The Washington Manual of Oncology, 3 Ed.

Thymoma and Mesothelioma

Eric Knoche • Siddartha Devarakonda • Daniel Morgensztern

 I. THYMOMA

1. Subjective complaints. The clinical presentation for patients with thymic neoplasms can range from an incidental radiographic finding to a symptom related to local extension or to a severe complication related to a variety of paraneoplastic syndromes. Up to 50% of patients present with an asymptomatic anterior mediastinal mass on the chest radiograph. The most common symptoms include cough, chest pain, and dyspnea. Other symptoms include hemoptysis, hoarseness, and dysphagia. Systemic complaints such as weight loss, fatigue, fever, and night sweats are less common and are more typical of lymphoma. The most common paraneoplastic syndrome is myasthenia gravis (MG), which occurs in approximately one-third of the patients. Among patients with MG, 10% to 15% are found to have thymoma during further investigation. Pure red cell aplasia (PRCA) occurs in approximately 5% to 10% of patients with thymoma, but half of the patients with PRCA have thymoma. This syndrome is suspected in patients with isolated anemia and low reticulocyte count. Hypogammaglobulinemia is present in up to 10% of the patients. The association of thymoma with combined B and T cell immunodeficiency is termed Good’s syndrome. This condition is characterized by an increased susceptibility to infections by encapsulated bacteria and opportunistic infections (J Clin Pathol 2003;56:12). Several other paraneoplastic syndromes have been described in association with thymoma (Table 14-1).
2. Objective findings. At an early stage, patients often have a completely normal physical examination. The thoracic expansion of the tumor with invasion or compression of the superior vena cava may cause the characteristic findings of facial and upper extremity swelling, whereas invasion of the innominate vein will cause left arm edema. Phrenic nerve invasion is also possible and may result in decreased breath sounds on the affected side. Some patients develop ocular findings such as ptosis or diplopia.
3. WORKUP AND STAGING
4. Imaging studies. Most cases of thymoma are detected initially by standard chest radiographs. On the posteroanterior (PA) view, there is usually a round or oval lesion, with a smooth or lobulated border, near the junction of the heart and great vessels. Although the tumor may be primarily located in the midline, it also usually extends into one of the hemithoraces. The trachea is rarely displaced, and the presence of an elevated hemidiaphragm may suggest the invasion of a phrenic nerve. A small percentage of tumors have calcification in the periphery or within the tumor. On the lateral view, the mass causes opacification of the anterior cardiac window. Further evaluation is obtained with a computed tomography (CT) scan of the chest, which will best visualize and evaluate the extent of the mass. Although CT scan is unreliable for the detection of mediastinal invasion, highly suggestive findings of invasion include complete obliteration of fat planes, encasement of mediastinal vessels, and pericardial or pleural thickening. The tendency to metastasize to the posterior basilar pleural space is unique of thymomas. Magnetic resonance imaging (MRI) is useful for the investigation of vascular invasion. Thymic tumors often express somatostatin receptors and may be detected by an indium-labeled octreotide scan.

