Patients with suspected thymoma require routine screening blood work and chemistry testing, but diagnosis is usually based on clinical radiographic findings. Historically, biopsy confirmation of an anterior mediastinal mass was avoided due to concerns about needle tract seeding.^5,⁶ Treatment without biopsy confirmation remains controversial. The value of neoadjuvant therapy cannot be properly assessed without a pretreatment biopsy.⁷ Computed tomography (CT) scanning or ultrasound imaging can guide a fine-needle aspiration biopsy, though a core biopsy increases accuracy.⁸ Bronchoscopy, video-assisted thoracoscopic surgery, mediastinoscopy, or anterior thoracoscopy also may help to yield a diagnosis before resection.

Pulmonary carcinoid requires a similar workup. Transbronchial biopsy or CT- or ultrasound-guided fine-needle aspiration biopsy may establish the diagnosis preoperatively. The role of fluorodeoxyglucose–positron emission tomography (FDG-PET) remains controversial due to the relatively low glucose uptake of carcinoid tumors.⁹

Patients with suspected mesothelioma should be asked about a history of asbestos exposure. CT of the chest is needed. Although thoracentesis, percutaneous fine-needle aspiration, or ultrasound-guided core biopsy may yield the diagnosis, the most accurate method is video-assisted thoracoscopic biopsy.

PRIMARY THERAPY

Complete en bloc surgical resection is the treatment of choice for all thymomas, except in rare advanced cases with extensive intrathoracic or extrathoracic metastasis.

Curative resection of localized primary lung carcinoids is the treatment of choice. Endoscopic laser ablation may be used to palliate tumor obstruction, improve atelectasis, and reduce inflammation before resection.

Pleurectomy and extrapleural pneumonectomy (EPP) are extensive surgical procedures for mesothelioma. Patients require careful assessment to ensure that the operation will be tolerated physiologically.

ADJUVANT THERAPY

Encapsulated, noninvasive, stage I thymomas do not require adjuvant postoperative radiation therapy. Radiation therapy can be an effective adjuvant therapy for invasive thymomas. It is unclear whether all stage II thymomas benefit from adjuvant radiotherapy (RT).¹⁰

Typical carcinoids usually do not require adjuvant therapy after resection. Certain symptoms, including flushing, can be relieved by pharmacologic agents such as octreotide.¹¹ Adjuvant RT has been used in patients with large tumors (>3 cm), positive nodes, positive margins, atypical histologic findings, residual disease, and inoperable disease.

For mesothelioma, high-dose postoperative RT can dramatically reduce ipsilateral thoracic failures. Postoperative irradiation should include the entire volume immediately adjacent to the pleural space, but it is technically difficult to deliver.

LOCALLY ADVANCED DISEASE

Preoperative adjuvant RT and primary RT alone have each been advocated in thymoma patients with unresectable advanced disease. Chemotherapy may produce an improvement in overall survival (OS) rates. Chemoradiation may be appropriate for some patients with locally advanced unresectable malignant thymoma.

RT has been used adjuvantly or to palliate symptoms from locally advanced or metastatic carcinoids.

EPP followed by irradiation may provide better local control of mesothelioma than surgery alone.

PALLIATION

RT can provide effective palliation in patients with symptomatic metastatic or unresectable disease. Primary thoracic tumors can originate from any intrathoracic organ or tissue, producing cancers such as lung cancer, lymphoma, esophageal neoplasms, mediastinal tumors (i.e., thymic, neurogenic, and germ cell tumors), cardiac malignant diseases, pulmonary or bronchial carcinoid tumors, mesothelioma, and tracheal tumors. This chapter discusses only the less common neoplasms: thymic tumors, pulmonary carcinoids, and mesothelioma.

Thymic Tumors

The thymus gland is a bilobed lymphoepithelial organ located in the anterior mediastinum, behind the sternum and in front of the great vessels. In early life, the thymus functions in T-lymphocyte differentiation and maturation and releases T lymphocytes into the circulation. It weighs 12 to 15 g at birth and 40 g at puberty, and during adulthood, it slowly involutes and is largely replaced by adipose tissue. The thymus is composed of an outer cortex consisting primarily of epithelial cells, degenerated keratinized epithelial cells (Hassall’s corpuscles), myoid cells, thymic lymphocytes (“thymocytes”), and B lymphocytes, which form rare germinal centers.¹²

Although various tumors and cysts can arise in the thymus, tumors of the thymus are uncommon. Most thymic tumors arise in the epithelial cells of the thymus. They account for approximately 50% of anterior mediastinal masses.^13,¹⁴ The most common thymic tumors are thymoma, thymic carcinoma, and thymic carcinoids. Thymomas, 90% of which are found in the anterosuperior mediastinum, are commonly associated with myriad paraneoplastic syndromes. They are the most common tumor found in the anterior mediastinum.^13,¹⁵ Thymomas are associated with an exuberant lymphoid component composed of immature cortical thymocytes. Although they appear benign histologically, they may exhibit invasive behavior clinically.

Thymic carcinomas (i.e., type C thymomas) also arise in the thymic epithelium, but they have a higher propensity for capsular invasion and widespread metastases, especially those with features of high-grade malignancy. The histologic subtypes include clear cell carcinoma, sarcomatoid carcinoma, and anaplastic carcinoma. Low-grade thymic carcinomas (well-differentiated squamous cell carcinomas, basaloid carcinomas, and mucoepidermoid carcinomas) also exist and are characterized by a relatively more favorable clinical course, with a lower incidence of local recurrence and metastasis.^16,¹⁷

Neuroendocrine tumors of the thymus are rare, accounting for less than 5% of all neoplasms of the anterior mediastinum. Like carcinoids at other sites, they are thought to originate from endodermal cell (or foregut cellular) precursors. Unlike carcinoids in other locations, most thymic carcinoids behave aggressively. They often invade locally and commonly metastasize to regional lymph nodes.¹⁸ Approximately 50% of patients may develop endocrine abnormalities.¹⁹

Etiology and Epidemiology

The etiology of thymic tumors is largely unknown. There is a reported association between Epstein-Barr virus (EBV) infection and tumors of the thymus. For instance, thymic diseases are more common in Far Eastern countries, where the incidence of EBV infection is high.^20,²¹ Defective viral genomes have been isolated in patients with lymphoepithelioma-like thymic carcinoma.²¹^–²⁴ Childhood thymus irradiation has been linked to the development of thymic tumors,²⁵ and familial cases have been reported, suggesting a possible relationship with cytogenetic abnormalities.^26,²⁷ In an analysis of secondary or concomitant neoplasms in 1495 patients with acute lymphoblastic leukemia enrolled in two consecutive multicenter protocols, an increased risk of solid tumors was identified.²⁸ Although the histologic characteristics of these second malignant tumors varied, thymoma was among the solid tumors identified in an adult survivor of acute lymphoblastic leukemia. Among patients with primary thymic carcinoid tumors, up to 30% were reported in the setting of multiple endocrine neoplasia type 1 and 2.^29,³⁰ Other studies have reported a distinctive chromosome abnormality involving translocation of fragments of chromosomes 15 and 19 [t(15:19)(q15:p13)] in thymic carcinoma, particularly in young adults and pediatric patients with high-grade thymic carcinoma.³¹^–³³ Deletion of the short arm of chromosome 6 is associated with benign thymomas.³⁴ However, the molecular mechanisms of thymic tumor oncogenesis are largely unknown. Aberrations involving chromosome 6 suggest that several putative tumor suppressor genes may contribute to the pathogenesis of thymoma.³⁵

In a small study of 37 cases, most type A thymomas did not show any chromosomal aberration, whereas type B3 thymomas and thymic carcinoma (i.e., type C thymoma) shared some genetic aberrations, including the loss of chromosome 6 and the gain of chromosome 1q.³⁶ The loss of chromosome 6, on which the human leukocyte antigen locus and some of the tumor suppressor genes have been identified, and the gain of chromosome 1q, to which growth promoter genes have been mapped,³⁶^–³⁸ may play a role in tumorigenesis and pathogenesis of the paraneoplastic autoimmunity characteristics of thymoma. Such chromosomal aberrations have been implicated in a variety of human neoplasms.^39,⁴⁰

The true incidence of thymoma is unknown, and the annual incidence in the United States has not been well defined. The SEER program reported a thymoma incidence of 0.13 to 0.15 per 100,000 people.¹ Although thymomas are uncommon, they are the most frequently diagnosed mediastinal masses, representing approximately 30% of anterior mediastinal lesions and 20% of all mediastinal tumors in adults.^{13–15,42–45} Most patients with thymoma are between the ages of 40 and 60 years, with a median age of 52 years and an equal overall gender ratio.⁴⁶^–⁴⁹ Thymomas are less common in children, accounting for approximately 15% of anterior mediastinal masses.^15,⁴⁶^–⁴⁹

Thymic carcinomas are distinct from invasive thymomas both pathologically and clinically and carry a poorer prognosis.⁵⁰ They account for 5% to 36% of all thymic neoplasms.^51,52–54 The wide range in incidences from various studies reflects differences and changes in the pathologic classification of this rare tumor. Patients with thymic carcinoma are typically middle-aged or elderly, and there is a slight male predominance. Thymic carcinoids represent less than 5% of anterior mediastinum lesions^55,⁵⁶ and typically affect middle-aged men.¹⁶

Prevention and Early Detection

A few small subgroups of cases are associated with thymic irradiation during childhood, EBV infection (associated with lymphoepithelioid thymic carcinoma), or familial cytogenetic abnormalities; the etiologic factors for most thymic tumors are unknown, however, and there is no known mechanism for prevention. Thymomas are characterized by an indolent growth pattern with a tendency toward local invasion. Thymomas are associated with autoimmune disorders, particularly myasthenia gravis, in 30% to 45% of cases.^57,⁵⁸ Most thymic tumors are discovered incidentally because of abnormalities observed on routine radiographs or during evaluation for myasthenia gravis. Approximately 10% to 15% of patients with myasthenia gravis have benign or malignant thymomas.^{59,60,61–63} Thymic carcinomas and carcinoids are commonly detected incidentally. They are locally invasive and are found to have metastasized to regional lymph nodes and distant sites in up to 30% of patients at diagnosis.^18,52,64

Biologic Characteristics and Molecular Biology

Thymomas are usually slow-growing tumors with an indolent natural history. Although histologically benign, they spread by direct extension and are capable of local and regional invasion and have a marked tendency for recurrence in the mediastinum and pleura. Intrathoracic recurrence can develop after complete surgical resection in up to 40% of those with invasive disease.⁶⁵ Late relapse is not uncommon.^60,66,67 Metastases are typically confined to the pleura, pericardium, or diaphragm.⁶⁸ Nodal and hematogenous metastases may occur but are rare.^45,⁶⁹ An increased risk for second malignant tumors has been reported.^70,71,72

Patients with thymoma may have dysregulation of the lymphocyte selection process associated with abnormal proliferation, autoimmunity, and immunodeficiency. Thymoma-associated autoimmune disease involves an alteration in circulating T-cell subsets.⁷³^–⁷⁵ Up to 70% of thymomas may be associated with paraneoplastic syndromes.⁵¹ Various autoantibodies have been described.^76,⁷⁷ In addition to T-cell defects, B-cell lymphopenia has been observed in thymoma-related immunodeficiency along with hypogammaglobulinemia (i.e., Good’s syndrome).^78,⁷⁹

Factors influencing the different biologic behaviors of thymoma subtypes are poorly understood. Some pathologic features, such as altered expression of TP53 and BCL2,^80,⁸¹ counts of argyrophilic nucleolar organizer regions,^82,⁸³ proliferating cell nuclear antigen, matrix metalloproteinases, and Ki-67 index,^82,⁸⁴ are associated with biologic behavior, clinical stage, and prognosis.⁸⁵ There is a tendency for up-regulation of adhesion and co-stimulatory molecules in thymoma.⁸⁶^–⁸⁹ Altered TP53 expression may be implicated in the initial stages of tumorigenesis, and increased expression of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) may play a role in thymoma genesis.⁹⁰ A decreased OS time is predicted by Src kinase and TP53 co-expression.⁹¹ Recently, it has been proposed that a deficiency in the autoimmune regulator (AIRE) gene has an oncogenic effect on thymomas. AIRE expression is lacking in approximately 95% of thymomas; therefore loss of AIRE expression may provide a potential mechanistic link for the well-recognized association of autoimmunity with thymoma.^92,⁹³

Thymic carcinomas possess overt features of malignancy similar to those of carcinoma arising in any other organ, with a higher propensity for capsular invasion and metastases than invasive thymomas. Associated paraneoplastic syndromes occasionally exist with well-differentiated lesions.^94,⁹⁵ Most variants of thymic carcinoma are highly lethal, producing frequent metastases to regional lymph nodes, bone, liver, and lung.⁹⁶^–⁹⁸ Thymic carcinomas may express high levels of EGFR,^90,^99,¹⁰⁰ but EGFR gene mutations are rare.¹⁰¹ Tumor and serum levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) can be elevated,^102,¹⁰³ and correlations among such growth factors, angiogenesis, and invasiveness have been observed.^102,¹⁰⁴ Thymic carcinoma has been associated with increased expression of epithelial membrane antigen, cytokeratin subtypes, and TP53 protein.^80,¹⁰⁵^–¹⁰⁹ Somatic KIT gene mutations are present in some thymic carcinomas but not in thymomas.¹¹⁰ Increased expression of CD70 may serve as a marker for thymic carcinoma.¹¹¹ Other surface antigenic molecules, such as CD5 and CD99, have aberrant expression in thymic carcinoma.¹¹²^–¹¹⁴ Cytoplasmic phosphorylated AKT serine 473 and insulin-like growth factor-1 receptor (IGF-1R) are expressed in a higher proportion of recurrent tumors and more aggressive subtypes according to the World Health Organization (WHO) staging system. IGF-1R was associated with a worse progression-free survival time.¹¹⁵ Thymic carcinomas can be distinguished from lung carcinomas by negative expression of thyroid transcription factor-1¹⁰⁵ and a distinctly different cytokeratin profile.¹¹⁶ Additionally, although mutations in the TP53 gene are common in lung carcinoma, TP53 gene mutation was not found in any of seven examined thymic carcinomas.¹¹⁰

Thymic carcinoids have a similar malignant clinical course with a poor prognosis, frequently worse than carcinoids of the gastrointestinal tract. They may secrete peptides, amines, kinins, prostaglandins, or other substances. In a study of 80 patients with thymic carcinoids, 74% were male, 72% had related symptoms, 6% had Cushing’s syndrome, and 16% had other endocrine abnormalities.¹¹⁷ Even after complete resection, recurrence is common (range, 36% to 87% of patients).^18,117,118 OS rates were only 28% and 10% at 5 and 10 years, respectively.

