Modern Thoracic Oncology

The following sections are included:

• Foreword
• Contents
• List of Contributors

Recent progress in molecular biology has revealed that several genetic and epigenetic alterations are implicated in both carcinogenesis and progression of esophageal squamous cell carcinoma (ESCC). Genetic alterations include a chromosomal loss or gain, loss of heterozygosity, and amplification or mutation of genes. Epigenetic changes, such as DNA methylation, histone modifications, and altered expression of microRNAs, regulate gene expression through mechanisms other than changes in the DNA sequence. In this section, we summarize the molecular basis of ESCC.

Esophageal cancer (EC) is one of the most common cancers. More than 482,000 new cases were diagnosed worldwide in 2008, and caused about 395,000 deaths in 2010. There are two main histological types of EC, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). In this section, we will briefly introduce the environmental and genetic risk factors of ESCC.

The following sections are included:

• Introduction
• Clinical Presentation
• Diagnosis
• References

Patients with esophageal carcinoma often present with advanced disease. Hence, modern imaging plays a critical role in individualized treatment selection. Accurate staging assesses tumor resectability as well as excludes distant metastatic disease to avoid futile attempts at radical curative therapy.

The prognosis of esophageal squamous cell carcinoma (ESCC) still remains poor largely due to the late diagnosis in its course. However, detection at an early stage is usually associated with a much improved survival and even cure. Therefore, an effective screening strategy for the high-risk mass of ESCC is essential when the disease is still slight and there are minimal lesions that cannot easily be found. Although this kind of screening standard is not established currently, the following methods have proven to be effective and helpful for screening ESCC.

Squamous cell carcinoma of the esophagus shows keratinocyte-like cells containing intercellular bridges (or keratin pearls) and it ranges from well-differentiated to poorly or undifferentiated lesions.

The following sections are included:

• Introduction
• Surgical Approach
• Lymphadenectomy
• Reconstruction
• Summary
• References

The following sections are included:

• Introduction
• Definitive Chemoradiotherapy
• Pre-Operative Chemoradiotherapy
• Radiation Therapy Technique
• References

A spectrum of single chemotherapy agents is active in esophageal carcinoma, including anthracyclines, fluorinated pyrimidines, taxanes and platinum drugs. Cisplatin is one of the most active agents for the treatment of squamous cell carcinoma. Combination chemotherapy regimens provide higher response rates than single-agent regimens, but at the cost of increased toxicity. The combination of cisplatin and 5-flurouracil (5FU) is the most commonly used regimen in both localized and metastatic esophageal cancer with response rates of up to 35–40%.

The following sections are included:

• Prognosis
• Surveillance
• References

By now, it is well established that gastroesophageal reflux disease (GERD) leads to Barrett’s esophagus. In addition, the transition of Barrett’s esophagus (BE) to low- and high-grade dysplasia and eventual esophageal adenocarcinoma (EAC) are accepted by the multiple medical disciplines that deal with these diseases. Current estimates are that patients with Barrett’s have a 30- to 125-fold risk of developing EAC, and the conversion rate from BE to EAC is estimated to be 0.5% to 1.0% per year. What has yet to be fully elucidated, however, is the complex series of molecular and genetic events that lead to the development of this premalignant precursor and eventual adenocarcinoma. The primary purpose of this section is to summarize what is currently known about these processes. For the clinician, the importance of understanding the basic science behind the development of EAC is two-fold. First, with the enhanced ability to assess the genetic makeup of tissue, it is highly likely that relevant biomarkers will become established predictors for the development of EAC in patients with BE. Secondly, as modern medical oncology transitions to the utilization of “targeted” therapies, it is imperative that clinicians understand the impact of these small molecule inhibitors on cellular signaling pathways.

The following sections are included:

• Introduction
• Descriptive Epidemiology
• Risk Factors
• Conclusions
• References

The most common presenting symptoms of adenocarcinoma of the esophagus are dysphagia, odynophagia and weight loss. Although these common symptoms often occur with solid food initially; over time swallowing of both solids and liquids can be affected. Additional symptoms may include coughing (from aspiration), pneumonia (from aspiration or trachea-esophageal fistula), chest pain, hematemesis, bony pain (metastases), hoarseness, and/or abdominal complaints.

The main imaging modalities used in the detection, staging, and post-treatment follow up of esophageal adenocarcinoma are endoscopic ultrasound, CT, and PET/CT. The combination is used to establish the clinical or pretreatment stage (cTNM), which bears important prognostic information and determines treatment planning. It is therefore important to recognize the strengths and limitations of each imaging modality so that they are appropriately utilized.

