MEDIASTINAL DISEASES Klymenko A.V.

Thymoma The thymus gland is located in the anterior portion of the mediastinum. Various tumors, cysts, and other abnormalities related to the thymus can develop. Problem Any discussion of masses and tumors of the mediastinum requires delineation of the boundaries of that area. The portion of the thorax defined as the mediastinum extends from the posterior aspect of the sternum to the anterior surface of the vertebral bodies and includes the paravertebral sulci. The mediastinum is limited bilaterally by the mediastinal parietal pleura and extends from the diaphragm inferiorly to the level of the thoracic inlet superiorly.

Etiology Thymic neoplasms and cysts The tumors and cysts found in the mediastinum result from several causes. Several different lesions originate from the thymus, including thymomas, thymic carcinomas, thymic neuroendocrine tumors, thymic hyperplasia, thymic cysts, and thymolipomas. Thymomas originate from either the cortical or medullary epithelial cells of the thymus. They are considered histologically benign tumors even though they may exhibit clinically invasive behavior.

Systemic Pathophysiology Certain mediastinal tumors can produce systemic abnormalities. Many of these manifestations are related to bioactive substances produced by specific neoplasms. The most common systemic manifestation associated with thymoma is myasthenia gravis. This occurs in 10-50% of patients with thymoma and is thought by many to be an autoimmune phenomenon because a high titer of antiacetylcholine receptor antibodies is present in these patients. Only approximately 10-15% of patients presenting with myasthenia gravis are found to have a thymoma. The vast majority of patients with myasthenia who do not have a thymoma are found to have thymic hyperplasia, and only approximately 10-20% have no identifiable abnormality of the thymus gland.

Indications Treatment selection for a given mediastinal tumor or cyst depends on the diagnosis of the lesion being investigated. Surgical resection is indicated in a large percentage of cases. Because complete surgical resection is the most critical factor in long-term patient survival, all neoplasms of the thymus gland (except widely metastatic thymoma) should be completely resected. This includes thymoma, thymic carcinomas, thymolipomas, and neuroendocrine tumors of the thymus. Thymic cysts are also generally treated with surgical resection because most manifest as cystic anterior mediastinal masses of an undefined etiology. Resection of the thymus is also indicated in persons with myasthenia gravis, although a thymic neoplasm is identified in only approximately 15-20% of these patients. The abnormality that is found is known as lymphoid or follicular thymic hyperplasia and is identified in more than 60% of patients with myasthenia. No thymic abnormality is identified in the remainder of these patients.

Workup Laboratory Studies Hemoglobin, hematocrit, and white blood cell count Gamma globulin levels: Hypogammaglobulinemia is associated with some cases of thymoma. Adrenocorticotropic hormone (ACTH) levels Antidiuretic hormone levels

CT scan of the chest and mediastinum

Imaging Studies Chest radiography CT scan of the chest and mediastinum Magnetic resonance imaging Radionuclide scanning Echocardiography and ultrasonography Positron emission tomography (PET) scan

Diagnostic Procedures Transthoracic needle biopsy Cervical mediastinoscopy and substernal extended mediastinotomy Anterior mediastinotomy Video-assisted thoracoscopy Sternotomy and thoracotomy

Treatment Medical Therapy Thymoma Although surgical resection is the preferred treatment for thymoma, patients with clinically unresectable extrathoracic disease require radiation therapy, chemotherapy, or both. Radiation therapy is an essential part of the treatment of any thymoma with invasive characteristics. Controversy exists regarding the use of radiation therapy for patients with stage I tumors; however, it is recommended unanimously for those with tumors in more advanced stages. Radiation therapy has also been used preoperatively to facilitate the resection of bulky tumors; however, this role is usually played by chemotherapy. Cisplatin-based chemotherapy regimens are often recommended for patients with unresectable stage III disease or with disseminated stage IV disease. Chemotherapy is also a useful induction agent for locally advanced thymomas to facilitate resection of these bulky tumors. Cisplatin-based regimens have shown promise for improving both resectability and long- term patient survival.

Outcome and Prognosis Prognosis after resection of a mediastinal tumor varies widely depending on the type of lesion resected. After resection of mediastinal cysts and benign tumors, prognosis is generally excellent. Thymic neoplasms included in this group are thymolipomas. Prognosis after treatment of malignant mediastinal tumors depends on the type of lesion, its biological behavior, and the extent of the disease present. Thymoma Thymomas are not considered benign neoplasms. Survival rates associated with tumors that are encapsulated or stage I is 95-97% at 5 years and % at 10 years. Invasive or stage II tumors are associated with a reduced 5-year survival rate of 60-70% and a 10-year survival rate of 40-50%. Survival rates for stage III tumors are reported to be less than 60% at 5 years and 14% at 10 years. Survival rates for stage IVA tumors have been reported at 40% for 5 years and 0% at 10 years.