1. Biopsy. The diagnosis of thymoma is usually made clinically, particularly in patients with paraneoplastic syndrome. When the tumor is small and confined to the thymus, surgical excision may facilitate diagnosis, treatment, and staging. Biopsy has an important role in patients with large and invasive tumors that may require a nonsurgical approach or neoadjuvant treatment, as well as in cases where lymphoma remains a strong possibility, because this malignancy is not primarily treated with surgery. The histopathologic diagnosis may be obtained through a fine needle aspiration (FNA) or surgical biopsy with success rates of approximately 60% and 90%, respectively. The sensitivity and specificity of FNA is limited due to the benign appearance of many thymomas when evaluated at a single cell level. There is limited data to support the concerns over seeding thymic tumors to the pleural space during the biopsy procedure. There are no reports of tumor seeding through the needle tract or biopsy site, and the pattern of spreading to the pleural space appears to be inherent of this malignancy, regardless of previous biopsy.
2. Pathology. The term thymoma should be restricted to neoplasms of thymic epithelial cells. Therefore, other tumors that may also involve the thymus such as seminomas and lymphomas should not be considered variants of thymoma. Most of the thymomas arise in the upper portion of the anterior mediastinum, corresponding to the location of the normal thymus gland. Rare locations include the posterior mediastinum, lower neck, perihilar tissues, lung parenchyma, and pleura (possibly arising from ectopic thymic tissue, which can be distributed throughout the mediastinum). Grossly, thymomas are largely or entirely solid, separated in lobules by connective tissue septa, and usually well-encapsulated. Microscopically, thymomas are composed of a mixture of neoplastic epithelial cells and a lymphocyte infiltrate. After many years of debate and several proposed schemes, the World Health Organization (WHO) developed a standard and unified classification for thymic epithelial neoplasms in 1999 (Table 14-2). In this report, two major types of thymoma were identified on the basis of the characteristics of the malignant epithelial cells, which could have a spindle or oval shape (resembling medullary cells) in type A or epithelioid appearance (resembling cortical cells) in type B. Tumors with both characteristics were designated as AB. Type B tumors were further subdivided into three groups, B1 to B3, depending on the progressive increase of the epithelial-to-lymphocyte ratio and the degree of atypia. An additional category, type C, was reserved for patients with thymic carcinoma, where there are overt characteristics of malignancy. There is a significant correlation between the WHO subtype and paraneoplastic syndromes, with MG occurring most commonly in subtype B and PRCA in subtype A.
3. Staging. The most commonly used staging system is the one proposed by Masaoka et al., in 1981 (Table 14-3). In this system, four clinical stages are created on the basis of the degree of invasion through the capsule and into the surrounding structures.

WHO, World Health Organization.

 III. THERAPY AND PROGNOSIS

1. Resectable disease
2. Surgery. Surgery is a treatment of choice for thymoma and should be offered to all patients except those with clinically grossly unresectable disease or where it is spread beyond the thorax. As surgery may precipitate respiratory failure in a patient with MG, any patient with diagnosed or suspected thymoma should be tested for anti-acetylcholine receptor levels prior to surgery to rule out MG. If present, MG should be treated prior to the surgery. In patients with grossly encapsulated lesions, the procedure of choice is a complete excision with total thymectomy. Patients with gross fixation of the tumor to nonvital adjacent structures such as lung, pleura, or pericardium should undergo the resection of the adjacent involved tissues. The presence of intrapulmonary metastasis does not constitute a contraindication for the surgery if accomplished by lobectomy. The role for pneumonectomy in this setting is questionable. Patients with unilateral phrenic nerve involvement should undergo surgery with curative intent, provided that they can tolerate the loss of function in that hemidiaphragm, which can be particularly problematic in patients with MG. The operative mortality is approximately 2.5%, and overall survival for patients with resected thymoma is usually very good (Table 14-4). Patients with stage III or IV are considered unresectable when there is extensive involvement of the trachea, great arteries, or heart, extensive bilateral pleural metastases, or distant metastases. The role of debulking or subtotal resection in advanced stages remains controversial. Patients with relapsed disease following a complete resection should be considered for a second operation.
3. Adjuvant therapy. Adjuvant radiation therapy is not indicated for R0 resections in stage I disease, should be considered for R0 resections in stages II to IV, and is indicated in cases of R1 resection. In the case of R2 resections, patients should be considered for the addition of chemotherapy to the adjuvant radiotherapy.
4. Locally advanced disease
5. Neoadjuvant therapy. Although the use of preoperative single modality radiation therapy has not been associated with survival benefit, several studies suggest improvement in both resectability and survival with the use of multimodality treatment in patients with Masaoka stage III and IV patients. The National Comprehensive Cancer Network currently recommends chemotherapy as the initial treatment for patients with locally advanced thymomas followed by surgical evaluation. In the case of resectable disease, the treatment of choice is surgery followed by adjuvant radiation therapy. Unresectable tumors should be treated with chemoradiotherapy (J Natl Compr Cancer Netw 2013;11:562).