Pathology and Pathways of Spread

There is no direct correlation between the histopathology of thymomas and their malignant potential.^49,^119,¹²⁰ However, an accurate histologic diagnosis is still crucial in patient management.

The histologic diagnosis of thymoma can be difficult, and a variety of systems have been proposed. The WHO classification, developed in 1999 and revised in 2004, is now the most widely accepted one. Tumors with true malignant cytologic characteristics are usually considered to be thymic carcinomas rather than thymomas. Malignant thymomas invade the capsule macroscopically or microscopically, with typically “bland” cytologic characteristics of thymic epithelial cells admixed with mature lymphocytes. The term invasive thymoma should be used instead of malignant thymoma to denote the tumor’s predilection for capsular invasion.

Grossly, thymomas are nodular, multilobulated, and firm. They may contain cystic spaces, calcification, or hemorrhage, and they may be neatly encapsulated, adherent to surrounding structures, or invasive. Thymomas generally display two cell types: epithelial and lymphatic cells. They are classified as predominantly epithelial, predominantly lymphocytic, mixed lymphoepithelial, or spindle cell type. Morphologically, these cells are rather large and may be round, oval, or spindle shaped with vesicular nuclei and small nucleoli. The cytoplasm is often eosinophilic or amphophilic. Thymic neoplasms arise from epithelial cells (Fig. 44-1). The lymphocytic component is mostly made up of normal-appearing mature lymphocytes. Some of the other microscopic features that may be seen in thymomas include Hassall’s corpuscles, keratinizing squamous epithelium, rosettes, glands, cysts, papillary structures, and germinal centers. Immunohistochemistry testing is often helpful in making the diagnosis. Thymomas typically stain positive for a number of thymic epithelial markers, including cytokeratin, thymosin ß3 and α1, and epithelial membrane antigen.

Figure 44-1 Lymphocyte-rich thymoma with dense lymphocytic cell population containing scattered larger epithelial cells with pale cytoplasm surrounding perivascular spaces. A, Low power (×100). B, High power (×400).

Thymic carcinoma histologic characteristics are more diverse. The tumor is cytologically malignant, and the largest proportion of cases have squamous cell histologic findings. Other subtypes include lymphoepithelioma-like carcinomas, clear cell carcinomas, sarcomatoid carcinomas, adenosquamous carcinomas, mucoepidermoid carcinomas, adenocarcinomas, and basaloid squamous cell carcinomas.¹⁶ Their histologic appearances are not different from carcinomas in other sites.¹²¹

The histologic features of thymic carcinoids are identical to carcinoid tumors in other organs. Unlike thymomas, they are rarely encapsulated. Immunohistochemically, they may stain positively with CAM 5.2, low-molecular-weight cytokeratins, chromogranins, synaptophysin, and leucine-7.¹¹⁷

The predominant pattern of spread of thymomas is by direct invasion into adjacent organs. The degree of encapsulation and the invasion of adjacent tissues define malignancy for these tumors rather than the histologic appearance.⁶⁶ Approximately 50% of cases in surgical series are noninvasive.* Thymomas may metastasize as implants on pleural surfaces or pulmonary nodules, but they rarely metastasize to extrathoracic areas.⁴⁵ When thymomas metastasize, the most common site is the pleural cavity, in which they form pleural plaques, malignant pleural effusions, and diaphragmatic masses. Invasion into the superior vena cava, brachiocephalic vein, lung, and pericardium may be observed.¹²⁷

Thymic carcinomas invade locally, often involve the pleura and mediastinal nodes, and sometimes spread regionally to the cervical and axillary lymph nodes.¹²⁸ Distant metastases to the lungs, liver, brain, and bone also occur. Distant metastases to bone, liver, or skin occur in 30% to 40% of cases of thymic carcinoids,¹⁹ and they may be seen in 70% of patients within 8 years from initial diagnosis.¹²⁹

Clinical Manifestations and Patient Evaluation

Approximately 30% to 40% of patients with thymomas, thymic carcinomas, or carcinoids are asymptomatic and are discovered incidentally.^45,^48,^58,¹³⁰ Clinical symptoms vary greatly, depending on the size of the tumor and effect on adjacent structures, but they are usually those of a mediastinal mass producing cough, chest pain, dyspnea, hoarseness, superior vena cava syndrome, and symptoms related to tumor hemorrhage.^16,^131,¹³² Patients may also have dysphagia, fever, weight loss, and anorexia.

Some thymomas present with symptomatic paraneoplastic syndromes; the most common is myasthenia gravis, which is seen in approximately 45% of patients.⁵⁸ Box 44-1 lists other syndromes.* Thymic carcinoids may also be associated with Cushing’s syndrome, Eaton-Lambert syndrome, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and hypercalcemia,¹⁹ but the classic carcinoid syndrome is rare. The causes of these syndromes remain obscure, although autoantibodies have been demonstrated, mostly in thymoma patients.^76,^77,¹³⁷

Box 44-1 Paraneoplastic Diseases Associated with Thymoma

• Addison’s disease

• Carcinoid syndrome

• Chronic mucocutaneous candidiasis

• Cushing’s syndrome

• DiGeorge syndrome

• Erythroid and neutrophil hypoplasia

• Hashimoto’s thyroiditis

• Hyperparathyroidism

• Hyperthyroidism

• Hypertrophic osteoarthropathy

• Hypogammaglobulinemia

• Lambert-Eaton syndrome

• Lupus erythematosus

• Myasthenia gravis

• Myocarditis polyarthropathy

• Myotonic dystrophy

• Myotonic dystrophy scleroderma

• Rheumatoid arthritis

• Sarcoidosis

• Sjögren’s syndrome

• Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

• Ulcerative colitis

• Whipple’s disease

Myasthenia gravis is an autoimmune neuromuscular junction disorder characterized by the presence of antiacetylcholine receptor antibodies, which cause an acetylcholine receptor deficiency at the motor end plate. The disease is characterized by rapid exhaustion of voluntary muscular contractions, with a slow return to the normal state.^138,¹³⁹ Myasthenia gravis is common with thymoma but rare in thymic carcinoma. Patients with thymoma and myasthenia gravis may have an increased operative mortality rate, and most surgical deaths are attributed to myasthenic crisis. Death of patients with thymoma and myasthenia gravis is commonly caused by complications of myasthenia gravis, whereas in patients without myasthenia gravis, death often is attributed to local progression of tumor.¹²⁴ The overall long-term prognosis does not appear to be adversely affected by the presence of myasthenia gravis.^60,¹²⁴

Prognostic Factors

The two most important prognostic factors for thymoma are invasiveness (stage) and completeness of surgical resection.† Capsular invasion is commonly used as the basis for designation as benign or malignant. Tumor size (>10 cm) and the presence of symptoms also have prognostic value.^43,^143,¹⁴⁴ Patients with complete or radical excision have significantly improved survival times over those with subtotal resection or biopsy only.^141,145 Although almost all noninvasive thymomas can be totally resected, the ability to achieve a complete resection in invasive cases varies from 58% to 73%.^60,125,141 Older series reported a poor prognosis associated with myasthenia gravis,^46,^47,¹²⁶ but several modern series have failed to confirm this observation.* Myasthenia gravis may even confer a survival advantage because neuromuscular symptoms may lead to earlier discovery of a small thymoma.^143,^152,¹⁵³ After thymectomy, patients with myasthenia gravis have attenuation of the severity of symptoms over time but not necessarily complete resolution of them.¹⁵⁴^–¹⁵⁶ About 50% of patients with pure red cell aplasia have thymoma, and about 10% of patients with hypogammaglobulinemia have thymoma. Patients with red cell aplasia, hypogammaglobulinemia, and lupus erythematosus appear to have a poorer prognosis.^{124,143,152,157}

Although the degree of tumor invasiveness is strongly related to stage and prognosis of thymoma, there are data to support the prognostic significance of the histologic findings, independent of tumor stage.146,158,159 The historical classification proposed by Marino and Muller-Hermelink categorized thymoma as cortical, mixed, and medullary types.¹⁶⁰ Thymomas arising from the epithelial cells of the cortex were classified as cortical thymomas, and those arising from the medullary spindle cells were classified as medullary thymomas. According to the Marino and Muller-Hermelink data, cortical thymomas have a more aggressive course than medullary thymomas and are more likely to be associated with myasthenia gravis. Of note, thymic carcinomas were categorized as a separate entity.

In 1999, the World Health Organization (WHO) published a classification including six subtypes of thymic tumor, based on the relative proportion of epithelial and lymphocytic cells (Box 44-2). This is the most widely accepted histologic classification system, and data have shown that the WHO cell type is an independent prognostic factor.^{159,161,162,163} A retrospective study of 324 patients found that patients with WHO types A, AB, and B1 had a 100% disease-specific survival rate without RT and therefore did not benefit from adjuvant RT.¹⁶⁴ There was no survival difference for cell types B2 and B3 with or without adjuvant RT. Another series, from Reiker and colleagues,¹⁶⁵ noted that survival rates of patients with types A, AB, B1, and B2 were better than rates for type B3, and that type C had the lowest OS rates. The prognostic value of the subtype of type B thymomas has been examined by one series that found no significant differences in recurrence or survival rates among the three subtypes of type B, but all patients who recurred had stage III disease, indicating that the Masaoka stage was predictive.¹⁶⁶ The risk of myasthenia gravis increases progressively with WHO type from A (~20%) to B3 (~60%).⁹³

Box 44-2 World Health Organization Classification of Thymic Epithelial Tumors

Type	Pathologic Classification	Prognosis
A	Medullary thymoma	Benign clinical course
	Spindle cell thymoma
AB	Mixed thymoma
B1	Lymphocyte-rich thymoma	Moderately malignant clinical course
	Lymphocytic thymoma
	Predominately cortical thymoma
	Organoid thymoma
B2	Cortical thymoma
B3	Epithelial thymoma
	Atypical thymoma
	Squamoid thymoma
	Well-differentiated thymic carcinoma
C	Thymic carcinoma	Highly malignant clinical course

Tumors that are mixed tend to have an intermediate prognosis.¹⁶⁷ The 10-year survival rates are approximately 100% for medullary thymomas, 76% for mixed thymomas, and 45% for cortical and well-differentiated thymomas.¹⁶⁷^–¹⁷⁰ In one series, no medullary and mixed thymomas (types A and AB) recurred, even though 30% had capsular invasion. Organoid and cortical thymomas (types B1 and B2) showed intermediate invasiveness and a low but significant risk of late relapse, even with minimal invasion.^29,159

Associated paraneoplastic syndromes occasionally exist with well-differentiated thymic carcinomas.^94,⁹⁵ However, clinical features have not proved useful as prognostic indicators for thymic carcinomas.¹⁵⁹ As with thymomas, total resection and stage at presentation are important prognostic factors for thymic carcinoma.¹⁸

Diagnostic Workup for Thymic Tumors

The diagnostic workup of a patient with an anterior mediastinal mass begins with a thorough history and physical examination. Particular focus should be given to detect signs and symptoms that may suggest myasthenia gravis, such as fatigue, diplopia, ptosis, and dysarthria. Constitutional symptoms such as fever, chills, and weight loss are more suggestive of lymphoma. Routine screening blood work and chemistry testing may give clues to the presence of associated syndromes. In the case of suspected Cushing’s syndrome, seen in 1% to 2% of patients, a dexamethasone suppression test and urinary cortisol level should be obtained., although some carcinoids can be suppressed, making diagnosis difficult. The differential diagnosis, in addition to thymic lesions, includes germ cell tumors, lymphomas, and thyroid proliferative disorders. Serum alpha-fetoprotein and beta-human chorionic gonadotropin levels should be obtained in young men if a nonseminomatous germ cell tumor is suspected.¹⁷¹^–¹⁷³ Exclusion of extrathymic primary tumors is important because carcinomas and carcinoids are rare in the thymus and may represent metastases.

The chest radiograph often demonstrates a mass in the hilar region that may be mistaken for the heart border or pulmonary artery (Fig. 44-2). CT defines^174,¹⁷⁵ the size, contour, tissue density, and homogeneity of a mediastinal lesion, as well as its relation to or invasion of other mediastinal structures. A CT scan with intravenous contrast dye is preferred to delineate the relationship between the thymoma and surrounding structures and to define the degree of the tumor’s vascularity. Thymic tumors are usually homogeneous, well-demarcated lesions with a round or lobulated shape, and they vary in size and occasionally have calcification¹⁷⁶ (Fig. 44-3). The presence of fat planes between the tumor and adjacent structures suggests localized disease. Pleural involvement may be seen in advanced disease. The radiographic presence of both an anterior compartment mass as well as “drop” metastases to the pleura is highly suggestive of the diagnosis. Thymic carcinomas often contain calcifications, cysts, or necrosis on imaging.¹⁷⁷ In the absence of symptoms and signs, extensive radiographic imaging is unnecessary. Magnetic resonance imaging (MRI) has not been superior to CT scanning.¹⁷⁸ The role of positron emission tomography (PET) has not been established, but early data suggest it can differentiate thymoma from thymic hyperplasia, and high uptake of fluorodeoxyglucose appears to correlate with the degree of tumor invasiveness.¹⁷⁹^–¹⁸¹

Figure 44-2 A, Anteroposterior chest radiograph demonstrates a mass (arrow) projecting over the left hilum. B, Lateral chest radiograph confirms the location of the mass in the anterior mediastinum.

Figure 44-3 Computed tomography (CT) demonstrates a mass (arrow) with calcification in the anterior mediastinum. A, Axial view. B, Coronal view.

Patients presenting with a thymic mass need a histologic diagnosis before definitive therapy is instituted. CT- or ultrasound-guided fine-needle aspiration biopsy of the mass may be performed to establish the diagnosis preoperatively.¹⁸² Such procedures have a sensitivity and specificity of 87% to 90% and 88% to 100%, respectively, for thoracic neoplasms.¹⁸³ When larger tumor samples are required to distinguish between lymphoma and lymphoid-predominant thymoma, core-needle biopsy provides sufficient specimens with an overall sensitivity of 96% and specificity of 100%.¹⁸³ Bronchoscopy, video-assisted thoracoscopic surgery, mediastinoscopy, or anterior thoracoscopy may help yield the diagnosis before resection, especially if enlarged lymph nodes are present.^172,^184,¹⁸⁵ The potential risk of breaching the capsule, leading to spillage and seeding of tumor cells during biopsy, has been debated and remains unsettled.^136,^186,¹⁸⁷

Staging

Bergh and associates ¹²² introduced the first clinical staging system for thymoma in 1978. Their staging system was subsequently modified and refined by Masaoka and associates in 1981¹⁴¹ and is the most widely accepted (Box 44-3). It is based on pathologic findings at time of surgery.

