lung cancer. Silencing of genes by aberrant promoter hypermethylation is viewed as a crucial component in lung cancer pathobiology. High throughput genomic analysis has identified scores of genes and metabolic pathways that appear to be associated with the progression of lung cancer.
Pathology
Lung cancer occurs more commonly in the right lung than the left, and the upper lobes are involved more commonly than the lower lobes or the right-middle lobe. Synchronous primary lung cancers occur in up to 7% of patients, and 10% of patients will develop a metachronous new tumor (2% per year risk postresection of early stage disease). Furthermore, patients with lung cancer are at higher risk of developing cancers of the upper respiratory tract, oral cavity, esophagus, bladder, and kidney presumably related to the “field effect” of smoking. Lung cancers typically spread by local extension to involve the visceral and parietal pleura, chest wall, great vessels, pericardium, diaphragm, esophagus, and vertebral column. Common sites of metastatic involvement include the ipsilateral pulmonary and hilar lymph nodes, the mediastinal lymph nodes, the lung, liver, bone, brain, adrenal glands, pancreas, kidney, soft tissues, and myocardium. The exact pathologic classification of lung cancer has not been uniform despite attempts at standardization by the World Health Organization. Functionally, however, squamous cell carcinoma, large cell carcinoma, and adenocarcinoma are grouped together under the designation of non-small cell carcinomas and constitute 80% of all lung tumors. Small cell carcinoma represents 15%-20%, while bronchial gland adenomas, including carcinoids, comprise the remaining 5%. The differential locations of some of these neoplasms are summarized in Table 18–6.
Table 18–6. Location of lung cancer by histologic type.
The major pathologic features of squamous cell carcinoma are keratinization, cellular stratification, and intercellular bridges. Squamous cell carcinomas account for about 20% of all cases of lung cancer and 70% of non–small cell tumors. Two-thirds are located centrally near the hilum and one-third peripherally. The growth rate and the rate of metastasis tend to be slower than those of other lung tumors.
Adenocarcinomas, which constitute 30% of lung cancers and 60% of non–small cell tumors, are characterized as acinar, papillary, lepidic (formerly nonmucinous bronchioloalveolar [BAC] with > 5 mm invasion), micropapillary and solid, as well as preinvasive lesions including atypical adenomatous hyperplasia and adenocarcinoma in situ (≤ 3 cm formerly BAC) and minimally-invasive (≤ 3 cm lepidic predominant tumor with a 5 mm invasion). Acinar adenocarcinoma is composed of glands lined by columnar cells that secrete mucin. Lepidic carcinoma is characterized by intraluminal papillary fragments that appear in alveoli or small bronchioles. The incidence of adenocarcinoma of the lung is increasing relative to squamous cell carcinoma, perhaps as a consequence of the rise in lung cancer among women, although the exact cause remains unclear.
Small cell (oat cell) carcinomas have small, round nuclei with nuclear chromatin and cytoplasm. They are biologically and clinically distinct from all other cell types such that the term non–small cell lung cancer (NSCLC) often is applied to all other cell types. Small cell carcinomas comprise 15%-20% of all lung cancers. They occur centrally, metastasize early but also can exhibit significant partial response to combined-modality treatment, albeit with limited 5-year survival.
Large cell carcinomas are composed of large polygonal spindle or oval cells arranged in sheets, nests, or clusters. Multinucleated giant cells, intracellular hyalin droplets, glycogen, and acidophilic nuclear inclusions may be present. These tumors are seen peripherally and are less common.
Adenosquamous tumors show both cellular features and are more biologically aggressive than other NSCLC. Survival percentages of patients with adenosquamous tumors are significantly lower than what is reported for adenocarcinoma or squamous cell cancer.