The following sections are included:

• Introduction
• Rationale for Screening
• Challenges to Screening
• Advances in Screening Techiniques
• Identifying the Target Population for Screening
• Stratification of Barrett’s Esophagus Cancer Risk
• Summary
• References

The following sections are included:

• Pathology
• Staging
• References

The following sections are included:

• Introduction to Endoscopic Eradication Therapy
• Endoscopic Mucosal Resection (EMR)
• Radiofrequency Ablation (RFA)
• Cryotherapy and Photodynamic Therapy (PDT)
• Summary
• References

The following sections are included:

• Introduction
• Pre-Operative Evaluation
• Tumor Location
• Brief Operative Details
• Complications
• Conclusion
• References

The following sections are included:

• Radiation Therapy as a Single Modality
• Dual-Modality Therapy: Adjuvant or Pre-Operative Radiation Therapy with Surgery
• Dual-Modality Therapy: Chemoradiation
• Tri-Modality Therapy: Surgery with Chemoradiation
• Radiation Therapy Delivery Techniques
• References

Multiple studies have shown over time that chemotherapy is useful in adenocarcinomas of the gastroesophageal (GE) junction and proximal gastric adenocarcinomas, when compared to best supportive care, in the first line and second line settings. Active agents include platinums, fluoropyrimindines, anthracyclines, taxanes and topoisomerase inhibitors.

The following sections are included:

• Prognosis
• Surveillance
• References

Dramatic improvements in our ability to stage esophageal cancer have significantly altered the management of these tumors over the last 20 years. Most notably, the introduction of endoscopic ultrasound (EUS) has improved the assessment of early disease and nodal involvement, facilitating the use of endoscopic mucosal resection (EMR) for high-grade dysplasia (HGD) and selected T1 tumors. Positron emission tomography combined with computed tomography (PET/CT) has greater sensitivity for nodal and metastatic disease compared to CT alone, which has improved patient selection for neo-adjuvant and non-surgical pathways.

Thymic malignancies represent a wide range of anatomical, clinical, histological, and molecular entities that may be aggressive and difficult to treat. The World Health Organization histopathologic classification distinguishes thymomas from thymic carcinomas; thymomas are further subdivided into different types (so-called A, AB, B1, B2, and B3) based upon the morphology of epithelial tumor cells (with an increasing degree of atypia from type A to B3), the relative proportion of the non-tumoral lymphocytic component (decreasing from type B1 to B3), and resemblance to normal thymic architecture. Thymic carcinomas are similar to their extrathymic counterpart, the most frequent subtype being squamous cell carcinoma.

The following sections are included:

• Clinical Presentation
• Diagnosis
• References

Thymic epithelial tumors (TETs) are rare and of these, thymoma is most common followed by thymic carcinoma and thymic carcinoid. The goal of imaging TETs is to diagnose, stage, and follow up for recurrence and/ or treatment response.

The following sections are included:

• Introduction
• Benign Conditions
• Malignant Tumors
• References

The following sections are included:

• Introduction
• Principles of Surgery for Thymic Neoplasms
• Summary
• References

Indications and techniques for post-operative radiation therapy (PORT) for invasive thymoma have evolved over the past decade. As increased evidence suggests high local control rates with surgery alone in Masaoka stage I disease, there is a general consensus that in early stages PORT can be omitted. In addition, as patterns of failure analyses have demonstrated a propensity for pleural failure, there has been interest in utilizing more extensive radiation fields, either as prophylaxis or when recurrence occurs. Finally, the advent of advanced radiation techniques has allowed for increased sparing of mediastinal structures such as the heart, great vessels, and lung. This reduction in dose may ultimately lead to lower side effects, thus enhancing the quality of life for survivors of this malignancy.

The following sections are included:

• Introduction
• Chemotherapy as Part of Curative Intent
• Palliative Chemotherapy
• Targeted Therapies
• Conclusions
• References

The prognosis for thymic epithelial malignancies is stage-dependent with a large multi-institutional experience from Japan reporting 5-year survival rates in 1,320 patients of 100%, 98.4%, 88.7%, 70.6%, and 52.8% for Masaoka stages I, II, III, IVa, and IVb, respectively. Furthermore, Magi, et al. reported 10-year disease-free survival rates in 241 patients of 74%, 71%, 50%, and 29% for stage I, II, III, and IV disease, respectively. The single most important prognostic factor is complete (R0) surgical resection, which has been associated with an 82% 7-year overall survival rate while incomplete resection and biopsy have only a 71% and 26% survival, respectively. Survival following complete resection has been similar in patients with both noninvasive and invasive tumors. While the presence of myasthenia gravis was once felt to be a poor prognostic factor, it actually may lead to earlier detection due to myasthenic symptoms. Patients rarely still develop myasthenic crisis, which leads to significant postoperative morbidity and even mortality. Data regarding survival based on World Health Organization (WHO) histologic subtype is inconclusive but may be prognostic in some situations. Postoperative adjuvant radiation (PORT) may improve the prognosis in patients with regional tumor spread (91% vs 86%; p = 0.12), but according to SEER registry data (1975–2003) patients with completely resected localized disease may actually fare worse with PORT (91% vs 98%; p = 0.03). PORT following incomplete surgical resection has associated local control rates of 35% to 74%. Furthermore 5-year survival rates range from 50% to 70% for stage III and 20% to 50% for stage IVa tumors following surgery and PORT. The prognosis for more advanced tumors, i.e,. unresectable stage III and IV thymomas, depends on responsiveness to multimodality therapy typically including preoperative (induction) chemotherapy, surgery, and PORT. In small institutional series, reported complete and overall response rates were as high as 25% and 92%, respectively, with a 7-year disease-free survival of 83%. Others document a disease-free survival as low as 43% at 8 years despite a complete (R0) resection rate of 39% following induction chemotherapy. The prognosis with new targeted therapies remains to be determined.