Box 44-3

Masaoka Staging System for Thymoma

Stage	Description
I	Macroscopically completely encapsulated with no microscopic detectable capsular invasion
II	Macroscopic invasion into surrounding mediastinal fatty tissue or mediastinal pleura or microscopic invasion into the capsule
III	Macroscopic invasion into surrounding organs (e.g., pericardium, great vessels, lung) or intrathoracic metastases, or both
IVA	Pleural or pericardial implants or dissemination
IVB	Lymphogenous or hematogenous metastases

Adapted from Masaoka A, Monden Y, Nakahara K, Tanioka T: Follow-up study of thymomas with special reference to their clinical stages, Cancer 48:2485-2492, 1981.

A separate, simplified staging paradigm was proposed by Suster and Moran.¹⁸⁸ Stage I lesions are localized and encapsulated; stage II lesions are locally invasive; and stage III lesions have nodal, visceral, or distant metastasis. A tumor-node-metastasis (TNM) type of staging system was proposed by Tsuchiya and associates¹⁸⁹ but has not been proved clinically, and it is not widely accepted. There is no formal American Joint Committee on Cancer (AJCC) staging system for thymoma.

Treatment

Surgery for Thymoma

Surgery is the mainstay of therapy in resectable cases. However, adjuvant or neoadjuvant radiation therapy plays an important role in subtotally resected or unresectable cases. Many patients who present with symptoms of myasthenia gravis benefit from undergoing a thymectomy.¹⁵¹ Consequently, surgical resection alone for stage II thymomas, in the hands of an experienced team, is a reasonable approach.^190,¹⁹¹ In general, surgical resection for thymoma carries low risks of morbidity and mortality; most surgical deaths can be attributed to a myasthenia gravis crisis, but the risk can be minimized with appropriate perioperative management, including plasmapheresis, in selected situations.^124,192 After an encapsulated thymoma without associated myasthenia gravis is removed without disturbing the integrity of the capsule, recurrences have been observed, but they are rare.^{46,60,123,193}

Successful surgical treatment of locally invasive thymoma depends on the completeness of resection.¹⁹⁴ Consequently, the surgeon should remove as much of the lesion as possible, including surrounding mediastinal fat, possibly to include an extended thymectomy.¹⁹⁵ However, resection of an involved phrenic nerve is controversial, and surgeons advocate debulking alone, leaving both phrenic nerves intact if there is bilateral phrenic nerve involvement, because of the respiratory morbidity that would result from resection. When complete resection is not possible, a debulking operation should be considered, because good long-term results can be achieved when such surgery is followed by postoperative radiation therapy.¹²⁴ Only about one-fourth of patients with stage IVA disease have resectable disease.⁵⁸ Surgical approaches have varied from discrete resection of pleural metastases to en bloc mediastinal dissection with EPP.¹⁹⁶ A few small single-institution series have suggested that EPP may improve local control rates.¹⁹⁶^–¹⁹⁸ The surgeon should delineate the extent of the tumor, specify the areas of invasion, and identify the areas of positive or questionable margins and residual disease with metallic clips to assist future radiation therapy planning.

Radiation Therapy for Thymoma

Although the role of adjuvant irradiation for invasive thymomas has never been tested in a prospective, randomized fashion, there is general agreement that RT is an effective adjuvant therapy for invasive thymomas,¹⁹⁹ and most retrospective studies have reported improvements in local tumor control and survival rates after adjuvant irradiation.* However, patients with encapsulated, noninvasive stage I thymoma do not require postoperative RT after complete resection, because the recurrence rate is approximately 0% to 2%.†

For patients with Masaoka stage II disease, there is controversy about whether postoperative RT should be used for completely resected invasive thymomas. A meta-analysis of 22 studies with 592 patients with completely resected stage II or III thymoma found no reduction in recurrence after adjuvant RT,²⁰³ but it is difficult to draw firm conclusions from the available data, particularly given the selection bias in retrospective series as to which patients received RT. Berman and colleagues¹⁰ reported a single-institution retrospective cohort comparison of 74 stage II thymoma patients after complete surgical resection. Patients who were thought to be at high risk for local recurrence by the operating surgeon and the thoracic oncology team were referred for adjuvant RT. The rate of locoregional recurrence was 8% in patients who were observed versus 0% in the RT group (p = .15). The researchers concluded that the rates of recurrence after complete resection of stage II thymoma were low and that no benefit of postoperative RT was observed in stage II thymoma patients as a group; however, a higher-risk subset of these patients may benefit from adjuvant therapy.¹⁰ Although some studies showed no benefit from adjuvant RT,^{164,190,191,204} the recurrence rates of surgery alone, even with complete resection, may approach 30%.^65,143 A SEER study of 901 patients showed a 10% absolute improvement in 5-year OS rates but no statistical difference in cause-specific survival rates in patients with stage II to III disease.²⁰⁴ In cases with gross fibrous adhesions of the tumor to the pleura at the time of surgery or microscopic invasion of the pleura on histologic studies, there is an increased risk for recurrence. Haniuda and colleagues^202,206 found that patients with fibrous adhesion to the mediastinal pleura without microscopic invasion benefited most from postoperative radiation therapy. The recurrence rates, with and without adhesion to the mediastinal pleura, were 36% and 0%, respectively. In another study by Monden and colleagues,⁷⁰ patients with resected stage II thymoma had recurrence rates of 8% and 29%, respectively, with and without adjuvant radiation therapy. Although postoperative radiation therapy may decrease local recurrence, it does not appear to decrease the incidence of subsequent pleural dissemination that may occur outside of radiation fields; in fact, the pleura is the most common site of failure after radiation.²⁰² This may be a reflection of the natural pattern of spread of this disease, with pleural dissemination occurring before, during, or after the time of surgery. Extended irradiation to include the entire pleura significantly increases the normal tissue toxicity and is not routinely employed.

Locally Advanced Thymoma and Palliation

For patients with stage III to IV disease, the evidence supporting the use of postoperative radiation therapy is robust. Urgesi and colleagues ¹⁴⁰ reported no in-field recurrences in a study of 33 patients with completely resected stage III thymoma treated with postoperative irradiation. Curran and associates⁶⁵ reported a 53% 5-year actuarial mediastinal relapse rate with stage II and III patients after surgery alone, compared with 0% after total resection and irradiation and 21% after subtotal resection or biopsy and irradiation. Similarly, in a study of 70 patients with Masaoka stage III to IV thymoma, the relapse rate for patients receiving postoperative radiation therapy was reduced from 50% to 20%, and most disease (80%) recurred outside of the irradiated field.²⁰⁷

Preoperative adjuvant radiation therapy has been advocated for unresectable or marginally resectable thymomas.^46,^71,^72,²⁰⁸ Several small studies assessing preoperative radiation therapy for extensive disease found a decrease in tumor burden at the time of surgery, with response rates as high as 80%, and described a theoretical decrease in the potential for tumor seeding during surgery.^{65,124,209,210} Onuki and colleagues²¹⁰ found that a dose of 12 to 20 Gy given to 21 patients with stage III thymomas resulted in a 76% response rate, with more aggressive WHO histologic subtypes having a less robust volume reduction. These series demonstrated that preoperative irradiation facilitated total or subtotal resection of the invasive thymoma mass by reducing the tumor volume.²⁰⁸

Primary radiation therapy alone as the definitive treatment has been advocated in nonsurgical candidates or patients with unresectable advanced disease. In a study of 12 patients who presented with unresectable tumors and were treated with primary radiation therapy, 7 patients were alive 1 year 8 months to 5 years 1 month later.²¹¹ Similar outcomes were reported for 31 patients with unresectable stage III or IV disease.²¹² Five-year survival rates of 53% to 87% and 10-year survival rates of 44% were reported for patients with advanced thymoma receiving irradiation after biopsy only or incomplete resection.^213,²¹⁴ Urgesi and associates²¹⁵ reported the use of radiation therapy alone in 21 patients with intrathoracic recurrences of thymoma. The 7-year survival rate of 70% was similar for those treated with irradiation alone and those treated with surgery and adjuvant therapy. However, the retrospective nature of these studies, small number of patients, differing amounts of clinical disease, and variations in radiation doses and techniques are significant confounding variables.

The role of preoperative and primary radiation therapy alone has fallen out of favor. Because of the improved response rates to chemotherapy, most patients with advanced disease are treated with a combined-modality approach.

Chemotherapy for Thymoma

In general, thymomas are chemosensitive tumors, and chemotherapy is reserved for locally advanced or metastatic disease. Numerous case reports and small series have reported antineoplastic activity for multiple and single agents in the treatment of patients with advanced thymoma.* However, there are no reported prospective, randomized trials comparing different chemotherapeutic agents.²³³ Platinum-based regimens have commonly been used over the past decade, with response rates ranging between 24% and 100%, and response rates of more than 50% have been found consistently with the application of cisplatin-based combination chemotherapy.²³⁴ Some of the commonly employed combinations are cisplatin, doxorubicin, and cyclophosphamide (PAC), with reported overall responses in excess of 70%,²³⁵^–²³⁷ and cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC).²³⁸ In a study by Fornasiero and colleagues,²²² 37 patients with stage III or IV thymoma were treated with ADOC, with an overall response rate of 92% and a 43% complete response rate. Loehrer and associates²³⁵ studied 23 patients with localized but unresectable thymomas treated with PAC followed by radiation therapy. The overall objective response rate was 70%, with five complete responders.²³⁹ The estimated 5-year disease-free survival rate was 54%, with a median survival time of 93 months. Multivariate analysis demonstrated that chemotherapy was associated with an improvement in OS rates for patients with stage III and IV disease. Similar results with combination PAC have been reported in Taiwan; all responders had overexpression of the topoisomerase 2α gene, but patients with no detectable expression progressed with treatment.²³⁹

Combined-Modality Therapy for Thymoma

The role of chemotherapy as an adjuvant therapy after resection has not been established, but there is anecdotal evidence that combining chemotherapy with irradiation with or without surgery can be effective with acceptable toxicity in selected cases.230,240,241,242 It has also been shown that neoadjuvant chemotherapy and then surgery, followed by additional chemotherapy and irradiation, may improve the resectability and survival rates of the patients with locally advanced disease.²⁴¹

In a phase II study of 22 patients with unresectable thymoma treated with induction PAC resection, adjuvant irradiation, and consolidative chemotherapy, there was a 77% response rate to chemotherapy, a 95% 5-year OS rate, and a 79% 7-year OS rate.²³⁷ A trial from the Japanese Clinical Oncology Group reported on 23 patients with unresectable stage III thymoma treated with weekly dose-dense cisplatin, vincristine, doxorubicin, and etoposide and found no deaths from toxicity, but only 57% were able to complete chemotherapy as planned.²⁴³ Thirteen of the patients were able to undergo resection, with nine R0 resections. With a 62% response rate, efficacy of the dose-dense regimen was no better than with conventional chemotherapy.^235,²³⁷

In a study by Macchiarini and colleagues,²³⁰ all seven patients with stage III invasive thymoma treated with neoadjuvant cisplatin, epirubicin, and etoposide were able to undergo surgical resection. Four had complete resections, and three had incomplete resections. Shin and colleagues²⁴⁰ reported that 9 of 11 patients with unresectable stage III and IV thymoma were able to undergo complete resection after induction chemotherapy consisting of cyclophosphamide, doxorubicin, and cisplatin. All nine patients were given additional postoperative radiation therapy and chemotherapy. Of these patients, seven were disease free at a median follow-up time of 43 months. Wright and associates²⁴⁴ reported on 10 patients with stage III to IVA thymoma treated neoadjuvantly with two cycles of cisplatin and etoposide and concurrent irradiation followed by surgery. Eight patients had R0 resections, and the 5-year survival rate was 69%.

Results of Thymoma Treatment

There are no large prospective, randomized, phase III clinical trials to evaluate the efficacy of primary or adjuvant radiation therapy in patients with invasive thymoma, but multiple retrospective reviews have suggested that RT reduces recurrence rates and improves outcomes for incompletely resected stage II to III thymomas. The role of postoperative RT for completely resected stage II to III thymomas is controversial. The local control rates after a complete resection and adjuvant radiation therapy have ranged from 65% to 100%, and rates are lower for incomplete resection and radiation therapy.* Curran and coworkers⁶⁵ reported a retrospective study of patients with stage II or III thymoma. Twenty-six percent (20 of 78) of the patients treated with surgery alone developed local recurrences, compared with 5% (2 of 43) of similar patients who had received postoperative radiation therapy. There was no significant difference in relapse rates or survival rates between patients undergoing biopsy and radiation therapy and those having subtotal resection and radiation therapy. The investigators reported a 5-year actuarial mediastinal relapse rate of 53% for patients treated with total resection alone, compared with no relapses in patients who received postoperative irradiation after total resection. Contrary to most studies, Kondo and Monden¹⁸ reported a multi-institutional, retrospective study of 1320 patients with thymic epithelial tumors and found no significant difference in the recurrence rates between two groups with stage II or III thymoma, one of which underwent surgery alone and the other surgery plus adjuvant irradiation. This observation may reflect the fact that most of the patients underwent complete resection (100% with stage II disease and 85% with stage III disease); as has been pointed out by the study authors, the recurrence rates they found were lower than in previous reports.