Bronchial gland adenoma is a misnomer, since the vast majority of these tumors are malignant. Included in this group are carcinoid tumors, adenoid cystic carcinomas, mucoepidermoid carcinoma, mixed tumors of the salivary gland type, and mucous gland adenoma. Carcinoid tumors are derived from Kulchitsky cells, have a vascular stroma, and tend to be located centrally in proximal airways. Although they are slow-growing, they can metastasize widely. Carcinoid syndrome is rarely associated with bronchial carcinoids, as opposed to intestinal carcinoids that metastasize to the liver. Adenoid cystic carcinomas—also referred to as cylindromas—feature groups of epithelial cells that form duct-like structures interspersed with cystic spaces. These neoplasms are locally aggressive and often extend beyond apparent gross pathologic margins. Metastases from adenoid cystic carcinomas often involve the lung, are slow growing, and are amenable to surgical excision. Mucoepidermoid carcinomas are rare tumors characterized by the presence of squamous cells, mucus-secreting cells, and an intermediate cell type. The cells are bland and less aggressive than those of adenosquamous carcinomas. Mixed tumors of the salivary type are extremely rare infiltrating tumors that are curable with wide local excision. Finally, mucus gland adenomas (papillary or bronchial cyst adenomas) are the only true benign “adenomas” of this group with no metastatic potential. These neoplasms are rare tumors of the major bronchi and consist of numerous mucus-filled cysts lined by a well-differentiated epithelium. Generally, bronchoscopic removal can be accomplished and results in long-term cure.
Clinical Presentation
Nearly 94% of patients present with symptoms from the effects of the primary tumor, regional spread, or metastatic disease. Local effects of the primary tumor account for 27% of presenting symptoms and vary depending on the location of the tumor. Central tumors are associated with cough, hemoptysis, respiratory difficulty (wheezing, stridor, or dyspnea), pain, and pneumonia. Peripheral tumors can cause cough, chest wall pain, pleural effusions, pulmonary abscess, Horner syndrome (ipsilateral miosis, ptosis, and anhidrosis), and Pancoast syndrome (ipsilateral shoulder and arm pain in the C8-T1 nerve root distribution, Horner syndrome, and a superior sulcus—usually squamous—lung cancer). Symptoms due to the effect of regional spread include hoarseness from recurrent nerve paralysis, dyspnea due to phrenic nerve paralysis, dysphagia from compression of the esophagus, superior vena cava syndrome from compression or invasion of the superior vena cava, and pericardial tamponade from invasion of the pericardium. Metastatic disease may present with symptoms of systemic illness (anorexia, weight loss, weakness, and malaise), local manifestations of distant metastases (jaundice, abdominal mass, bony pain or fracture, neurologic deficits, mental status changes, seizures, and soft tissue masses). A number of paraneoplastic syndromes associated with lung cancer have been identified (Table 18–7).
Table 18–7. Paraneoplastic syndromes associated with lung cancer.
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Cardiovascular Thrombophlebitis Nonbacterial thrombotic endocarditis Neuromuscular Subacute cerebellar degeneration Dementia Limbic encephalitis Optic neuritis, retinopathy Subacute necrotic myelopathy Autonomic neuropathy (small cell) Myasthenic (Eaton-Lambert) syndrome (small cell) Polymyositis Gastrointestinal Carcinoid syndrome (carcinoid and small cell) Anorexia, cachexia Hematologic Erythrocytosis Leukocytosis Metabolic Inappropriate adrenocorticotropic hormone (ACTH) (small cell) Inappropriate antidiuretic hormone (ADH) (small cell) Hypercalcemia (squamous cell carcinoma) Inappropriate gonadotropins Dermatologic Acanthosis nigricans (adenocarcinoma) Dermatomyositis Erythema gyratum Ichthyosis Other Hypertrophic pulmonary osteoarthropathy (squamous cell, large cell, and adenocarcinoma) Nephrotic syndrome Fever |
Diagnosis & Evaluation
Lung cancer is usually suspected from abnormal findings on a chest x-ray obtained in the course of a routine physical examination or, more commonly, after a complaint of pulmonary symptoms (see previous discussion). Findings vary from a small peripheral nodule to an unresolving infiltrate or even total lung atelectasis. Occasionally, the location of the abnormality may suggest certain cell types (seeTable 18–7). Once the diagnosis of lung cancer is suspected, a definitive diagnosis can be obtained in over 90% of patients with either bronchoscopy for proximal lesions or fine-needle aspiration cytology for peripheral lesions.