4. Advanced disease. Thymomas are sensitive to chemotherapy, and several chemotherapeutic drugs, either as a single drug or in combination regimens, have been shown to be active. The intergroup phase II trial evaluated the PAC regimen (cisplatin 50 mg/m², doxorubicin 50 mg/m², and cyclophosphamide 500 mg/m² every 3 weeks) in 30 patients with metastatic or recurrent thymoma and thymic carcinoma (J Clin Oncol 1994;12:1164). The overall response rate was 50% with median survival of 38 months and a 5-year estimated survival of 32%. PAC is currently the standard treatment for thymoma. The combination of cisplatin (60 mg/m² on day 1) and etoposide (120 mg/m² on days 1 to 3) resulted in a 56% response rate and median survival of 4.3 years (J Clin Oncol 1996;14:814). For patients with thymoma and positive indium-labeled octreotide scan, octreotide 0.5 mg subcutaneously three times daily for up to 1 year resulted in a 12.5% response rate. When combined with prednisone (0.6 mg/kg/day), octreotide showed a 31% response rate with median survival of 15 months (Cancer 2002;94:1414).
5. Prognosis. Prognosis is usually related to the stage at presentation, presence or absence of complete resection, and the histologic subtype. Most of the thymomas are slow-growing encapsulated tumors that can be cured by surgical resection. Staging, regardless of the system used, remains the single most important prognostic determinant, and the outcomes are significantly better in patients undergoing complete resection. There is a linear progression of malignancy among the WHO histologic subtypes, with A and AB thymomas behaving as benign tumors, B1 and B2 as low-grade tumors, and B3 as an aggressive tumor similar to thymic carcinoma. This correlation is reflected in both the likelihood of invasion and the overall survival.

 IV. THYMIC CARCINOMA. Thymic carcinomas are rare tumors characterized by overt histologic and cytologic features of malignancy such as nuclear atypia, increased mitotic activity, and necrosis. Tumors are usually located in the anterosuperior mediastinum, and patients usually present with symptoms of local invasion such as dyspnea, cough, and chest pain. Most of the patients present with advanced disease with invasion of contiguous mediastinal structures and lymphadenopathy seen in approximately 80% and 40% of patients, respectively. Paraneoplastic syndromes are rarely seen. Owing to the paucity of cases, the optimal treatment remains undefined. Surgical resection is the mainstay of treatment, but complete resection is possible in only a few patients in view of the advanced stage. Adjuvant radiation therapy should be considered in patients with stage II to IV undergoing R0 resection. In the case of R1 or R2 resection, patients should receive adjuvant chemoradiotherapy. In patients with advanced disease, a small study including 23 patients with thymic carcinoma showed a 22% response rate, 5-month progression-free survival (PFS), and 20-month median survival with the combination of carboplatin and paclitaxel (AUC 6 and 225 mg/m² on day 1) (J Clin Oncol 2011;29:2060), which has become the regimen of choice for thymic carcinoma.

1. TARGETED THERAPY. The most frequent alterations in thymomas occur on the locus of the major histocompatibility complex (chromosome 6p). Abnormalities effecting EGFR gene amplification and overexpression, HER2overexpression, c-KIT overexpression, BCL2 overexpression, TP53 overexpression, and PI16INK4A loss of expression have been identified. Approximately 12% of patients with thymic carcinoma harbor c-KIT mutations, and several studies have shown response to tyrosine kinase inhibitors including imatinib, sorafenib, and sunitinib, occasionally lasting more than 12 months (Ann Oncol 2012;23:2409).

 VI. BACKGROUND. Thymomas are the most common primary tumors of the anterior mediastinum in adults. Most of the patients are between the ages of 40 and 60 at the time of diagnosis, and there is no sex predilection. The overall incidence is 0.15 cases per 100,000 person-years.