Postoperative radiation therapy has resulted in improved survival rates for patients with invasive thymomas after complete and incomplete resections.²³³ In a study of 141 patients with thymoma, Nakahara and associates¹²⁵ reported a 5-year survival rate of 92% for patients with stage II disease and 88% for patients with stage III disease who were treated with postoperative irradiation. Patients undergoing radical surgery with complete resection before adjuvant radiation therapy often had substantially better local control and 5-year survival rates compared with those undergoing biopsy alone or limited tumor resection.^{124,125,209,246}

After complete resection, invasive thymomas still tend to carry a poorer prognosis than noninvasive tumors.^47,^233,²⁴⁷ Survival rates continue to fall with long-term follow-up, and 10-year survival rates may be considerably lower.¹⁴⁹ The 5-year and 10-year survival rates for well-encapsulated thymomas without invasion are more than 90%, and for invasive thymomas, the rates range from 30% to 70%† The 5-year survival rates according to Masaoka stage are 83% to 100% for stage I disease, 86% to 98% for stage II disease, 68% to 89% for stage III disease, and 50% to 71% for stage IV disease.^{18,68,141,248} The approximate 10-year survival rates are 80%, 78%, 47%, and 30%, and the 15-year rates are 78%, 73%, 30%, and 8% for stages I to IV, respectively.⁶⁸ Table 44-1 provides a summary of treatment results.

TABLE 44-1 Summary of Adjuvant Therapy Results of Thymoma

Anecdotal studies have demonstrated good local control of thymomas treated with primary irradiation. Of 23 patients treated with irradiation alone, 8 had complete regression, 10 had partial regression, and 5 had no regression of disease.⁴⁶ In a report by Marks and colleagues,²⁴⁹ tumor was controlled in all nine cases treated with megavoltage irradiation. The average follow-up was 5.5 years (minimum, 30 months). Ariaratnam and associates²⁵⁰ observed tumor control in 8 of 11 patients with malignant thymoma with a minimum follow-up of 2 years. Two of the three patients who died had received only 30 Gy in 3 weeks to the mediastinum. Overall, irradiation as monotherapy may result in local control rates of approximately 65% and 5-year survival rates of 40% to 50%.^213,^214,²³³

In patients with mostly advanced thymoma, the results of combination chemotherapy with or without surgery or irradiation are encouraging, with an overall response rate of approximately 60%.^222,^224,²³⁶ All patients who achieved a pathologic complete response had received cisplatin-containing regimens. An intergroup study of 26 patients with unresectable disease treated with two to four cycles of PAC followed by RT (54 Gy) in those without progression was well tolerated. There was a 70% response rate to induction chemotherapy and a median survival rate of 93 months, and a 53% 5-year OS rate, which compares well with neoadjuvant chemotherapy followed by resection.²²⁹

Treatment of Thymic Carcinoma

Although the optimal treatment of thymic carcinoma is unclear, surgical extirpation remains the cornerstone of therapy, and in most published studies, surgery has been followed by adjuvant radiation therapy.^17,^64,²⁵¹^–²⁵³ Because many series are gathered over decades, it has been difficult or impossible to control for the changes in pretreatment tumor imaging, surgical techniques, and thoracic radiation therapy planning and delivery, all of which may contribute to the inconsistent results in the literature. A prescriptive dose range has yet to be identified, with most studies using 40 to 70 Gy with a standard fractionation scheme (1.8 to 2 Gy per fraction), but in general, doses of 45 to 55 Gy are used in the adjuvant setting, whereas 60 Gy or more is used for definitive irradiation. Although a survival benefit has not been seen, there is a trend toward improved survival and local control rates with adjuvant therapy.^17,²⁵² No dose-related survival advantage has been established, although a relationship between dose and local control rates has been demonstrated.²⁵⁴

In a series of 26 patients treated with surgery and postoperative irradiation, Hsu and associates ²⁵² observed a 77% 5-year OS rate, with respective 82% and 66% survival rates for completely resected and subtotally resected cohorts. With a median dose of 60 Gy (range, 40 to 70 Gy), an excellent 5-year local control rate of 91% was observed. For a cohort of 40 patients receiving definitive or adjuvant radiation therapy, Ogawa and associates¹⁷ reported an absence of local recurrence for those with complete resection and radiation doses greater than 50 Gy. Kondo and Monden¹⁸ reported the largest retrospective, comparative study and found no statistically significant survival benefit from the addition of adjuvant irradiation to surgical resection, although the study authors stipulated that no definitive conclusions could be made regarding the role of adjuvant radiation therapy because of subgroup sample size limitations and the retrospective nature of the study.

Although local control rates are increased with irradiation, a survival benefit remains to be demonstrated. For patients with any question of clinical resectability, neoadjuvant platinum-based chemotherapy is a reasonable treatment consideration.²⁵⁵ Table 44-2 summarizes some of the treatment results of thymic carcinoma.

TABLE 44-2 Summary of Thymic Carcinoma Treatment Results

Treatment of Thymic Carcinoid

Complete surgical resection is the preferred method of treatment, although recurrence and distant metastases are common.18,256,257 A SEER analysis of 160 patients found that the median survival time was 79 months in patients who had surgical resection compared with 26 months in those who did not have surgery Patients who received irradiation had a worse OS rate, but patients who received irradiation were more likely to have advanced disease.²⁵⁷ In a study of 40 patients, the recurrence rate was 64%, even though 35 of the 40 patients had a complete resection,¹⁸ and the 5-year survival rate was 84%. Despite a lack of conclusive evidence, incomplete resections followed by irradiation or chemotherapy, or both, may improve local control rates without significantly increased morbidity and mortality rates.^55,^129,²⁵⁸^–²⁶⁰ However, distant metastases occur in approximately 30% of patients.²⁶⁰ The long-term prognosis is poor, with an overall 5-year survival rate of 0% to 31%.^256,²⁶¹

Techniques of Irradiation

High-energy (>10-MV) x rays usually are preferred for irradiation. A CT scan is indispensable for adequate treatment planning. Clips placed at the time of surgery denoting the extent of resection in completely resected tumors or outlining regions of residual disease are useful in guiding postoperative irradiation. The planning target volume (PTV) should include the gross tumor volume (GTV) and the thymus, if any, and the tumor bed with a 1.5- to 2-cm margin. A four-dimensional breathing scan, if available, should be used to determine tumor motion. This information can be used to create an internal target volume (ITV) or to plan for radiation-coordinated breathing control, wherein the patient is treated only during a particular phase of the breathing cycle. Although the latter approach requires significant patient training and cooperation, it can provide superior sparing of normal lung.²⁶² Depending on histologic and surgical findings, areas of suspicious subclinical disease and regional lymphatics are commonly included. However, treatment of the entire mediastinal and supraclavicular nodal basin prophylactically is not advised, because of the low incidence of lymph node involvement and a higher normal tissue complication rate when large target volumes are used.^235,^245,^263,²⁶⁴ A SEER database analysis of 1334 patients from 1973 to 2005 by Fernandes and colleagues²⁶⁵ found no increase in long-term cardiac mortality rates or rates of secondary malignant tumors for patients treated with RT compared with patients treated with surgery alone.

Conventional port arrangements may include a single anterior port, two opposed anteroposterior ports (weighted 2 : 1 or 3 : 2), wedged-pair techniques, and other multiple-field arrangements. Given the advanced technical capabilities available, three-dimensional conformal RT (3DCRT) or intensity-modulated radiation therapy (IMRT) should be considered to provide dose homogeneity and allow better sparing of normal critical structures. Figure 44-4 shows a postoperative radiation therapy field with multileaf collimators shaping the surgical tumor bed. Figure 44-5 shows a 3DCRT field with IMRT. The isodose lines more closely conform to the shape of the PTV. The risks of side effects depend on normal tissue tolerance, surrounding critical organs, prior treatments, irradiation dose, other concurrent therapies, and the general health of the patient.

Figure 44-4 Anteroposterior view (A), oblique view off the spinal cord (B), and multifield view (C) by computed tomography (CT). Postoperative radiation therapy field (outer white square) with custom blocks (black lines) covering the surgical tumor bed (inner white line) and upper mediastinum. The isodose lines cover the planning target volume (orange) very well.

Figure 44-5 Axial (A), coronal (B), and sagittal (C) views for intensity-modulated radiation therapy (IMRT). Isodose lines are closely conformal to the shape of planned target volume (red).

Various dose and fractionation schemes for thymoma are reported in the literature, and it is unclear if there is a dose response.^233,²⁶⁶ Although one retrospective study did not find any relationship between radiation dose and local control rates,^209,254 others have found that radiation dose was a significant prognostic factor for local control rates, with good results reported when doses higher than 40 Gy were used for subclinical or microscopic disease.^246,267 Retrospective data from Zhu and co-workers²⁶⁸ found a 5-year survival rate of 82% in patients given a dose greater than 50 Gy, compared with 70% for doses less than or equal to 50 Gy. The most important prognostic factors were Masaoka stage and extent of resection.

Postoperative doses of 45 to 55 Gy given by conventional fractionation have been used effectively in most cases.* The dose to the spinal cord should be limited to 45 Gy and can be accomplished using oblique mediastinal fields or IMRT. For patients with gross residual disease after resection or unresectable disease, doses of 60 Gy or more are probably required,^145,212,246 but higher doses correlate with higher risks of complications.²⁶⁹ Sophisticated treatment planning with IMRT may facilitate delivery of high doses to gross tumor while respecting dose limits to organs at risk.²⁷⁰

Treatment Algorithm and Controversies

The initial treatment for thymic tumors is surgery if the disease is resectable. Adjuvant irradiation or chemotherapy should be considered for patients with features indicating a high risk for recurrent disease and those with an unresectable or inoperable tumor. Optimal treatment must be customized, and the following guidelines should be considered:

1 Pathologic stage I to II thymoma (WHO types A, AB, B1, B2, B3) does not routinely require adjuvant therapy after a complete thymectomy (R0 resection, negative margins). Adjuvant RT may be considered in patients with B2 and B3 disease. If observation without RT is decided upon, patients with B2 and B3 disease should be closely observed with biannual or annual CT scans.

2 Pathologic stage II thymoma (WHO types A, AB, B1, B2, B3) patients with less than a complete thymectomy (as outlined in guideline 1) may benefit from postresection thoracic irradiation. A dose of 50 to 66 Gy (depending on the amount of residual disease) can usually be safely administered.

3 Pathologic stage II thymic carcinoma (WHO type C) can be treated with multimodality adjuvant therapy, which includes concomitant chemoradiation with or without consolidation chemotherapy after a complete thymectomy (R0 resection, negative margins).

4 Pathologic stage III to IVA thymic neoplasms (WHO types A, AB, B1, B2, B3, C) are treated with multimodality adjuvant therapy (as outlined in guideline 3) even after a complete thymectomy (R0 resection, negative margins).

5 Clinically unresectable stage III to IVA thymic neoplasms are treated with neoadjuvant chemoradiation, followed by sequential thymectomy, postoperative thoracic irradiation, and consolidation chemotherapy.

Pulmonary Carcinoid Tumors

Neuroendocrine lung tumors have a spectrum of clinical behaviors and include typical carcinoids (the most indolent type), atypical carcinoids, large cell neuroendocrine tumors, and small cell lung carcinomas (the most aggressive type).²⁷¹ The term carcinoid (from the German karzinoide) was originally defined as a carcinoma-like lesion without malignant characteristics by Oberndorfer in 1907.²⁷² Pulmonary carcinoids used to be known as bronchial adenomas because they were believed to be benign, but they are now recognized as malignant because of their potential to metastasize. Pulmonary or bronchial carcinoid tumors are typically low-grade malignant neoplasms that arise from neuroendocrine cells of the amine precursor uptake and decarboxylation (APUD) system that have migrated from the embryonic neural crest. These cells are the Kulchitsky (enterochromaffin) cells, which are located in the basal layer of bronchial epithelium.^273,²⁷⁴ Approximately 25% of carcinoids are located in the respiratory tract, which is the second most common site after the gastrointestinal tract. Pulmonary carcinoids are frequently centrally located and confined to the main or lobar bronchi.²⁷⁵ These tumors are rare, and their biologic behavior mostly depends on their histologic characteristics.

Etiology and Epidemiology

The cause of pulmonary carcinoid is unknown, and no environmental risk factors have been identified. Carcinogens that are associated with lung cancer have not been consistently associated with pulmonary carcinoids,²⁷⁶ although a few studies revealed a higher frequency of smokers with atypical carcinoids.²⁷⁷^–²⁷⁹ Some of the neoplastic cells express mutant retinoblastoma (RB1) or mutant TP53 gene products, and they show occasional loss of heterozygosity, especially in atypical carcinoids.²⁸⁰ Most familial pulmonary carcinoids have been reported in patients with multiple endocrine neoplasia type 1 (MEN 1). In cases of atypical and typical lung carcinoids, there is a characteristic allelic loss within the region of 11q-13, which harbors the MEN1 gene, a tumor suppressor gene.²⁸¹^–²⁸⁵ Other frequently detected genetic alterations in lung carcinoids, especially atypical carcinoids, include losses of 3p, 5p, 9p, 10q, and 13q.^283,²⁸⁴ Ki-67 expression in more than 5% of nucleoli is a poor prognostic factor for survival.²⁸⁶

The annual incidence of carcinoid tumors is one or two cases per 100,000 people in the United States.^2,²⁷⁶ For bronchopulmonary carcinoids, the reported incidence is 0.6 per 100,000 people.³ Carcinoid tumor of the lung represents 1% to 2% of all lung malignant tumors, with an equal frequency of these tumors occurring in men and women²⁷⁶; approximately 3500 new cases were reported in 2004.^287,288 Bronchial carcinoids are the most common primary lung tumor in children, typically presenting in late adolescence. Typical carcinoids are about four times more common than atypical carcinoids. Data from the SEER program of the National Cancer Institute have shown a trend of relative increase of pulmonary carcinoids.^3,276

Prevention and Early Detection

There is no known preventive measure for pulmonary carcinoids. Carcinoids are detected like other space-occupying tumors. The most common findings on a chest radiograph include a hilar mass with occasional atelectasis. Functioning carcinoids are suspected on the basis of the symptoms and signs, and the diagnosis is confirmed by demonstrating increased urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). Thyroid transcription factor-1 is expressed in 80% of metastatic pulmonary carcinoids but not in intestinal carcinoids, and it may be of value in the workup and diagnosis of pulmonary carcinoids.^289,²⁹⁰ Sometimes, localization of the tumor may require an extensive evaluation, including laparotomy. If hepatic involvement is suspected, a specific liver scan may be sufficient to demonstrate metastases.

Biologic Characteristics and Molecular Biology

Carcinoid tumors often occur sporadically and are thought to arise from neuroendocrine cells, which are present in a wide range of organs. The WHO classification of lung neuroendocrine tumors describes two different subtypes of carcinoids, typical and atypical carcinoids, with distinctive clinical behaviors and different prognoses.288,291 Based on the criteria proposed by Travis and associates,^271,291 the spectrum of neuroendocrine tumors also includes large cell neuroendocrine carcinoma and small cell lung carcinoma.