CT scanning is an integral part of the assessment of patients with lung cancer. Chest CT scans should also include the upper abdomen to assess two of the most common sites of metastases (liver and adrenal glands). Injection of intravenous contrast while the scan is obtained facilitates evaluation of the mediastinum. Additional radiographic evaluation includes tests to evaluate other common sites of metastases, such as bone and brain. A serum alkaline phosphatase is essential, and a bone scan and brain CT scan (or preferably MRI) should be obtained if indicated by elevated alkaline phosphatase levels, neurologic symptoms, or bone pain or if advanced-stage disease (stage III or beyond) is present. Fluorodeoxyglucose (FDG) PET has evolved into a critical staging test. It is most effective as a tool for assessing for distant occult disease. It can be helpful for predicting mediastinal node involvement, but it is not definitive. False-positive rates as high as 15%-20% have been reported. Furthermore, nodules less than 1 cm in diameter generally are not imaged reliably by PET scanning. Combination high-resolution CT scan and PET scan assessment permits improved correlation of abnormal CT findings with FDG uptake suggestive of tumor.
Thoracentesis or thoracoscopy (or both) should be performed in any patient with evidence of a pleural effusion to exclude diffuse involvement of the pleura (M1 or stage IV disease) which indicates metastatic disease. Despite increasing reliance on PET scan to stage the mediastinum, patients with NSCLC but without metastatic disease should be evaluated with endobronchial ultrasound guided FNA, cervical mediastinoscopy or parasternal mediastinotomy (Chamberlain) if necessary to document the status of the mediastinal nodes in equivocal cases. PET scanning is informative but tissue confirmation typically is necessary. For small cell lung cancer staging should be directed at assessing the presence of extrathoracic disease, to confirm limited-stage tumor extent. The use of CT scans alone is inaccurate in 40%-60% of patients with enlarged lymph nodes over 1 cm (false positive) and 15% of patients without “significant” lymphadenopathy (false negative).
Once all the information from these staging procedures is in hand, the patient with NSCLC can be classified into one of three categories: (1) early lung cancer without mediastinal involvement, that is, stage I/II (see next section); (2) locally advanced lung cancer, that is stage IIIA/B; and (3) metastatic lung cancer, or stage IV. Therapy is determined by disease stage. Patients with small cell lung cancer usually are grouped into two categories: disease limited to the ipsilateral hemithorax, including supraclavicular nodes (limited disease), or disease extending beyond the thorax (extensive disease, eg, below the diaphragm or brain metastases).
Several recent analyses indicate that lung cancer screening by either regular routine chest radiography or sputum cytology is not recommended. Low-dose screening chest CT can be considered, but only among select individuals in the context of multidisciplinary comprehensive care that includes not only screening but also image interpretation, evaluation, management and appropriate treatment of findings.
Staging
By 1987, the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) had developed a joint staging system for lung carcinoma based on data gathered primarily by Clifford Mountain of the MD Anderson Cancer Center. The most recent iteration (7th edition) of the lung cancer staging system, published in 2007, is based on the tumor (T), the status of regional lymph nodes (N), and the presence or absence of distant metastases (M), as outlined in Table 18–8.
Table 18–8. TNM stage groupings.
Treatment
Treatment for small cell carcinoma consists primarily of chemotherapy and radiation, although recent data indicate that for early disease (T1-T2 lesions without hilar adenopathy) resection may improve local control and result in increased long-term survival (as high as 50%), particularly when combined with postoperative chemotherapy.
Treatment for NSCLC varies with stage. Early-stage disease (stage I/II) has historically been treated with surgery alone. Notably, several randomized prospective trials have demonstrated a statistically significant improvement in lung cancer survival among patients treated with adjuvant chemotherapy for early stage (stages II and III) NSCLC. Combined-modality therapy utilizing induction chemotherapy or chemoradiotherapy appears to confer a survival advantage for patients with potentially resectable stage IIIA disease, although overall survival was not improved compared with patients receiving chemotherapy with definitive-dose radiation therapy. Locally advanced and surgically unresectable disease (stage IIIB) is best managed with concurrent platinum-based chemotherapy and fractionated radiation therapy. Among patients with metastatic disease (stage IV), chemotherapy is best for palliation of symptoms. Radiotherapy in this case also is reserved primarily for symptomatic lesions. Combined-agent chemotherapy offers 2-3 months (20%) survival extension to advanced-stage patients. It has been shown to be cost-effective and improve quality of life and is generally well tolerated by patients with reasonable performance status. New biologic agents—so-called targeted therapies—are showing activity in clinical trials and should improve overall survival statistics. It is hoped that with advances in targeted and conventional therapies, the current overall survival (< 15% at 5 years) of patients with lung cancer can be improved.