Mediastinitis Introduction Mediastinitis is a life-threatening condition with an extremely high mortality rate if recognized late or treated improperly. Although long recognized as a complication of certain infectious diseases, most cases of mediastinitis are associated with cardiac surgery (>300,000 cases per year in the United States). This complication affects approximately 1-2% of these patients. Although small in proportional terms, the actual number of patients affected by mediastinitis is substantial. This significantly increases mortality and cost.

Etiology Postoperative –Most cases of mediastinitis in the United States occur following cardiovascular surgery. –Risk factors for the development of mediastinitis include the following: In general, the use of pedicled bilateral internal mammary artery (BITA) grafts carries increased risk for mediastinitis after coronary artery bypass graft (CABG). This risk is even higher among patients with diabetes, thus rendering many surgeons reluctant in using BITA grafting in this subgroup of patients. However, the use of skeletonized BITA grafts may reduce this risk, patients with and without diabetes could be considered for skeletonized BITA. Emergency surgery External cardiac compression (conventional cardiopulmonary resuscitation) Obesity (>20% of ideal body weight)7 Postoperative shock, especially when multiple blood transfusions are required Prolonged bypass and operating room time Reoperation Reexploration following initial surgery Sternal wound dehiscence Surgical technical factors (eg, excessive use of electrocautery, bone wax, paramedian sternotomy)6 Esophageal perforation Trauma, especially blunt trauma to the chest or abdomen Tracheobronchial perforation, due to either penetrating or blunt trauma or instrumentation during bronchoscopy Descending infection following surgery of the head and neck, great vessels, or vertebrae Progressive odontogenic infection (Ludwig angina)Ludwig angina Mediastinal extension of lung infection Chronic fibrosing mediastinitis due to granulomatous infections Microbiology The frequency of various microbiological pathogens isolated in cases of postoperative mediastinitis. –Most mediastinitis cases occur after cardiac surgery and indicate gram-positive cocci,6 with Staphylococcus aureus12 and Staphylococcus epidermidis accounting for 70-80% of cases. Mixed gram-positive and gram-negative infections account for approximately 40% of cases. Isolated gram-negative infections are rare causes. –Fibrosing mediastinitis is most commonly associated with Histoplasma capsulatum and Mycobacterium tuberculosis, although mediastinitis is an extremely rare complication of these infections.11

Pathophysiology Infection from either bacterial pathogens or more atypical organisms can inflame any of the mediastinal structures, causing physiological compromise by compression, bleeding, systemic sepsis, or a combination of these. The origin of infection following open heart operations is not known in most patients. Some believe that the process begins as an isolated area of sternal osteomyelitis that eventually leads to sternal separation. Others hold that sternal instability is the inciting event, and bacteria then migrate into deeper tissues. Inadequate mediastinal drainage in the operating room may also contribute to the development of a deeper chest infection. The patient's own skin flora and the bacteria in the local surgical environment are possible sources of infection. Because some bacterial contamination of surgical wounds is inevitable, host risk factors are likely critical in promoting an active infection.

Physical Vital signs generally may show tachycardia and fever. In more advanced cases of sepsis, hypotension may be present and the patient may require large volumes of crystalloid or vasopressor medication for support. The Hamman sign is a crunching sound heard with a stethoscope over the precordium during systole. Its presence should alert the clinician to possible mediastinitis, although its absence does not change the probability of disease. Direct signs of sternal infection may be among the initial presenting signs or may be delayed until after the diagnosis is already considered. Sternal pain, instability, or click; local cellulitis; and drainage can all be observed. Distinguishing between a superficial wound infection and a deeper chest infection associated with mediastinitis can be challenging. Systemic signs of sepsis strongly suggest mediastinal involvement. Local wound exploration should be utilized as a mechanism to distinguish a superficial wound infection from a deep sternal wound infection.

Indications Operative exploration includes reopening the previous sternotomy and debridement of necrotic and infected tissue. The sternum is separated from the ventricle bypass grafts and the aorta carefully to not cause bleeding. Cultures are sent to direct antibiotic therapy. Wound closure is usually delayed until reasonable control of infection is achieved; however, some surgeons perform closure with muscle flaps at the initial debridement with good results. Delayed closure is usually accomplished with muscle flaps (pectoralis, rectus) and recently is aided by vacuum-assisted closure.1,13,14 Sterile sternal dehiscence, which is described as a sternal nonunion, is usually not treated. Occasionally, patients abruptly separate their sternum in close proximity to cardiac surgery, necessitating sternal reclosure. Also, some have extreme pain or cannot tolerate the clicking and discomfort of the nonunion and require sternal reclosure.