Although most pulmonary carcinoids are nonfunctional, some have the ability to synthesize and secrete a variety of physiologically active substances, leading to paraneoplastic syndromes, including carcinoid syndrome, Cushing’s syndrome, and acromegaly.²⁷⁴ Serotonin (5-hydroxytryptamine [5-HT]) is one of the frequently encountered vasoactive substances released by carcinoid tumors. Other substances, including corticotropin, histamine, dopamine, substance P, neurotensin, prostaglandins, and kallikrein, have been reported.²⁹²^–²⁹⁷

The biologic behavior of these tumors varies depending on the histologic characteristics. Typical carcinoid tumors of the lung generally have a better prognosis than other primary lung cancers, with a 5-year survival rate greater than 90%. For atypical carcinoids, 5-year survival rates range from 25% to 75%, depending on the series.²⁹⁸^–³⁰³ A population-based study of over 1400 patients from several European countries showed a 5-year OS rate of 78% for pulmonary carcinoids as a whole.³⁰⁴ Although typical carcinoids have an indolent clinical course, atypical carcinoids behave more aggressively, with nodal involvement in 20% to 60% of cases and a higher rate of distant metastases. Figure 44-6 shows a right-sided hilar atypical carcinoid tumor with associated mediastinal adenopathy. The recurrence rates and stage at presentation frequently are higher than for typical carcinoids. In atypical carcinoids, there is a high frequency of molecular alterations and inactivation of tumor suppressor genes, such as the TP53, RB1, CDKN2A (previously designated p16), and CDKN2D (previously designated p19) genes. The proliferation rates, as assessed by MIB-1 and Ki-67, are also higher than for typical carcinoids.^288,^305,³⁰⁶

Figure 44-6 Atypical carcinoid. A, The preoperative CT scan shows a right hilar mass. B, There was also right paratracheal adenopathy. Lymph node involvement is seen more commonly in atypical carcinoid than typical carcinoid.

Pathology and Pathways of Spread

Carcinoids are thought to be derived from different embryonic divisions of the gut and are classified accordingly. Foregut carcinoids are often found in the lungs, bronchi, and stomach, and midgut and hindgut tumors are typically seen in the small and large intestines. Histologically, they may stain positive with silver or Grimelius stains, cytokeratin 7 and 11, neuron-specific enolase, synaptophysin, carcinoembryonic antigen, and chromogranin; there is no marker exclusive to carcinoids, however.^289,^307,³⁰⁸ Microscopically, they are characterized by small uniform cells and the presence of numerous membrane-bound, neurosecretory eosinophilic granules containing a variety of hormones and biogenic amines in the cytoplasm. Most pulmonary carcinoids (70% to 90%) are typical carcinoids or well-differentiated neuroendocrine tumors, which are characterized by small cells with well-rounded nuclei; atypical carcinoids (10% to 30%), or poorly differentiated neuroendocrine tumors, have malignant histologic features of increased nuclear atypia with high mitotic activity (>2 mitoses per 10 high-power fields), lymphovascular invasion, nuclear pleomorphism, and areas of necrosis.^{291,308–311}

It is sometimes difficult to establish the specific diagnosis of carcinoid because of small biopsy samples or to differentiate atypical carcinoid from small cell lung carcinoma without immunohistochemical tests.291,312–314 Well-differentiated carcinoids are often indolent, with a relatively low risk of nodal or distant metastasis of 3% to 15%.^{287,311,315–317} Atypical carcinoid may have an aggressive clinical course, with frequent organ metastases.^280,318,319 The risk of nodal metastasis, frequently to mediastinal lymph nodes, is 30% to 57%.^287,320,321 Distant metastases occur in more than 20% of patients.²⁸⁷ The most common sites of distant metastasis include liver, bone, adrenal glands, brain, skin, and soft tissue.^288,^299,³²²^–³²⁴

Clinical Manifestations, Patient Evaluation, and Staging

Most patients with pulmonary carcinoids present in their 50s.2,276,287,319 Carcinoids in children are rare.³²⁵ Between 70% and 80% of these tumors are located centrally near the hilum within the tracheobronchial tree and may produce a variety of clinical symptoms and neuroendocrine manifestations at the time of diagnosis.^326,327 About 25% of patients present with symptoms such as recurrent pneumonia, cough, hemoptysis, or chest pain. Carcinoids are vascular tumors and can bleed secondary to bronchial irritation. Hyperparathyroidism may be seen. At least 50% of pulmonary atypical carcinoid tumors present in the periphery of the lung.³²⁸ Patients with peripheral lesions may be asymptomatic, and their lesions are usually discovered incidentally.^300,³²⁹

Carcinoids may produce various amines and polypeptides with corresponding signs and symptoms, often precipitated by emotional upset, food ingestion, or alcohol. The serotonin metabolite 5-HIAA, which is excreted in urine, acts on smooth muscle to produce bronchoconstriction or diarrhea, colic, and malabsorption. 5-HIAA levels are often greater than five times the upper limit of normal. Histamine and bradykinin, through their vasodilator effects, cause flushing. The release of such vasoactive substances into the systemic circulation can cause the carcinoid syndrome, characterized by episodic flushing, typically of the head and neck; asthmatic wheezing; abdominal cramps with recurrent diarrhea resulting in malabsorption syndrome; and valvular heart disease, including right-sided endocardial fibrosis, leading to pulmonary stenosis and tricuspid regurgitation.³³⁰ Bronchial carcinoids generally have low serotonin content because the tumor cells lack the aromatic amino acid decarboxylase enzyme and cannot make serotonin and its metabolites. Hence, the secretion of 5-hydroxytryptamine (5-HTP) is increased and 5-HIAA urinary excretion is normal. Lesions of the left side of the heart, which have been reported with bronchial carcinoids, are rare because serotonin is destroyed during passage through the lung. Some patients complain of decreased libido and impotence. However, the incidence of carcinoid syndrome or other paraneoplastic syndromes, including Cushing’s syndrome and acromegaly, is usually no more than 3% to 5% of cases, and these syndromes mainly occur in patients with larger tumors (>5 cm) or metastatic disease.* Carcinoid syndrome is seen more commonly in gastrointestinal carcinoids than in pulmonary carcinoids. Carcinoid syndrome is seen in 1% to 5% of patients, usually in those with metastatic disease or large primary tumors.³³² Paraneoplastic syndromes in the absence of lymph node or distant metastases do not affect the prognosis.^329,³³³ Levels of human chorionic gonadotropin and pancreatic polypeptide are occasionally elevated.

Patients with a suspected lung mass require thorough history taking and a physical examination. Routine screening blood tests and chemistry tests may give clues to the presence of associated syndromes (Table 44-3). The differential diagnosis, in addition to bronchopulmonary carcinoid, includes lung carcinoma and metastasis from an extrapulmonary primary tumor. Conventional radiographs of the chest and comparison with older films are often helpful. CT and bronchoscopy are two of the most valuable diagnostic procedures. Up to 80% of carcinoids manifest with type 2 somatostatin receptors, and the receptors can be targeted by radioactive octreotide or pentetreotide. Somatostatin receptor scintigraphy with indium-111–radiolabeled octreotide (¹¹¹In-octreotide) has demonstrated reliable uptake in primary tumors and been used to detect early recurrence.³³⁴^–³³⁶ The result of FDG-PET is often negative.^278,³³⁷^–³³⁹ PET with copper-64 (⁶⁴Cu) TETA-octreotide as a tracer has been investigated in carcinoids.³⁴⁰ Carbon-11 (¹¹C) 5-HT PET scanning is more sensitive than somastostatin receptor scintigraphy, but the short half-life of the compound (20 minutes) has prevented its routine use.³⁴¹

TABLE 44-3 Presenting Symptoms in Patients with Pulmonary Carcinoids

Transbronchial biopsy or CT- or ultrasound-guided fine-needle aspiration biopsy of the mass may establish the diagnosis preoperatively. Bronchoscopy, video-assisted thoracoscopic surgery, or mediastinoscopy may help yield the diagnosis before resection, especially if enlarged lymph nodes are present. Three-quarters of bronchopulmonary carcinoids are centrally located and are amenable to a bronchoscopic biopsy.

The prognostic factors are atypical histologic findings, nodal involvement, and the presence of symptoms at the time of presentation.† A high mitotic rate, tumor size larger than 3.5 cm, and female gender have also been implicated as prognostic factors for patients with atypical pulmonary carcinoids.²⁷⁷ There is no specific staging system for pulmonary carcinoids, and the American Joint Committee on Cancer (AJCC) lung cancer staging system (TNM) is commonly used.

Treatment

Primary Therapy

Curative resection is the treatment of choice.288,323,324,342,343 After complete resection, the long-term results are generally excellent.^{287,323,327,342} Conservative surgical resection, consisting of wedge or segmental resection, is the preferred therapy for localized pulmonary carcinoids.^344,³⁴⁵ Patients with central lesions may require bronchial sleeve resection or sleeve lobectomy.³⁴³ Endoscopic laser ablation is not considered curative but may be used to alleviate tumor obstruction, improve atelectasis, and reduce inflammation before resection.³¹⁶ Intraoperative nodal evaluation should be performed, and if the results are positive, complete nodal dissection is indicated. Because of higher rates of local recurrence in patients with atypical carcinoids, a more extensive surgical procedure, such as lobectomy or pneumonectomy with nodal dissection, should be considered.^288,^323,^324,³⁴⁶ Patients may present with metastatic or unresectable disease, however, and curative resection may not be obtainable. Debulking and other cytoreduction procedures may be of benefit in cases of gastrointestinal carcinoids,^347,³⁴⁸ but these procedures are of uncertain benefit for patients with pulmonary carcinoids.

Medical Treatment

Certain symptoms, including flushing, can be relieved by pharmacologic agents. Ondansetron, one of the specific 5-hydroxytryptamine-3 (5-HT3) antagonists, provides sustained symptomatic relief in patients with carcinoid syndrome.³⁴⁹ Somatostatin analogs are potent inhibitors of neuropeptide release and gut exocrine or endocrine function. These analogs are effective in relieving symptoms by binding to somatostatin receptors (mainly, receptor 2),³⁵⁰ which are present in approximately 80% of carcinoids, leading to inhibition of hormone secretion.^351,³⁵² Octreotide and lanreotide, long-acting analogs of somatostatin, are the drugs of choice for controlling diarrhea and flushing. The response rate is about 70% for symptomatic improvement, and there is a more than 50% reduction in urinary 5-HIAA secretion, with a median duration of response of 12 months. Data suggest that these somatostatin analogs may have a direct antitumoral effect, with stabilization of tumor growth and reduction of tumor size in patients with carcinoids of various sites.^351,³⁵²

Radiation Therapy

There are no prospective trials that address the use of adjuvant therapy for patients with bronchopulmonary carcinoids. In general, typical carcinoids do not require adjuvant radiation therapy or chemotherapy after curative resection.287,323,327,342,353 A series of 25 patients with node-positive bronchial carcinoids treated at the Memorial Sloan-Kettering Cancer Center (MSKCC) (12 typical and 13 atypical tumors) found no survival benefit from postoperative radiation therapy.²⁷⁵ Recurrence and survival rates appeared to depend on cell type rather than nodal status. In another study of 163 patients (including three-fourths of patients with typical carcinoids, most of which were stage N0), however, the prognosis depended on the presence (N positive versus N negative) and extent (N1 versus N2) of nodal involvement rather than histologic subtype.²⁹⁸ In most studies, the role of adjuvant radiation therapy is unsettled because of the retrospective nature of studies and the small number of patients.^277,^318,³⁵⁴ Although prospective, randomized data are lacking, adjuvant radiation therapy has been used in patients at high risk for locoregional recurrence, including those with large tumor size (>3 cm), positive nodes, positive margins, atypical histologic findings, residual disease, and inoperable disease.^311,^318,^354,³⁵⁵ Recently, Mutyala and colleagues³⁵⁶ reported a series of 59 patients who underwent resection with permanent iodine-125 (¹²⁵I) interstitial seed implantation for a variety of thoracic malignant tumors, including pulmonary carcinoid with close or positive margins. They reported an excellent 2-year local control rate of 67% with minimal added morbidity from this procedure.³⁵⁶

Palliative radiation therapy can be considered in patients with metastatic typical or atypical pulmonary carcinoids. Tumor-targeted irradiation with radioactive somatostatin analogs (¹¹¹In-octreotide or ¹³¹I-metaiodobenzylguanidine [¹³¹I-MIBG]) has been used, often as second- or third-line therapy.^355,^357,³⁵⁸ The results have been inconclusive, with occasional long-term survivors reported.

Chemotherapy

Unlike chemotherapy for patients with small cell lung cancer, systemic chemotherapy has produced only limited success in patients with metastatic carcinoid tumors.³⁵⁵ Although no effective chemotherapeutic regimen has been established, aggressive treatment with adjuvant systemic chemotherapy is recommended in high-risk patients with stage III atypical or metastatic carcinoid.³²⁰ Several trials have shown response rates of 21% to 33% with various combinations of doxorubicin, streptozocin, cyclophosphamide, etoposide, and fluorouracil in patients with metastatic carcinoids.^{320,359–362} There was no significant difference in survival rates between treatment groups, and the side effects were substantial. Patients with atypical carcinoids treated with a combination of cisplatin and etoposide appear to have a higher response rate than patients taking other regimens.