Induction Chemotherapy
Recently completed clinical trials and several ongoing studies suggest survival benefit of treatment with platinum-based chemotherapy prior to resection. Induction chemotherapy has been standard for locally advanced surgically resectable disease, but evidence is accumulating to support induction therapy in early stage NSCLC.
Table 18–9. Medical and surgical contraindications to pulmonary resection.
Preoperative assessment is directed toward evaluating both cardiopulmonary reserve and overall patient fitness. The patient’s general performance status or functional classification is probably the most accurate factor in predicting a successful outcome following operation. Advanced age alone is not a contraindication to resection. A thorough cardiac evaluation is also necessary since lung cancer and cardiovascular disease share common risk factors (eg, smoking). Patients with cardiac symptoms, an abnormal EKG, or other findings suggestive of ischemic heart disease should be screened by a stress test (eg, exercise treadmill, dipyridamole- or adenosine-thallium study, dobutamine echocardiogram). Significant coronary artery disease should be treated with coronary artery bypass or catheter-based intervention as indicated, prior to any contemplated pulmonary resection. Furthermore, significant pulmonary hypertension and myocardial infarction within 3 months has been associated with up to 20% perioperative mortality and constitute absolute contraindications to standard resection. Other high-risk findings include myocardial infarction within 6 months, ventricular arrhythmias and heart block, particularly left posterior fascicular hemiblock. Finally, the patient’s pulmonary function and predicted ability to tolerate the required pulmonary resection should be assessed. This is accomplished with pulmonary function tests (spirometry, diffusing capacity, exercise oximetry) and with differential (quantitative) ventilation-perfusion scanning when appropriate. In a 70-kg patient, the following preoperative studies suggest high risk for perioperative morbidity and are relative contraindications to resection: forced expiratory volume in 1 second (FEV1) below 0.8 L, a predicted postoperative FEV1below 0.8, a predicted maximum voluntary ventilation under 50%, a Paco2 higher than 45 mm Hg, and a PaO2 less than 50 mm Hg. A diffusion limitation capacity of carbon monoxide (DLCO) less than 60% predicted is correlated with an increase in perioperative mortality. Generally, for patients whose predicted postoperative values for FVC, FEV1, or DLCO are projected to be less than 40% predicted, further assessment of functional status and operability are recommended.
The overall mortality rates following segmental resection, lobectomy, and pneumonectomy are 1.4%, 2.9%, and 6.2%, respectively, in centers with large experience. Complications following pulmonary resection include cardiac arrhythmias, hemorrhage, infection (empyema), bronchopleural fistula, respiratory insufficiency, and pulmonary embolism.
Adjuvant radiation therapy following resection has been extensively studied by the Lung Cancer Study Group and has been found to decrease local or nodal recurrence but not to prolong overall survival. A much-disputed meta-analysis (the PORT study) showed a decrease in survival for stage II patients treated with postoperative radiation. Differences in radiotherapy techniques within the analysis may account for the worse outcomes. Preoperative radiation has been used with T3 lesions, particularly Pancoast tumors, with improved survival; however, there is no objective evidence that radiation must be given preoperatively. A multicenter intergroup trial (SWOG) has shown a significant survival advantage for combined chemoradiotherapy (etoposide, platinum, and 4500 cGy) prior to resection for Pancoast (superior sulcus) tumors that were N1 or less. Complete resection rates were improved, 20%-25% complete pathologic responses were achieved, and survival was significantly improved (45%-50% at 3 years) over surgery alone or preoperative radiotherapy and surgery. Intraoperative radiation has been investigated but to date has been associated with unacceptably high morbidity. Among patients with metastatic disease, therapeutic radiation is indicated in patients with symptoms of pain, neurologic symptoms, and symptoms of superior vena cava compression.