 VII. MESOTHELIOMA

1. Presentation
2. Subjective. The symptoms of mesothelioma are usually insidious and nonspecific. Therefore, a delay in diagnosis is typical. The median time between the onset of symptoms and the diagnosis is 2 to 3 months. The most common presenting complaints are dyspnea and nonpleuritic chest wall pain. Constitutional symptoms such as weight loss and fatigue are more frequent in the later stages of the disease but may occur in approximately one-third of the patients at presentation. Some patients may be asymptomatic, and their disease is first noticed incidentally on a routine chest radiograph.
3. Objective. Common findings on physical examination include signs of unilateral pleural effusion including dullness to percussion and decreased air entry in the involved lung base. Fixed hemothorax, characterized by the lack of expansion of the chest, is present in large tumors and usually represents a late finding. Occasionally, patients with advanced disease may have palpable supraclavicular lymph nodes or a palpable chest wall mass. Clubbing is rare. Some patients may have no physical signs owing to the presence of a localized pleural mass without effusion.
4. Workup and staging
5. Imaging studies. Radiographic evaluation begins with a PA and lateral chest radiograph, which usually demonstrates a unilateral pleural effusion and occasionally a pleural-based mass. Approximately 20% of the patients have radiologic evidence of asbestos exposure on chest radiograph such as pleural plaques. CT scan often shows an effusion with or without pleural mass and allows the evaluation of tumor extent. In some patients, mesothelioma produces a localized lobular thickening, whereas in others, it causes a rind of tumor encasing the lung. MRI may help to further define the local extension of pleural mesothelioma to the chest wall and diaphragm. Positron emission tomography (PET) scan can be used to differentiate between benign and malignant pleural masses. This functional imaging modality may also allow the detection of lymph node or extrathoracic involvement.
6. Diagnosis. Despite the presence of typical, clinical, or radiographic findings, the definitive diagnosis of mesothelioma should be made by pathologic evaluation. The initial diagnostic procedure is usually a thoracentesis. Cytology of the pleural fluid does not always provide a definitive diagnosis because the yield can be low. Furthermore, when abnormal cells are present, it is often difficult to differentiate mesothelioma cells from reactive mesothelial cells and other malignancies such as adenocarcinoma. The diagnostic value of cytology may improve with the use of immunohistochemical (IHC) stains. When the cytology is inconclusive, patients should undergo a pleural biopsy. Histology samples may be obtained either by a CT-guided biopsy or through direct thoracoscopy.
7. Pathology. Mesothelioma is classified into three histologic subtypes: epithelial, sarcomatoid, and mixed. The epithelial type is the most common, comprising 50% to 60% of all cases. The sarcomatoid type is present in approximately 15% of cases and is characterized by spindle cells that are similar to fibrosarcomas. The mixed or biphasic subtype contains features of both epithelioid and sarcomatoid elements. Because the diagnosis of mesothelioma may not be easily accomplished from the pathologic specimen, IHC studies are commonly used to differentiate between mesothelioma and metastatic or primary lung adenocarcinomas. Stains that are typically positive in mesothelioma include epithelial membrane antigen (EMA), Wilms’ tumor antigen-1 (WT1), cytokeratin 5/6, calretinin, and mesothelin. Negative stains include carcinoembryonic antigen (CEA), thyroid transcription factor-1 (TTF-1), B72.3, CD15, MOC-31, Ber-P4, and Bg8. Electron microscopy should be reserved for difficult cases with equivocal IHC results. The epithelial form is composed of polygonal cells with long microvilli, prominent desmosomes, and abundant tonofilaments. The electron microscopy on the sarcomatoid variant reveals elongated nuclei and abundant rough endoplasmic reticulum.
8. Serum markers. Soluble mesothelin-related protein (SMRP) is a soluble form of mesothelin, which is elevated in most of the patients with mesothelioma. SMRP levels correlate with disease progression or response to therapy, and may be useful in in the early detection for patients at risk.