Locally Advanced Disease and Palliation

For patients with locally advanced or metastatic disease, surgery is generally limited to those whose metastases are confined to one site amenable to local resection, because aggressive debulking may enhance the outcome in terms of symptomatic relief.^347,³⁶³ Radiation therapy has been used successfully to palliate symptoms in patients with locally advanced or metastatic disease.³⁶⁴ Local control and symptomatic relief can be achieved in most patients with 4000 to 5000 cGy. Endoscopic resection and laser photoablation have been used for palliation of symptoms.³¹⁶ Somatostatin analogs alone or in combination with chemotherapy or interferon-alpha may be considered for symptomatic treatment or tumor stabilization.³⁶⁵

Results of Therapy

In general, patients with typical carcinoid tumors treated with surgery alone have a very good outcome. However, patients with atypical pulmonary carcinoid tumors and regional lymph node metastases are at high risk for recurrent disease and have worse survival rates when they are treated with surgical resection alone.³¹⁹ The 5-year OS rate ranges from 78% to 100% for all resected pulmonary carcinoids, 90% to 100% for typical carcinoids, 25% to 69% for atypical carcinoids, and 18% to 38% for metastatic carcinoids.* Ten-year rates are 10% to 20% lower than 5-year rates. Some of the published results are summarized in Table 44-4. Although the role of adjuvant radiation therapy as part of multimodality treatment is undefined, adjuvant irradiation may improve the outcome of high-risk patients with atypical carcinoid tumors, positive nodes, or positive margins.³²² The National Comprehensive Cancer Network (NCCN) recommends adjuvant therapy for stage II and III atypical carcinoids.³⁶⁸

TABLE 44-4 Treatment Results for Pulmonary Carcinoids

Irradiation Techniques

The same general principles of thoracic irradiation apply to irradiation of pulmonary carcinoids. High-energy (>10-MV) x rays are preferred with a CT scan for treatment planning. As in treating other tumors, surgical clips denoting the extent of resection or outlining regions of residual disease are useful in guiding postoperative irradiation. The PTV should include the gross or residual tumor volume and tumor bed with a 1.5- to 2-cm margin. Depending on the histologic and surgical findings, areas of suspicious subclinical disease and regional lymphatics are included. Treatment field arrangements may resemble the typical lung tumor fields. There are no consistent guidelines regarding dose and fractionation regimens in the literature. Postoperative doses of 45 to 58 Gy delivered in conventional fractionation of 1.8 to 2 Gy per day have been reported (see Table 44-4). For patients with gross residual or unresectable disease, a higher total dose may be justified as long as the dose to other critical structures does not exceed the tolerance of normal tissues.

Treatment Algorithm and Controversies

Surgery is the primary treatment for typical and atypical pulmonary carcinoids. Although conservative resection has resulted in low recurrence rates and excellent long-term survival rates for patients with well-differentiated pulmonary carcinoids, the adequacy of such resection in patients with atypical carcinoids has not been settled. More extensive surgical procedures, with higher treatment-related morbidity rates, have been advocated by some investigators.320,369 Adjuvant radiation therapy or systemic chemotherapy may be considered even for patients with early-stage disease because of the high incidence of regional and distant failure.³¹⁸ Palliative irradiation should be considered for those with symptomatic disease.

Mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive malignant disease, and local disease progression is the main cause of symptoms and death. Disseminated disease is usually reported only very late in the course of MPM.³⁷⁰^–³⁷⁴ MPM spreads by direct extension and seeding throughout the pleural space, including fissures, diaphragmatic and pericardial surfaces, through the chest wall, and into the mediastinum, peritoneum, and lymph nodes. The major problem for patients with MPM is poor local disease control in the thorax. Aggressive surgery alone, even in carefully selected patients with early-stage disease, has not improved the 2-year survival rate of 10% to 33%.³²³^–³²⁵ Combined-modality treatment suggests improved local control and survival rates,³⁷⁵^–³⁷⁷ but local recurrence is still the most common site of first relapse.³⁷⁸

Even after EPP, the diffuse nature of most malignant mesotheliomas and the manipulation of the exposed tumor during surgery put the entire ipsilateral chest wall, diaphragm insertion, pericardium, mediastinum, and bronchial stump at very high risk for local recurrence. The hemithorax and mediastinum have an irregular shape and are adjacent to critical structures, such as the spinal cord, liver, kidneys, esophagus, heart, and contralateral lung. Conventional irradiation of the hemithorax and mediastinum is limited by the ability of these organs to tolerate radiation ^371,^378,³⁷⁹ and by the total volume of tissue being irradiated.

Etiology and Epidemiology

MPM has an incidence of approximately 10 cases per million people per year in the United States.³⁸⁰ The incidence has been increasing and represents a significant clinical problem in populations exposed to asbestos. The Center for Lung Cancer and Related Disorders estimates approximately 3000 new cases of MPM per year, with a peak incidence of approximately 4000 per year expected to occur in about 2025. The incidence is rising due to the long latency between asbestos exposure and clinically apparent disease; most cases occur over 20 years after exposure. The median age at diagnosis is approximately 60 years.

Approximately 90% of mesothelioma cases can be attributed to prior asbestos exposure. This is typically an occupational exposure (e.g., construction work, automotive brake repair, boiler work, shipbuilding), and it explains the approximately 90% male predominance. However, other sources of exposure may include a spouse or parent asbestos worker. Even a history of living near asbestos-using businesses, such as automotive shops (from brake linings) or cement manufacturers (which may have added asbestos), can increase the risk of mesothelioma. Patients from certain regions of the world (e.g., central Turkey, Western Australia) also have endogenous environmental asbestos exposure. There is no direct association between mesothelioma and smoking, but smoking greatly increases the risk when there is also asbestos exposure.³⁸¹ Radiation exposure has been shown to be causatively linked to mesothelioma, with an increased incidence identified in adults with previous thoracic radiation treatment.

Clinical Evaluation and Staging

Dyspnea, chest pain, cough, and weight loss are common presenting symptoms of MPM. All patients should be asked about their history of asbestos exposure. Pulmonary function tests demonstrate a restrictive pattern resulting from “trapping” of the lung or chest wall involvement. MPM has a tendency to grow along tracks of previous chest tubes. All sites of previous instrumentation should be identified and examined for evidence of tumor seeding. Such chest wall progression may manifest as pain, a nodule, or an ulcer. Particularly when transthoracic extension is identified, the axillary and supraclavicular lymph nodes should be palpated for involvement. Sometimes, scoliosis can occur because of ipsilateral lung volume loss.

Imaging

A chest radiograph should be used for initial evaluation. Careful attention should be paid to the presence of pleural effusions or calcified pleural plaques. Nodular irregularities often can be identified. Sites of rib tenderness should be evaluated for direct tumor extension, although chest pain is more often attributable to involvement of the endothoracic fascia.

Contrast-enhanced CT of the chest is the mainstay of radiographic staging. Circumferential pleural thickening, an irregular pleural contour, and/or contraction of the ipsilateral hemithorax are common findings. Invasions of the diaphragm and/or chest wall are difficult to detect in early cases, so CT may underestimate the extent of disease. Miliary disease can be present on the undersurface of the diaphragm or peritoneum and remain undetected by modern imaging. MPM tends to manifest late in the disease course, often with large masses and pleural effusions. Pleura-based irregular masses are common, particularly in dependent regions of the pleural space. The interlobar fissures are often involved. MPM can invade adjacent structures, such as the chest wall, mediastinum, great vessels, vertebral body, or heart. Mediastinal and hilar lymph nodes can be involved with tumor, but the pattern of spread is often different from that of non–small cell lung cancers. MPM spreads to the lower paraesophageal nodes (level 8), pulmonary ligament nodes (level 9), and diaphragmatic nodes much more commonly than lung cancers. Pericardial effusions and ascites can also be seen on CT, and they should be evaluated pathologically before any attempt at curative resection. The anteromedial extent of tumor, particularly extension across the midline, should be determined before surgery. Because surgery obliterates the costomediastinal space, the anterior pleural reflection cannot be accurately delineated on postoperative studies.

The utility of MRI in the staging of mesothelioma is controversial. MRI may slightly more accurately predict the extent of chest wall invasion. This finding should not preclude surgery, however, as long as the region of invasion can be removed with a limited chest wall resection. Invasion to the peritoneal surface of the diaphragm cannot always be appreciated without invasive staging. FDG-PET or PET/CT scanning has been applied to mesotheliomas ³⁸² because they tend to avidly take up FDG. Sensitivity and specificity of 90% or more has been reported and is helpful in distinguishing between benign pleural thickening and MPM.^383,³⁸⁴ Furthermore, PET/CT, when compared with CT, in a series of 35 patients, upstaged tumors and therefore prevented unnecessary surgery in 40% of patients.³⁸⁵

Invasive Staging

The diagnosis of mesothelioma can be difficult because of the relative rarity of the disease and the cytologic similarity to more common metastatic neoplasms, such as adenocarcinoma. Thoracentesis is often the first procedure performed to obtain diagnosis, but it has a diagnostic sensitivity of only 32%.³⁹⁴ Percutaneous fine-needle aspiration biopsy similarly has low diagnostic sensitivity, although ultrasound-guided core-needle biopsy has been reported to improve accuracy.³⁹⁵ Before beginning multimodality treatment, accurate preoperative staging is necessary. An open pleural biopsy is the gold standard.³⁸⁶ Surgical intervention with open thoracotomy or video-assisted thoracoscopic surgery can also be done. Diagnostic thoracentesis is an alternative, though it has a lower yield than video-assisted thoracoscopic surgery.³⁸⁷

Mesothelioma has a tendency to track along sites of chest wall violation, and tumor may recur at previously placed thoracoscopy port sites if they are not excised at the time of definitive surgery. Limiting the number of port sites at the time of video-assisted thoracoscopic surgery and placing the port sites where they are easily excised help to reduce local chest wall recurrence. When it is difficult to establish entrance into the pleural space, it is preferable to perform a limited open biopsy of the parietal pleura by extending the port site incision slightly, rather than to perform a formal thoracotomy. A thoracotomy performed for diagnosis significantly compromises potentially curative surgery.

Unfortunately, preoperative assessment of mesothelioma tumor stage is less than ideal. Although CT, PET, and MRI are reasonably accurate in defining tumor volume within the thorax and chest wall and in identifying sites of distant disease, they are less successful in determining tumor involvement at two critical sites: contralateral mediastinal nodal involvement and tumor invasion through the diaphragm. Tumor involvement at either site negates resection, and we therefore think that an accurate assessment of these areas is necessary before performing EPP. All patients at our institution undergo pretreatment laparoscopy with peritoneal lavage and cervical mediastinoscopy. At the M.D. Anderson Cancer Center, of 118 patients with MPM who were clinically and radiographically determined to have resectable disease, laparoscopy and peritoneal lavage revealed transdiaphragmatic or peritoneal involvement in 12 (11%) of 109 patients and mediastinoscopy identified positive contralateral nodes in 4 (4%) of 111 patients. Overall, 15 (13%) patients were identified with occult advanced disease and spared unnecessary EPP.

Staging

The AJCC seventh edition staging system for mesothelioma is shown in Box 44-4 and is based on the International Mesothelioma Interest Group (IMIG) staging system. The staging systems are useful only after surgical staging, and no clinical staging system has been developed or validated.

Box 44-4

TNM Staging of Mesothelioma

Primary Tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor limited to the ipsilateral parietal pleura, with or without mediastinal pleura and with or without diaphragmatic pleural involvement
T1a	No involvement of the visceral pleura
T1b	Tumor also involving the visceral pleura
T2	Tumor involves each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:
	(1)involvement of diaphragmatic muscle
	(2)extension of tumor from visceral pleura into underlying pulmonary parenchyma
T3	Locally advanced but potentially resectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:
	(1)Invasion of the endothoracic fascia
	(2)Invasion into mediastinal fat
	(3)Solitary completely resectable focus of tumor invading the soft tissues of the chest wall
	(4)Nontransmural involvement of the pericardium
T4	Locally advanced, technically unresectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:
	(1)Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction
	(2)Direct transdiaphragmatic extension to the peritoneum
	(3)Direct extension to mediastinal organs
	(4)Direct extension to the contralateral pleura
	(5)Direct extension into the spine
	(6)Extension to the internal surface of the pericardium with or without a pericardial effusion or tumor involving the myocardium
Regional Lymph Nodes (N)
NX	Regional nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastases in the ipsilateral bronchopulmonary and/or hilar lymph node(s)
N2	Metastases in the subcarinal or ipsilateral mediastinal lymph nodes (including ipsilateral internal mammary and peridiaphragmatic nodes)
N3	Metastases in the contralateral mediastinal, internal mammary, or hilar lymph node(s) and/or the ipsilateral or contralateral supraclavicular or scalene lymph node(s)
Distant Metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
Stage Groupings
I	T1N0M0
IA	T1aN0M0
IB	T1bN0M0
II	T2N0M0
III	T1-2N1M0
	T1-2N2M0
	T3N0-2M0
IV	T4 Any NM0
	Any TN3M0
	Any T Any NM1
Residual Tumor (R)
RX	Presence of residual tumor cannot be assessed
R0	No residual tumor
R1	Microscopic residual tumor
R2	Macroscopic residual tumor

From Edge SB, Byrd D, Compton CC, et al, editors, for the American Joint Committee on Cancer: AJCC Cancer Staging Manual, ed 7. New York, 2010, Springer.

Several important prognostic markers have been identified for MPM. Metastases to any nodal station predict a worse outcome. However, unlike non-small cell lung cancer, it is not clear that mediastinal metastases reflect a worse prognosis than hilar or intrapulmonary nodal metastases. The completeness of resection is also prognostic. Patients with R1 or R2 resections have been reported to have a worse outcome in some series.³⁸⁸

Another poor prognostic marker is nonepithelioid histologic findings. Epithelioid histologic characteristics are found in 50% of cases. Pure epithelioid mesothelioma may be difficult to distinguish from metastatic adenocarcinoma of the lung, so immunohistochemistry or electron microscopy is essential.³⁸⁹ Patients with sarcomatoid (10% of patients), mixed (30% of patients), and desmoplastic tumors fare much worse than patients with epithelioid histologic types.^390,391,392 Thrombocytosis and high levels of platelet-derived growth factor predict a worse outcome. Several reports suggest that serum levels of mesothelin are elevated in most patients at diagnosis and that they fall after surgery. Serum mesothelin may be a marker for tumor recurrence.³⁹³ Good prognostic factors include young age, early-stage disease, performance status of 0 to 1, lack of chest pain, and presence of symptoms for longer than 6 months.³⁹²

Treatment

Surgery

Pleurectomy

Pleurectomy for treatment of MPM has been advocated by many surgeons, although some believe it offers inferior disease control than EPP. Local recurrences are significantly higher than after EPP. Because the ipsilateral lung is preserved by pleurectomy, the procedure is often preferred for patients with poor contralateral lung function. Pleurectomy is effective in allowing expansion of the trapped lung and reduces the likelihood of recurrent pleural effusion. Unfortunately, mesothelioma usually involves the visceral and parietal pleural surfaces of the lung, and these extend into the pleura-lined pulmonary fissures. Cytoreduction is not as complete as that achieved with EPP. A large retrospective study of 663 patients actually showed improved OS rates with pleurectomy as compared with EPP. Patients treated with pleurectomy and decortication had a higher rate of local recurrence of disease, whereas patients undergoing EPP had greater surgical morbidity and mortality rates.³⁹⁶ Because the lung and hemidiaphragm remain after pleurectomy, tumoricidal postoperative external beam radiation therapy cannot be effectively administered, so some centers have been exploring the addition of photodynamic therapy in lieu of external beam radiation therapy.