Table 18–10. Adjuvant trials favoring use of chemotherapy in completely resected non–small cell lung cancer.1
Immunotherapy using bacillus Calmette-Guérin (BCG), levamisole, IL-2, TNF-α, lymphokine-activated killer (LAK) cells, and tumor-infiltrating lymphocytes has not proved beneficial in any clinical studies to date.
Molecular-based therapies targeting overexpressed growth receptors (EGFR1, HER-2/neu) by monoclonal antibody or small molecules have demonstrated clinical effectiveness among select patient populations. Additional agents targeting signal transduction pathways (eg, farnesyl transferase inhibitors) for the ras pathway as well as antisense oligonucleotide and gene therapies are all in advanced clinical testing stages and in combination with standard cytotoxic chemotherapy appear to enhance response rates. Prospective randomized trials evaluating the efficacy of EGFR tyrosine kinase inhibitor therapy have not been able to validate the findings of earlier non-randomized (phase I/II) trials.
Prognosis
The survival of patients with NSCLC is highly dependent on the pathologic stage. Overall, the 5-year survival of patients with stages I, II, IIIA, IIIB, and IV is 43%-64%, 20%-40%, 15%-25%, 5%-7%, and less than 2%, respectively. A breakdown of survival by TNM classification is set forth in Table 18–11. Improved survival will likely depend on earlier diagnosis and further coordinated efforts among surgeons, medical oncologists, and radiation oncologists.
Table 18–11. Survival in non–small cell lung cancer.
Patients with limited-stage disease achieve a median survival of 12-16 months with 5%-25% 2-year survival, while those with extensive-stage disease have a median survival of only 7-11 months, with only 1%-3% surviving 2 years.
Albain KS et al: Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379.
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Pignon JP et al: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552.
Shah A et al: Cost-effectiveness of stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer. Cancer Online publication May 29, 2013.
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Travis WD et al: IASLC/ATS/ERS international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244.
UNUSUAL PULMONARY NEOPLASMS
Malignant Neoplasms
Bronchial adenomas are a group of low-grade malignancies arising from the bronchial tree. Carcinoid tumors constitute 85%-90% of these neoplasms, with adenoid cystic carcinoma (10%) and mucoepidermoid carcinoma (< 5%) accounting for most of the remainder. Carcinoid tumors are classified as either typical or atypical, with markedly different histologic characteristics (Table 18–12). Adenoid cystic carcinomas occur in the lower trachea; infiltrate locally along submucosal and perineural tissue planes, often far beyond the boundaries of gross tumor; and metastasize late. Mucoepidermoid carcinomas resemble salivary tumors, with varying numbers of three distinct cell types: mucous, squamous, and intermediate. Patients with bronchial adenomas complain of cough, recurrent pulmonary infections, hemoptysis, pain, and wheezing. Only 15% of patients are completely asymptomatic. Carcinoid syndrome is rare with pulmonary carcinoid tumors. Most bronchial adenomas are diagnosed with a combination of plain chest radiography, CT, and bronchoscopy. Biopsy at the time of bronchoscopy can be associated with significant bleeding, and measures to control this must be readily available.
Table 18–12. Characteristics of typical and atypical carcinoid tumors.
Lung resection is indicated for these tumors, with lobectomy being the most common procedure. Sleeve and bronchoplastic resections are particularly useful to preserve pulmonary function in these patients and make standard pneumonectomy rare. Removal of adenoid cystic carcinomas requires generous margins and frozen section examination of the margins at the time of surgery. Up to 8 cm of trachea can be removed with primary anastomosis. In addition, postoperative radiation may be indicated for close margins. With the possible exception of atypical carcinoid, chemotherapy is generally not indicated in the treatment of these neoplasms.
The long-term outlook is good for patients with metastatic disease. Even patients with adenoid cystic carcinoma and distant metastases may do well for extended periods due to the slow-growing nature of this malignancy; however, lymph node and distant metastases in patients with carcinoid tumors generally carry a poor prognosis.