9. Staging. Although several staging systems have been proposed for mesothelioma, none achieved universal acceptance. The International Mesothelioma Interest Group (IMIG) proposed a new staging system for mesothelioma (Table 14-5). This tumor (T), lymph node (N), and metastases (M) staging system includes T descriptors that are much more detailed than in previous systems. In addition, the descriptors for nodal involvement are the same as those used in the staging of non–small cell lung cancer. This new system allowed a more accurate staging of mesothelioma patients according to prognosis. Median survival by stage was 35 months, 16 months, 11.5 months, and 5.9 months for stages I through IV, respectively.
10. Treatment. Mesothelioma is an essentially incurable disease, and the primary goal of therapy is to improve the quality of life and prolong survival. In most cases, the tumor spreads along the serosal surface and infiltrates the underlying vital thoracic organs, preventing a complete surgical resection. Furthermore, mesothelioma often arises from multiple sites in the parietal pleura. Patients are commonly elderly with significant comorbidities, and the insidious symptoms frequently delay the diagnosis. The choice of treatment is determined by the stage of the disease and the patients’ comorbidities.
11. Surgery. There are three main surgical procedures used in the management of patients with mesothelioma: pleurodesis, pleurectomy with decortication (PD), and extrapleural pneumonectomy (EPP). Pleurodesis is commonly used in the treatment of persistent dyspnea caused by large pleural effusions. This procedure is effective in preventing fluid accumulation and should be performed early during management. As the disease progresses, the tumor grows along the visceral pleura and encases the lung, preventing the re-expansion. The resultant trapped lung is usually refractory to pleurodesis. PD refers to the surgical removal of the visceral, parietal, and pericardial pleura from the lung, apex to diaphragm, without the removal of the lung. A complete resection is possible only in very early stages of the disease, and most of the patients develop a disease recurrence. EPP is the most aggressive procedure and involves the en bloc resection of the visceral and parietal pleura, lung, pericardium, and ipsilateral diaphragm. EPP achieves the greatest degree of cytoreduction and, because the lung has been removed, higher doses of adjuvant radiation to be delivered to the ipsilateral hemithorax. A retrospective study compared the two surgical modalities in 663 consecutive patients operated between 1990 and 2006. EPP was associated with increased operative mortality (7% vs. 4%) and decreased survival in a multivariate analysis adjusting for age, gender, histology, stage and addition of chemotherapy, and/or radiation therapy (HR 1.4; 95% confidence interval 1.18 to 1.69; p < 0.001) (J Thorac Cardiovasc Surg 2008;135:620). Although both PD and EPP are performed with curative intent, neither appears to provide a significant improvement in survival when used as a single modality therapy.
12. Radiation therapy. Mesothelioma cells are relatively sensitive to radiation therapy. However, owing to the diffuse nature of the cancer, the dose of radiation for mesothelioma is limited by the need to irradiate the entire hemithorax, which includes vital organs such as lung, heart, esophagus, and spinal cord. Radiation therapy has minimal effects on increasing survival. There are three main indications for the use of radiation therapy: palliation of pain, prophylaxis against needle tract metastases, and adjuvant therapy. Most of the patients treated with palliative radiation therapy achieve a short-lived pain control. Because mesothelioma is characterized by direct local invasion, it often invades tracts after local procedures. In these cases, radiation may be used as a prophylactic measure. Owing to the high rates of local relapse after surgery, radiation therapy has been used in the adjuvant setting in an attempt to eradicate residual tumor. Studies in patients undergoing EPP have shown decreased local relapse with disease palliation, but no definitive survival improvement.