Extrapleural Pneumonectomy

Most experts consider EPP to be the operation of choice for mesothelioma because it achieves the greatest ³⁹⁷ degree of cytoreduction possible and allows adjunctive therapies such as chemoperfusion, photodynamic therapy, or hemithoracic irradiation to be given without risk to the remaining vital organs. A review of 34 studies of EPP for patients with MPM found a perioperative mortality rate of nil to 11.8% and a median OS time of 9.4 to 27.5 months. Without adjunctive therapy, EPP has been associated with recurrence rates as high as 80%, but with current multimodality techniques, studies have reported local recurrence rates of between 40% and 50%. One study³⁹⁸ reported a local recurrence rate of 13% (7 of 55 patients) for patients treated with hemithoracic irradiation to 54 Gy after EPP.

EPP is an extensive surgical procedure, removing the ipsilateral lung along with the parietal pleura, pericardium, and most of the hemidiaphragm, so patients require careful assessment preoperatively to exclude the presence of locally advanced or distant disease (which would preclude resection) and meticulous cardiopulmonary screening to ensure that the operation can be tolerated physiologically. We perform EPP only after surgical staging of the mediastinum and abdomen (with washings). In general, patients should have adequate cardiac function (i.e., ejection fraction >40% and no reversible ischemia on radionuclide imaging) and have an estimated postoperative forced expiratory volume in 1 second (FEV₁) value of greater than 0.8 L/min, or 30% of predicted. The ideal patient is young, with epithelial histologic typing and a good performance status and without lymph node involvement. Even in centers with extensive experience with carefully selected patients, EPP has a high rate of complications and is not considered the standard of care.³⁹⁹ Due to the extremely poor prognosis of the sarcomatoid subtype, some have argued against EPP for this histologic group.⁴⁰⁰

Chemotherapy

Chemotherapy for mesothelioma has not met with much success. Reviews ^401,⁴⁰² describe modest success with several chemotherapeutic agents. Reported response rates of more than 25% include the use of methotrexate (37%),⁴⁰³ gemcitabine plus cisplatin (48%),⁴⁰⁴ pemetrexed plus carboplatin (50%),⁴⁰⁵ pemetrexed plus cisplatin (38%),⁴⁰⁶ mitomycin plus cisplatin (26%),⁴⁰⁷ raltitrexed plus oxaliplatin (26%),⁴⁰⁸ and doxorubicin plus cisplatin (28%).⁴⁰⁹ At the M.D. Anderson Cancer Center, hyperthermic intraoperative cisplatin has been used following EPP, with an MPM recurrence rate of 51% and an ipsilateral recurrence rate of 17%.⁴¹⁰

Perhaps the most exciting development in chemotherapy for mesothelioma is the use of cisplatin plus the antifolate pemetrexed.⁴¹¹ A total of 456 patients were randomized to cisplatin alone versus cisplatin and pemetrexed. The median survival time was 12.1 months for the pemetrexed plus cisplatin arm and 9.3 months for the cisplatin alone arm (p = .020). Toxicity was dramatically reduced by the addition of vitamin supplementation, but this did not influence the effectiveness of therapy. Time to progression was improved from 3.9 to 5.7 months by the addition of pemetrexed (p = .001). The response rate was 17% for cisplatin alone compared with 41% for combined treatment.⁴⁰⁵ Krug and colleagues^405a recently reported the results of a multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by EPP and irradiation for MPM, with a promising median survival time of 29.1 months and a 2-year survival rate of 61.2%.

The British Thoracic Society performed a randomized trial to assess the role of chemotherapy in palliation.⁴¹² Of the 242 patients registered, 109 were randomized to active symptom control or one of two chemotherapy regimens (i.e., mitomycin C, vinblastine, and cisplatin or vinorelbine alone). They found that active symptom control with chemotherapy provided better palliation of chest pain and shortness of breath than active symptom control alone.

Rationale for Irradiation

MPMs are almost impossible to cure with radiation therapy as a single modality. The tumors are large, and potential cure requires commensurately large radiation doses. The treatment volumes are very large, extending from the supraclavicular fossa to the insertion of the diaphragm, because the entire pleural space is at risk for recurrence, even the intrapulmonary fissures. The treatment volumes are very close to radiosensitive structures, such as the lung, kidney, liver, esophagus, and heart.

Although technical challenges remain, several lines of evidence suggest that radiation therapy can be effective in treating mesothelioma. First, mesothelioma cell lines are not particularly radioresistant in vitro, and they have radiosensitivities similar to those of non–small cell lung cancer.^413,⁴¹⁴ Second, there is a clinically meaningful dose-response relationship for symptom palliation, such that doses greater than 40 Gy seem more effective than lower doses.^370,⁴¹⁵ This dose-response relationship suggests that clinically significant cell killing results from modest radiation doses. Third, modest radiation doses can dramatically reduce the local failure rate at thoracotomy or other instrumentation sites. These data demonstrate that irradiation can effectively kill mesothelioma cells in regions where the tumor burden is low. Because MPM is moderately radiosensitive, it follows that postoperative irradiation can be effective in preventing locoregional recurrence and potentially improve survival rates.

Curative Radiation Therapy

Radiation Therapy Alone

Irradiation alone is not the treatment of choice for MPM. The lung is very sensitive to irradiation, and the volume of lung irradiated above 20 Gy has been linked to pulmonary toxicity.

Normal tissue sparing is difficult if the lung and diaphragm remain in place for two reasons. First, the fissures are bathed in pleural fluid and, therefore, with mesothelioma cells. The intrapulmonary fissures are complex, three-dimensional structures surrounded by lung. Respiratory motion is the second and most important problem. When the diaphragm is in place, there can be 2 to 3 cm of superoinferior motion, 1 to 2 cm of mediolateral motion along the mediastinum, and 1 to 1.5 cm of anterior chest wall motion. Expanding the PTV to account for motion can result in liver toxicity in right-sided MPM, the most common type, and delivery of very high cardiac and bowel doses in left-sided cases. Radiation therapy without surgery is best considered a palliative treatment.

Radiation Therapy Combined with Surgery

Several groups have reported promising outcomes for MPM patients treated with surgery and irradiation, with or without chemotherapy. Operative approaches have used pleurectomy or decortication or employed EPP.

Radiation Therapy after Pleurectomy or Decortication

Thirty-four patients with pathologically proven MPM were treated between 1982 and 1988 at the Helsinki University Central Hospital.^416,⁴¹⁷ Twenty-nine patients had partial pleurectomy, and the others had only biopsy. Patients were irradiated with one of three schedules that delivered between 55 Gy and 70 Gy to the hemithorax, and significant pulmonary damage occurred in many patients. A similar study at the MSKCC⁴¹⁸ treated 41 patients with partial pleurectomy, and all had residual gross disease that was given a boost dose with permanent ¹²⁵I implantation at surgery. Photon and electron fields were combined to treat the superficial chest wall and spare the underlying lung. Radiation doses were 45 Gy to the pleural surface, but the dose to “most of the lung” was kept below 20 Gy. Local recurrence developed in 29 of 41 patients, with 22 having distant failures. The median time to local failure was 9 months. Radiation-related toxicity occurred in four patients (one each of radiation pneumonitis, symptomatic pulmonary fibrosis, pericardial effusion, and esophagitis), but the severity of toxicity was not described.

These results were updated with results for 105 patients treated with pleurectomy or decortication from 1976 to 1988.^371,³⁷⁴ Forty-one patients received external beam radiation treatment only, and 53 patients received external beam irradiation with an intraoperatively placed ¹²⁵I boost to gross disease. The median survival time was 12.6 months, but 12 patients developed radiation pneumonitis and 8 developed radiation pericarditis. The severity of these reactions and the local control rates were not described.

One article ⁴¹⁹ described the results of 24 patients treated with pleurectomy or decortication, intraoperative radiation therapy (IORT), and postoperative external beam radiation therapy. Fourteen patients were irradiated using three-dimensional conformal radiation therapy, and IMRT was used to treat 10 patients. IORT was targeted mainly to the intrapulmonary fissures, pericardium, and diaphragm, with doses ranging from 5 to 15 Gy. The target volumes for the external beam treatments were not described, but the doses ranged from 30.1 to 48.8 Gy (median, 41.4 Gy). Twelve patients also received chemotherapy (i.e., cyclophosphamide, doxorubicin, and cisplatin). Despite the relatively early stage of disease, the outcome was relatively poor, with a median OS time of 18 months and a progression-free survival rate of 12 months. Major complications included radiation pneumonitis in four patients, pericarditis in one patient, and esophageal stricture in one patient who had received previous radiation therapy to the esophagus. Tumor recurrence was “mostly locoregional” at sites of previous gross tumor. Only the number of IORT sites was predictive of the OS rates, suggesting that higher external beam doses might be required for this approach to be widely used. The MSKCC group also reported their experience with high-dose-rate IORT after pleurectomy or EPP. There were serious complications in three of six patients (50%) of the EPP/IORT group and in one of five patients (20%) of the PD/IORT group, and they have abandoned IORT after EPP.⁴²⁰

Pleurectomy or decortication followed by irradiation can reduce locoregional failure rates compared with historical controls. However, local failure is common, and survival rates are disappointing even when modern IMRT techniques are applied. Although the overall median survival time in these pleurectomy or decortication studies tends to be about 2 years, carefully selected patients with early-stage disease treated with EPP can expect median survival times of more than 4 years.³⁷⁷ Unfortunately, there are no prospective, randomized trials to guide therapy.

Intrapleural Photodynamic Therapy

The Food and Drug Administration (FDA) has approved photodynamic therapy for non–small cell lung cancer and cancer of the esophagus. However, photodynamic therapy is being investigated for treatment of mesothelioma. Photodynamic therapy uses light activation of sensitized tumor cells to achieve sterilization. It is delivered intraoperatively immediately following pleurectomy or EPP with the goal of sterilizing microscopic disease throughout the thorax.³⁹⁶

The theory being investigated at the University of Pennsylvania is that if photodynamic therapy effectively eradicates residual disease after a meticulous pleurectomy, it is not necessary to remove the lung itself. Prior to surgery, the patient is infused with a photosensitizer that accumulates in malignant tissue. This sensitizer is activated by 630 nm of red light in the operating room, producing reactive oxygen species. The singlet oxygen destroys tumor via direct damage to malignant cells as well as the tumor miscorvasculature.⁴²¹

A phase I trial of Foscan-mediated photodynamic therapy found that the maximum tolerated dose of photosensitizer was 0.1 mg/kg 6 days prior to surgery.⁴²² Dose-limiting toxicity at the next dose level consisted of systemic capillary leak syndrome and led to death in two of three patients treated. Other photodynamic therapy-related toxicities included wound burns and skin photosensitivity. Fourteen patients were treated at the maximum tolerated dose (MTD) without significant complications.

One advantage of photodynamic therapy is direct visualization of regions at risk for recurrence. Light sensors placed in the chest allow measurements of light, permitting delivery of a uniform measured dose throughout the hemithorax. The depth of penetration of the light is a few millimeters, so it poses a low risk of damage to the lung parenchyma. Photodynamic therapy does not preclude the use of other adjuvant therapies such as external beam radiation therapy and chemotherapy.⁴²⁴ Studies validating the use of photodynamic therapy after pleurectomy are ongoing.

Radiation Therapy after Extrapleural Pneumonectomy

The first large report of combined-modality therapy that included EPP was described in 1997.³⁷⁸ In this series, 49 patients underwent EPP. Four to six cycles of chemotherapy were given postoperatively, followed by irradiation in 35 patients. The target volumes, stage, and technique were not described. The prescribed dose was 30.6 Gy to the “hemithorax,” followed by a boost to bring the dose to about 50 Gy. Sixteen irradiated patients had a “local” recurrence. However, of the patients with “abdominal” failures, five had a chest mass extending into the abdomen, two had ascites, and four had a “retroperitoneal mass.” This latter fact is potentially important because the diaphragm is reconstructed much higher than the insertion of the diaphragm, “abdominalizing” the retroperitoneal posterior chest wall (Fig. 44-7). Failure to irradiate this region, which can occasionally be below the ipsilateral kidney, can result in apparent retroperitoneal recurrences. The true rate of locoregional failure was at least 21 of 49 cases and possibly as high as 25 of 49 cases. Despite this finding, the 3-year OS rate was 34%. Radiation-related morbidity was tolerable, including esophagitis³⁷¹ and thrombocytopenia.³⁷⁴ No radiation pneumonitis was described, but five patients experienced “respiratory compromise,” one of whom died of pneumonia. These data suggest that postoperative radiation therapy can reduce local recurrence rates and result in the long-term survival of well-selected patients.

Figure 44-7 Extrapleural pneumonectomy (EPP) can abdominalize portions of the posterior costophrenic recess. A, A preoperative radiograph shows that the diaphragm on the contralateral side (black arrow) is higher than the ipsilateral hemidiaphragm (white arrow). B, After EPP, the posterior insertion of the reconstructed hemidiaphragm (white arrow) is well above the now flattened, remaining hemidiaphragm (black arrow). In this example, the posterior insertion of the diaphragm is about 15 cm higher than before surgery.

Encouraging results have also been reported from the MSKCC.³⁷⁴ From 1995 to 1998, 54 patients underwent EPP followed by radiation therapy.⁴²⁵ Two-thirds of the patients had stage III disease. The target volume was described as the “hemithorax” and drain sites, and the inferior field edge “rarely” included the ipsilateral kidney. The treatment technique involved photon irradiation to a dose of 54 Gy in 30 fractions. The spinal cord was shielded after 41.4 Gy, and the liver, heart, and stomach were appropriately shielded. The chest wall in the shielded regions was irradiated with matched electron fields so that the goal dose of 54 Gy could be more safely achieved. The median survival time was about 18 months. Only seven patients had local recurrences; two had only local recurrences. Another 22 patients had “peritoneal” or “ipsilateral visceral” recurrences. It is not clear whether any of these were in the radiation fields or whether some might have been marginal misses. It is critical to distinguish marginal failures (which require better definition of the clinical target volume [CTV]) from in-field failures (which require more dose or perhaps less inhomogeneity in dose).