Benign Neoplasms
Benign neoplasms of the lung are uncommon, accounting for less than 1% of all pulmonary tumors. Most are hamartomas, but fibromas, leiomyomas, neurofibromas, myoblastomas, and benign metastasizing leiomyomas also occur. Most lesions are peripheral and asymptomatic; however, central lesions can produce symptoms of cough, wheezing, hemoptysis, and recurrent pneumonia. Typically, the lesions are discovered on routine chest radiographs and appear as a 1- to 2-cm well-circumscribed, bosselated lower lung nodule with calcifications in 10%-30%. Central lesions may require bronchoscopy for diagnosis, but a pathologic diagnosis is most often obtained by fine-needle aspiration biopsy or surgery. Surgical resection should be conservative and limited to wedge excision unless the lesion occupies the proximal bronchial airway and is associated with recurrent distal infections or bronchiectasis. In such cases, lobectomy is indicated. Following resection, the prognosis is excellent.
SPECIAL PROBLEM: THE SOLITARY PULMONARY NODULE
With the frequent use of chest radiography, solitary pulmonary nodules (“coin lesions”) are frequently found in patients without pulmonary symptoms. These lesions pose a diagnostic problem for clinicians because they may represent something as benign as a nipple shadow or as malignant as lung cancer. The overall incidence of cancer in coin lesions is as low as 10%. Other diagnostic possibilities include: (1) infections due to mycobacteria (tuberculosis), fungi (histoplasmosis, coccidioidomycosis), and helminths (echinococcosis); (2) inflammatory nodules from rheumatoid arthritis, focal pneumonitis, and Wegener granulomatosis; (3) congenital anomalies, such as bronchogenic cysts and arteriovenous malformations; (4) benign neoplasms such as hamartomas, hemangiomas, papillary tumors, fibrous tumors of the pleura; (5) malignant neoplasms of the lung; and (6) miscellaneous processes such as hematomas, pulmonary infarcts, pleural plaques, loculated effusions, chest wall masses, and mucoid impaction. Although certain radiographic findings may suggest malignancy or benignity, solid pathologic proof that the nodule does not represent a malignancy rests with the clinician. In general, malignant neoplasms are larger and grow rapidly, appear spiculated, often with surface umbilication or notching and eccentric excavation. In addition, cancers often occur in smokers (or former smokers) over the age of 40 with negative skin tests for tuberculosis, histoplasmosis, or coccidioidomycosis (although positive tests do not exclude cancer), and in nodules that lack calcium (CT Hounsfield units < 175). In contrast, benign lesions are small (< 1 cm), stable (> 2 years), and calcified (“target” or “popcorn” distribution; CT Hounsfield units > 175) and are associated with positive skin tests in 70%-90% of patients.
Evaluation of these patients usually includes chest CT scan, but sputum cytology, cultures, bronchoscopy, and mediastinoscopy are sometimes helpful. FDG-PET scanning plays an important role in the evaluation of tumors that are suspicious for malignancy. PET scan can often differentiate among lesions suspicious for malignancy.
With the advent of spiral CT scanning, the incidence of asymptomatic pulmonary nodules can vary from 25% to 70%. The vast majority of these lesions now identified are less than 1 cm and often as small as 2-3 mm. In one series, the incidence of lung cancer in the asymptomatic 10 pack-year smoking history population over the age of 50 years was 27% of all lesions identified, followed, and treated. Ongoing trials are assessing the efficacy and cost-effectiveness of CT screening for lung cancer. In the properly selected high-risk patient population (eg, over 60 years of age, moderate COPD, FEV1 < 70%), and an over 20 pack-year smoking history), spiral CT may prove to be cost-effective and will save lives.
Ultimately, a pathologic diagnosis must be made. In some instances, fine-needle aspiration cytology may be helpful, particularly if a tissue diagnosis of hamartoma can be made or if cultures demonstrating infectious organisms are obtained. The vast majority of solitary pulmonary nodules require excisional biopsy to exclude the possibility of malignancy. Currently, this is accomplished with video-assisted techniques in most patients, particularly if the lesion is in the periphery of the lung. If a benign lesion is encountered, nothing further is warranted, but if a lung cancer is diagnosed, immediate lobectomy is indicated. The prognosis following resection of a coin lesion that turns out to be a bronchogenic carcinoma is good, with a 5-year survival of as high as 80%-90% for lesions smaller than 1 cm.