Workup Laboratory Studies CBC count –CBC count shows leukocytosis, often with a left shift on the WBC count differential. –The hematocrit value decreases if bleeding has occurred. –The platelet count increases in the early stages of sepsis or decreases as sepsis worsens or disseminated intravascular coagulation occurs. Blood cultures –Bacteremia can be observed and blood cultures should be obtained as clinically indicated. –Results from properly collected blood cultures should be reflexive in the workup when mediastinitis is considered, especially in the postoperative patient several days after cardiothoracic surgery in the presence of sepsis. Gram stain: Samples of any sternal drainage should be sent for Gram stain and culture. This helps to establish a diagnosis and to tailor antimicrobial therapy. At operative exploration, additional cultures should be taken to direct antibiotic therapy. Cultures of mediastinal pacing wires –Mediastinal pacing wires should be sent for culture if they are still present and no longer needed. –One study found that results from pacing wire culture have a sensitivity of 75%, a specificity of 83%, a positive predictive value of 12%, and a negative predictive value of 99%.15

Imaging Studies Delays in the diagnosis of mediastinitis greatly increase morbidity and mortality. The condition is typically recognized because of high clinical awareness in susceptible populations. Occasionally, radiology studies, including chest CT scan, can be helpful in diagnosis if it is in question. Local wound exploration is the predominant method to distinguish between superficial wound infection and deep sternal wound infection. Chest radiographs –Findings include pneumomediastinum and air-fluid levels within the mediastinum. –Air-fluid levels are often best seen on lateral films. –Mediastinal widening is not a reliable sign of mediastinitis, especially postoperatively. CT scans –CT scans are more accurate for helping to identify air-fluid levels and pneumomediastinum. A CT scan image may demonstrate sternal separation and substernal fluid collections. These examinations can be helpful when the diagnosis is in question or in the late postoperative period. They should not take the place of prudent wound exploration to identify a deep sternal wound infection. –The later the scans are performed following surgery, the more accurate the results.16 If performed after the second postoperative week, CT scans have a sensitivity and specificity of almost 100%, although most wound infections occur prior to this time.16 The specificity of CT findings is clearly time-dependent. –CT findings consistent with mediastinitis can also be found in patients without sternal wound infections after cardiac surgery for as many as 21 days following the procedure. This makes integrating CT scan findings with clinical data and awareness critical. MRI –MRI is poorly suited as a diagnostic modality in persons with mediastinitis. Postoperative patients may have sternal wires, vascular clips, metallic valves, and pacing wires that contraindicate MRI. –Also, logically performing an MRI study on an intubated, critically ill patient is difficult. –Findings from nuclear medicine scans/radioactive WBC scans involving labeled WBCs are reported to have very high specificity; however, few studies have been performed on postoperative patients.

Surgical Therapy Surgical options for mediastinitis after cardiac surgery Effective treatment for simple sternal dehiscence without infection is rewiring the sternum. This usually yields reasonable long-term results. Cultures should be taken to exclude active infection in the cases of sternal dehiscence. Failure to adequately debride and sterilize the mediastinum during the first reoperation is the most common cause of repeat postoperative mediastinitis. Options for mediastinitis after cardiac surgery are immediate closure after sternal debridement, delayed closure after sternal debridement, and sternal irrigation after sternal debridement. Each has its advantages and disadvantages. The best strategy for accomplishing this depends on the duration of the infection, the condition of the mediastinal structures, and the experience of the surgeon. Most surgeons prefer to leave the wound open or treat with vacuum-assisted closure for subsequent debridement efforts after initial sternal reexploration. In this case, the wound is packed daily until it appears clean with adequate granulation tissue. At this point, muscle flap closure is achieved. Usually, bilateral pectoralis muscle flaps are used. Occasionally, the rectus abdominus muscle, which is opposite the internal mammary artery used for bypass, is used for coverage. Both the surgeon's experience and patient factors influence the type of flap procedure used. If a large anterior retrosternal dead space exists, it must be obliterated in order to achieve cure. Although often achieved with a muscle flap, the omentum provides lymphocytes and angiogenesis factors that may prove beneficial. Disadvantages of this delayed approach are the altered thoracic mechanics, which may lead to ventilator dependence, and a risk of bleeding from the exposed heart and vessels, with muscle flap closure for mediastinitis in an attempt to decrease the incidence of this bleeding. Some surgeons uniformly perform muscle flap closure at the initial debridement with good results. Other surgeons elect to close the wound site primarily in less-advanced cases of mediastinitis and use large-bore drainage and irrigation tubes to infuse various antibiotic or antiseptic solutions for many days. Although the most commonly used solution in the past has been povidone iodine, this should be used with caution. Case reports have indicated the development of serious iodine toxicity manifesting as seizures and renal failure. The lack of a bony anterior sternal wall may be unacceptable to some patients and has prompted some surgeons to attempt sternum-sparing procedures, even in more advanced cases. This is often a difficult decision, requiring excellent surgical judgment. Clearly advanced cases of sternal osteomyelitis are extremely difficult to cure, and most patients with muscle or omental flaps do very well from a functional standpoint.

Outcome and Prognosis The development of mediastinitis dramatically raises the chance of mortality and lengthens the hospital stay. One study showed that postoperatively, a patient's chance of dying doubled to 12% when mediastinitis developed compared with 6% for those without the condition. Some studies report death rates as high as 47%. Mediastinitis also raises the 2-year mortality rate from 2% to 8% following coronary bypass grafting. Patients with postoperative mediastinitis stay in the hospital 6-7 times longer than those without the condition, and total costs may triple.