The results of 28 patients treated with EPP followed by IMRT have been reported ⁴²⁶^–⁴²⁸ from the M.D. Anderson Cancer Center. Twenty-six had stage III disease, most had involved lymph nodes, and all patients required partial chest wall resection. During EPP, radiopaque surgical clips were placed at the insertion of the diaphragm, including the crus, and at the anteromedial pleural extension, which often crosses the midline over the heart. The target volume included the entire hemithorax and all surgical clips, all sites of instrumentation, and the ipsilateral mediastinum. Boosts were given to any close or positive resection margins. All volumes were reviewed with the surgeon. The goal dose was 45 to 50 Gy to the hemithorax and 60 Gy to the boost volume. All irradiation was completed in 25 fractions. The 2-year OS rate was 62%. There were no in-field failures. Two marginal misses occurred, one near the crus and one across the midline anterior to the heart. Major toxicities included nausea and vomiting, fatigue, and skin irritation. This series has been extended to 100 patients; EPP followed by IMRT to 45 or 50 Gy resulted in a 13% local or regional recurrence rate.⁴²⁹ There were three (5%) in-field failures. For patients with stage N0 disease and epithelioid histologic typing (about half of patients), the 3-year OS rate was 41% and the median survival time was 28 months.

An update of the MSKCC experience has been published, regarding their radiation therapy technique and outcome.⁴³⁰ Thirty-five patients underwent radiation therapy after EPP, with the goal of delivering 54 Gy in 30 fractions. The target volume was the ipsilateral hemithorax from the top of vertebra T1, ideally to the bottom of vertebra L2, and laterally to flash the skin. All drain sites were included. The medial field edge was the contralateral edge of the vertebral bodies if mediastinal lymph nodes were negative; otherwise, the field was extended 1.5 to 2 cm beyond the contralateral edge of the vertebral bodies. For right-sided lesions, the liver and ipsilateral kidney were blocked. For left-sided lesions, the heart was blocked after 19.8 Gy. The blocked regions were boosted to the target dose with electrons. After 41.4 cGy, the medial field edge was moved to the ipsilateral edge of the vertebral bodies. Patients tolerate this therapy well, with the main toxicities being nausea, vomiting, and dysphagia.

The results of this study, however, were difficult to interpret. Local failure was documented in 13 of 35 patients, but in-field failures were not distinguished from marginal misses. It is not clear whether the pattern of failure resulted from inadequate margins or inadequate doses. However, of the remaining 22 patients with local control, only 5 are disease free. Better systemic therapy is needed.

Perrot and colleagues ⁴³¹ reviewed 60 patients treated with induction chemotherapy, EPP, and hemithoracic RT (≥50 Gy) and found that in stage N0 patients, the median survival time was 59 months, with a 5-year disease-free survival rate of 53%.

These data demonstrate several important points (Table 44-5). First, high-dose postoperative irradiation can dramatically reduce ipsilateral thoracic failures. Second, irradiation after pleural decortication results in a much higher rate of locoregional failure than irradiation after EPP. Consequently, the use of hemithoracic photodynamic therapy after pleurectomy is being studied to decrease the local failure rate with less morbidity than EPP. Third, true in-field failure needs to be well documented. Fourth, postoperative irradiation is well tolerated. Fifth, postoperative radiation therapy changes the pattern of relapse so that distant metastases become more prevalent, requiring the integration of systemic therapy into the treatment regimen.

TABLE 44-5 Large Studies Combining Surgery with Postoperative Radiotherapy

Palliative Radiation Therapy

Pain Control

Irradiation can provide effective palliation for patients with MPM. A radiation dose-response relationship has been reported after the review of outcomes of 29 courses of palliative external beam radiation therapy delivered to 17 patients with MPM.³⁷⁴ Four of six patients treated with more than 40 Gy achieved significant relief of symptoms. Only one patient treated with lower doses achieved significant palliation of any symptom, and this was for a painful chest wall mass.

In another study,⁴³² 26 radiation therapy courses were reviewed for symptomatic improvement. Pain was improved in 13 of 18 cases, and the response was similar regardless of dose or fractionation (i.e., 20 Gy in 5 fractions or 30 Gy in 10 fractions). Although the sample size is small, palliation was achieved in about half of the cases in this very mixed patient group. The duration of response was not assessed in either study. These data demonstrate that symptoms from mesothelioma can usually be palliated effectively with brief courses of irradiation.

Therapy for Drain Sites

Unlike most malignant tumors, MPM has a tendency to recur along tracks of previous chest wall instrumentation.^433,⁴³⁴ There is randomized evidence both in support of and against use of local irradiation to drain and biopsy sites.⁴³⁵ One group took 40 consecutive patients with pathologically proven MPM and randomized them to immediate irradiation to each site of instrumentation or to observation. Elective treatment was 21 Gy in three fractions delivered using en face electron fields. There were no local failures in the irradiated patients compared with eight failures (40%) in the untreated patients.⁴³³ A slightly larger randomized trial found no reduction in the incidence of tumor seeding in the irradiated patients.⁴³⁶ Because such recurrences typically are painful, elective irradiation is a reasonable means of maintaining the patients’ quality of life.

Irradiation Techniques

Patient Immobilization and Setup

Two basic techniques have been described for thoracic irradiation following EPP.^428,⁴³⁰ A description of the IMRT techniques for the postoperative treatment of MPM has been described.^427,⁴²⁸ This level of detail is required to ensure that the very complex target volumes can be identified and reproducibly treated for 5 weeks.

Computed Tomography Simulation

MPM tends to recur at sites of previous instrumentation, and all incision and drain sites should be included in the CTV. Laparoscopy or mediastinoscopy sites have not been included within the CTV as long as the mediastinoscopy was pathologically negative. Radiopaque wires mark the surgical incisions, and the tissue equivalent bolus extends to 4 cm around the wires. Patients are immobilized supine on the CT simulator using a combination of a vacuum bag and an “extended wing board with T-bar handgrip” immobilization device used in conjunction with a headrest. The patient should be scanned from the middle neck to the anterior superior iliac spine. This low inferior border allows complete definition of both kidneys so that accurate dose-volume histograms can be constructed.

Target Volume Delineation

The ipsilateral mediastinum should be included in the target volume,427,435,437 even for node-negative patients. The superior border should be placed at the thoracic inlet. The medial border includes the ipsilateral nodal regions, the trachea and subcarinal regions,⁴²⁸ or the vertebral body.⁴³⁰ The posterior mediastinal structures behind the heart need not be included, because no failures in this region have been recorded (unpublished data) despite their omission from the CTV.⁴²⁷

The anteromedial pleural reflection is a potential problem for target volume delineation. As shown in Figure 44-8, A, the medial pleural space sometimes can cross the midline. This anatomic relationship can be lost after surgery (see Fig. 44-8, B). When possible, this region should be marked intraoperatively with radiopaque clips. Alternatively, the medial extent of the pleura could be identified on preoperative CT scans and then estimated on the treatment-planning CT scan. This has been the site of a marginal miss in our series (see Fig. 44-8, C, arrow).

Figure 44-8 The costomediastinal sulcus can cross the midline. A, Preoperatively, pleural thickening crosses the midline anteriorly (arrow). B, This involvement is obliterated by the extrapleural pneumonectomy (EPP), and the medial edge of the clinical target volume (CTV) was placed at the insertion of the rib (arrow). C, Unfortunately, the tumor recurred immediately adjacent to the CTV (arrow) in a region that received less than 40 Gy.

The inferior border should be the insertion of the diaphragm. The location of this is quite variable, ranging from vertebrae L1 to L4. Because of this variability, the diaphragm insertion should be marked by intraoperative placement of radiopaque clips ⁴²⁶ or by suturing the neodiaphragm in this location.⁴³⁰ When the border of the intrathoracic contents and the abdominal contents is well marked, the radiation therapy margins can be maximally reduced. Because there can be great difficulty in differentiating liver from thoracic fluid, the use of radiopaque Gore-Tex patches for diaphragm reconstructions is helpful.

Another potential source of contouring error is the medial extent of the crus of the diaphragm, especially at its most inferior extent. The ipsilateral crus is usually very difficult to identify after surgery without clips. The best way to individualize the inferior edge of the target volume is with extensive intraoperative placement of radiopaque clips, with particular attention to the crus.

When the entire region is extensively clipped, a pattern such as that seen in Figure 44-9 emerges, with regions of potential pitfall highlighted. These potential problem areas include the anterior medial pleural reflection, the crus of the diaphragm, and the inferior aspect of the diaphragmatic insertion.

Figure 44-9 Potential problem areas for clinical target volume (CTV) determination. Three parts of the CTV are potentially difficult to discern without great care: the anteromedial pleural reflection of the sternopericardial recess (1), the inferior and medial extents of the crus of the diaphragm (2), and the inferior insertion of the diaphragm (3).

Treatment Planning

Three-Dimensional Conformal Radiation Therapy

The three-dimensional conformal radiation therapy approach has been described best in two reports from the MSKCC.^425,⁴³⁰ The technique applies anteroposterior-posteroanterior beam geometry to the hemithorax using the volumes described previously as the CTV. For right-sided cases, an abdominal block is present throughout treatment, and the region is boosted with electrons at 1.53 Gy per day, which accounts for scatter under the block. For left-sided cases, the kidney and heart are blocked. The kidney block is present throughout treatment, and the heart block is added after 19.8 Gy. The spinal cord is shielded after 41.4 Gy in all cases. The goal dose to the target volume is 54 Gy in 30 fractions, with the dose calculated at the midplane with equally weighted beams. Patients were treated with arms akimbo.

Treatment by this approach results in good coverage of most volumes at risk to the target dose of 54 Gy. Doses are very homogeneous within the regions at risk, although regions such as the crus, the pericardium, and the neodiaphragm may be difficult to treat. Radiosensitive structures such as the liver and heart can be spared well. Protection of the ipsilateral kidney is better than with IMRT.

Intensity-Modulated Radiation Therapy

The target doses and the dose-volume limits for the critical structures are listed in Table 44-6. Treatment is delivered with 13 to 27 intensity-modulated fields using 8 to 11 gantry angles, typically with 100 segments per intensity-modulated field. Because patients have only one lung after EPP, the Duke group recommends contralateral lung irradiation limited to a mean lung dose of less than 9.5 Gy.⁴³⁸ This is consistent with the results of whole-lung irradiation.⁴³⁹ The University of Pennsylvania dose constraints are slightly more conservative, with a mean lung dose of less than 9 Gy, a V5 of less than 60%, and a V20 of less than 20%.⁴⁴⁰ With experience, the mean lung dose can be kept to well under 8 Gy.^440,⁴³⁹

TABLE 44-6 Goal Dose or Constraint Dose of the Target or Organ

Target or Organ	Goal Dose or Constraint Dose
CTV	50 Gy in 25 fractions
bCTV	60 Gy in 25 fractions
Lung	<20% to receive >20 Gy and mean <9.5 Gy
Liver	<30% to receive >30 Gy
Contralateral kidney	<20% to receive >15 Gy
Heart	<50% to receive >45 Gy
Spinal cord	<10% to receive >45 Gy
Spinal cord	No portion to receive >50 Gy
Esophagus	<30% to receive >55 Gy

bCTV, boost clinical target volume; CTV, clinical target volume; Gy, Gray.

IMRT is more complicated and takes longer to deliver than three-dimensional conformal radiation therapy, but very good coverage of the target can be achieved. IMRT has dosimetric advantages over three-dimensional conformal therapy due to improved coverage and homogeneity, but there is more dose spillage into the contralateral lung and an increase in the mean lung dose.441,442 A combined electron and 3DCRT to a dose of 54 Gy had significant reduction to the contralateral lung, contralateral kidney, and heart when compared with IMRT to a dose of 45 Gy.⁴⁴¹ Figure 44-10 shows field and block arrangements employed with the use of a combined electron-photon technique. The IMRT plan of 50 Gy to the isodose line in Figure 44-11 encompasses most of the CTV. Review of the dose-volume histogram for this case (Fig. 44-12) demonstrates that the target volume is well covered and the normal tissue constraints are met. The liver and contralateral lung are spared with this technique. In this patient, it was possible to spare the ipsilateral kidney because the organ was particularly low. The ipsilateral kidney usually receives a high dose because the CTV typically abuts its posterior edge. Adequate contralateral renal function is ensured by pretreatment renal scans. For left-sided lesions, the spleen is likely to receive a high radiation dose and pneumococcal prophylaxis is recommended.

Figure 44-10 The total prescribed dose from the AP (A) and PA (B) photon fields and supplemental electron fields was 54 Gy in 1.8-Gy fractions. At the start of treatment, blocks were placed in the region of the abdomen. During treatment of the left hemithorax, an anterior heart block was placed at 19.8 Gy. Blocked areas were subsequently delivered 1.53 Gy daily through an en face electron field. At 41.4 Gy, anterior and posterior blocks were placed over the spinal cord.

Used with permission from Hill-Kayser CE, Avery S, Mesina CF, et al: Hemithoracic radiotherapy after extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma. A dosimetric comparison of two well-described techniques, J Thorac Oncol 4:1431-1437, 2009.

Figure 44-11 A to C, The dose distributions for intensity-modulated radiation therapy (IMRT) demonstrate good coverage of the clinical target volume (CTV) and the high-dose gradients achievable with this technique. The goal was 50 Gy to the CTV. The 50-Gy, 30-Gy, and 10-Gy isodose lines are shown in magenta, orange, green, and blue, respectively.

Figure 44-12 The dose-volume histogram demonstrates that coverage of the target volumes is adequate. The contralateral kidney was well below the goal dose, as was about 25% of the ipsilateral kidney. The mean lung dose was about 9.5 Gy. In this left-sided case, the heart dose was slightly higher than the goal dose (60% to 45 Gy, rather than 50%).

Summary

A review of the limited patient studies (see Table 44-5) in MPM suggests that EPP followed by irradiation gives better local control than pleurectomy followed by irradiation in selected patients. The addition of photodynamic therapy to pleurectomy may improve local control rates, but randomized data are lacking. Postoperative irradiation should include the entire volume immediately adjacent to the pleural space that is at highest risk for microscopic residual disease. This volume should include all sites of pleural reflection, the ipsilateral mediastinum, and the insertion of the diaphragm. The technique by which irradiation is delivered (traditional technique or IMRT) is probably not as important as the target volume delineation and coverage. Prospective trials integrating systemic therapy with EPP and postoperative irradiation are being conducted. Treatment of mesothelioma requires a multidisciplinary approach by an experienced team consisting of a pulmonary specialist, thoracic surgeon, thoracic radiation oncologist, and medical oncologist.