SECONDARY LUNG CANCER
Autopsy studies have demonstrated that 30% of all patients with malignancies develop pulmonary metastases, and 12% have been shown to have isolated lung disease that is totally resectable. In addition, 10% of these latter patients (1.2% of all patients) have solitary lung metastases. Most pulmonary metastases occur through hematogenous spread from the primary site—lymphatic or transbronchial spread is extremely rare. Secondary metastatic spread to the pulmonary and mediastinal lymph nodes, however, can also occur.
In patients with known extrathoracic primary cancers, multiple pulmonary lesions almost always represent metastatic disease. Solitary lesions, however, may be due to benign disease (18%) or new primary lung cancer (18%) as well as metastatic disease (64%). Most patients with pulmonary metastases are asymptomatic even with extensive disease. If symptoms do develop, cough, hemoptysis, fever, dyspnea, and pain are common. The diagnosis is generally initially suggested by routine chest radiography, and CT of the chest should always be ordered to assess the lungs for other nodules. Although CT scans are more sensitive, detecting nodules as small as 3 mm, they are also less specific (false-positive rate of 55%) than plain x-rays. Pathologic confirmation of the diagnosis is essential and usually is obtained at the time of resection. For patients who are not surgical candidates, fine-needle aspiration cytology is useful for peripheral lesions, while central lesions may require bronchoscopy for tissue diagnosis.
Medically fit patients with resectable disease are surgical candidates as long as the following criteria are fulfilled: (1) the primary tumor must be controlled or imminently controllable; (2) no other sites of disease may exist; (3) no other therapy can offer comparable results; and (4) the operative risk must be low. Since adenocarcinomas (especially breast cancer) commonly involve multiple organs, it is imperative that with this histology a full evaluation be performed, including bone scan and head CT or MRI. Solitary squamous cell nodules, even in the presence of a previous squamous cell carcinoma (eg, head and neck tumors), should be addressed as a new primary (lung) cancer.
Pulmonary resection can be accomplished through a standard posterolateral thoracotomy, median sternotomy, or bilateral anterior thoracotomies. The latter approach is particularly beneficial for bilateral disease involving the lower lobes. Video-assisted thoracoscopy is increasingly applied to metastatic disease in an attempt to reduce the morbidity of multiple resections. On occasion, during open operations for metastatic disease, several unsuspected nodules are found by direct palpation that might be missed with thoracoscopy. Wedge resection is the treatment of choice unless the lesion is a solitary squamous cell carcinoma or adenocarcinoma. These latter lesions cannot be distinguished from primary lung cancer on frozen section pathologic examination, and they must therefore be treated as primary lung cancers with lobectomy and mediastinal lymph node dissection. Occasionally, other malignant tumors identified by histologic examination may require lobectomy or, rarely, even pneumonectomy because of involvement of the proximal pulmonary artery or bronchus.
The success rate with surgical removal of pulmonary metastases has been greatest with testicular (51% 5-year survival) and head-neck cancers (47% 5-year survival). Other types of tumors, such as osteogenic and soft tissue sarcomas, renal cell carcinoma, and colon carcinoma, are all associated with prolonged survival in 20%-35% of patients. Results of resection for melanoma are less favorable (10%-15% survival benefit). Isolated, resectable pulmonary metastases from rectal cancer can have as high as a 55% 5-year survival with metastasectomy alone.
Furthermore, multiple thoracotomies over periods in excess of 10 years are not unusual with the sarcomas. Numerous studies have been conducted in attempts to identify prognostic factors that could aid in the selection of patients for resection. Adverse prognostic factors have included: (1) multiple or bilateral lesions; (2) more than four lesions seen on CT scan; (3) tumor doubling time less than 40 days; (4) a short disease-free interval; and (5) advanced age.
Although no consensus has developed regarding the selection of candidates for surgical exploration, it is generally agreed that no single criterion should be used to exclude patients from surgical resection. In all series, long-term benefit and survival hinges on complete resection. If a complete resection is not deemed possible, resection should not be offered.
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MULTIPLE CHOICE QUESTIONS