3. Chemotherapy. Chemotherapy has been used in the neoadjuvant or adjuvant setting in patients treated with multimodality treatment or as single modality in advanced cases where the role of chemotherapy remains palliative, because even trimodality therapy does not appear to achieve cure or significantly prolong survival. Among several regimens, the combination of pemetrexed and cisplatin emerged as the standard of care after a phase III study showed improved survival compared with single agent cisplatin (J Clin Oncol 2003;21:2636). In this study, 456 patients were assigned to cisplatin alone (75 mg/m² day 1 every 3 weeks) or in combination with pemetrexed (500 mg/m² day 1 every 3 weeks). The combination arm resulted in significant benefit including improved response rate (41% vs. 16%, p <0.0001), median time to progression (5.7 months vs. 3.9 months, p = 0.001), and median survival (12.1 months vs. 9.3 months, p = 0.02). Carboplatin combined with pemetrexed is an acceptable alternative for patients who cannot tolerate cisplatin. This combination yielded median survival of 12.7 months in a first-line phase II study (Clin Lung Cancer 2010;11:30) and showed no response differences when compared with cisplatin with pemetrexed. Patients who cannot tolerate pemetrexed may be candidates for the combination of gemcitabine and cisplatin with comparable survival data (Br J Cancer 2002;86:342). Single-agent options include pemetrexed or vinorelbine in either first- or second-line settings.
4. Targeted therapy. Several novel approaches for the systemic treatment of mesothelioma have been recently investigated. A phase II trial of cisplatin, pemetrexed, and bevacizumab failed to reach a 33% improvement in PFS at 6 months compared with the historical control of 48%. (Lung Cancer 2012;77:567). The addition of bevacizumab to carboplatin and pemetrexed led to a median PFS of 6.9 months, which also failed to reach the primary end point of increase from the historical 6 months to a meaningful 9 months (Br J Cancer 2013;109:552). The Cancer and Leukemia Group B conducted a phase II study evaluating the role of gefitinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase in previously untreated patients with mesothelioma (Clin Cancer Res 2005;11:2300). Among the 43 enrolled patients, the response rate was 4% and median survival 6.8 months. EGFR expression was not correlated with response or survival. The tyrosine kinase inhibitor sunitinib targets the receptors of Vascular endothelial growth factor VEGF and Platelet-derived growth factor PDGF. A phase II study investigated sunitinib in patients progressive after systemic chemotherapy. Median time to progression was 3.7 months and median overall survival was 8.2 months (J Thorac Oncol2012;9:1449). Other investigational therapeutic strategies include proteasome inhibitors, mTOR inhibitors, HDAC inhibitors, and immune modulators such as thalidomide (J Natl Compr Cancer Netw 2012;10:42).
5. Prognosis. The prognosis for patients with mesothelioma is poor, with median survival of approximately 12 months from diagnosis. Factors associated with poor prognosis include advanced stage, poor performance status, male sex, chest pain, weight loss, thrombocytosis, leukocytosis, anemia, older age, and sarcomatoid histology. Two prognostic systems have been developed on the basis of data collection from patients enrolled into large cooperative group trials. In the European Organization for Research and Treatment of Cancer (EORTC) study, the risk factors identified were Eastern Cooperative Oncology Group (ECOG) performance status 1 or 2, white blood cells more than 8,300/µL, hemoglobin decrease equal to or greater than 1 g/dL, probable or possible diagnosis, and sarcomatoid histology (J Clin Oncol 1998;16:145). Patients were subdivided into two prognostic groups: good prognosis with up to two risk factors and poor prognosis with three or more risk factors. Outcomes were significantly better for patients in the good prognosis category, with improved median survival (10.8 months vs. 5.5 months), 1-year overall survival (40% vs. 12%), and 2-year survival (14% vs. 0%). In the Cancer and Leukemia Group B (CALGB) study, the significant risk factors included poor performance status, chest pain, dyspnea, platelet count greater than 400,000/mL, weight loss, serum lactate dehydrogenase (LDH) greater than 500 IU/L, pleural involvement, anemia, leukocytosis, and age above 75 years (Chest 1998;113:723). There were six identified prognostic subgroups with median survival times ranging from 1.4 to 13.9 months.
6. Background. Malignant mesothelioma is an aggressive tumor of the serosal surfaces. The incidence is increasing worldwide as a result of widespread exposure to asbestos. There are approximately 2,500 new cases per year in the United States. The main risk for the development of mesothelioma is exposure to asbestos. Although approximately 80% of patients with mesothelioma have a history of asbestos exposure, only approximately 10% of those exposed will develop mesothelioma.

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