The following sections are included:

• Introduction
• Epidemiology of Mediastinal Germ Cell Tumors
• References

The following sections are included:

• Clinical Presentation and Diagnosis
• Rare Presentations of Primary Mediastinal Non-Seminomatous Germ Cell Tumors
• Conclusion
• References

The following sections are included:

• Mature Teratoma
• Primary Mediastinal Seminoma
• Primary Mediastinal Non-Seminoma
• References

Radiotherapy was once the mainstay of therapy for mediastinal seminomas, but the advent of cisplatin-based chemotherapy has largely supplanted its role. This section will focus on the role of radiotherapy in the management of mediastinal seminomas. Non-seminomatous germ cell tumors were included in many of the initial case series cited below — they are generally not responsive to radiotherapy, and there is currently no role for radiotherapy in the treatment of non-seminomatous germ cell lesions of the mediastinum.

It has been well established that overall survival after multimodality treatment of primary mediastinal non-seminomatous germ cell tumor (PMNSGCT) is inferior compared to non-seminomatous germ cell tumors originating in the testes. Goss et al. reported on a 14-year experience in Toronto with 24 PMNSGCT patients and found a 47% survival at five years. A multicenter retrospective study from Spain involving 27 PMNSGCT patients, reported a 32% five-year survival; however, 12 of these patients had metastatic disease at the time of presentation. Fizazi and coworkers reviewed 38 PMNSGCT patients, 29 of whom were referred for primary treatment to their institution. Only ten of these patients have remained disease-free after a median follow-up of 89 months. Inferior survival has been mainly attributed to a higher incidence of cisplatin-refractory non-seminomatous germ cell cancer including non-germ cell cancer present in PMNSGCT as compared to testes non-seminomatous germ cell tumors.

Neurogenic tumors originate from neural cells. These tumors are occasionally seen in posterior mediastinum and paravertabral sulcus. They are associated with the sympathetic neural chain, spinal cord, and intercostal nerves; so neurogenic tumors can be seen in any neural tissue. In both paravertebral sulci, they are reported in equal percentages. Out of all primary mediastinal tumors, 11–21% and 35–46% consist of neurogenic tumors in adults and children, respectively…

Sarcomas of the chest wall arise either from the soft tissue or bony structures and account for approximately 10,000 cases a year in the United States. Complete surgical resection (R0) with sufficient negative margins has been the foundation of treatment for decades to minimize recurrence and to achieve long-term survival. Reconstruction of the chest wall defect including soft tissue coverage completes the intraoperative surgical management. Improvements in surgical techniques, anesthesia, critical care, and the development and refinement in reconstruction techniques have allowed extensive chest wall resections to be performed in all patients with acceptable morbidity and mortality…

Chest wall sarcomas are rare, and the literature consists of series that are difficult to compare given variations in the histological subtypes (soft tissue versus bony sarcomas), sites (superficial trunk, thoracic, or grouped with extremities), presentation types (primary versus recurrent), and use of adjuvant (or neoadjuvant) therapies included in study periods often extending over the span of decades. Primary management of chest wall sarcomas is surgical, with oncologic resection often requiring a wide full-thickness chest wall resection, skeletal reconstruction, and soft tissue coverage of the defect. Even with surgical management, radiation may improve outcomes. To that end, a multidisciplinary approach is required for optimal therapy.

The following sections are included:

• Overview
• Etiology and Genetics
• Clinical Presentation and Diagnosis
• Imaging
• Staging
• Biopsy
• Pathology
• Histologic Classification
• Prognosis
• Treatment of Localized Disease
• Metastatic Disease
• Surgery for Metastatic Disease
• Surveillance
• References

Prognosis for chest wall sarcomas is often hard to tease out in the literature, given that many series include this location with retroperitoneal and trunk tumors as well as bone chest wall tumors and extremity soft tissue sarcomas. Because of the uncommon nature of this tumor, it is often difficult to delineate prognostic indicators. We cannot necessarily extrapolate prognostic variables from soft tissue sarcomas as the majority are located in the extremities.

Primary tumors of the diaphragm are quite rare. The first diaphragmatic tumor was reported in 1868 by Grancher. About 150 cases have been reported in the English literature since then. Most primary tumors of the diaphragm are benign (lipoma being the commonest benign tumor). Fibrosarcoma appears to be the commonest in the malignant subgroup. The histological origin of these tumors is from the mesenchymal components of the diaphragm tissue, which consists of a musculotendinous membrane. Various benign and malignant subtypes of diaphragmatic tumors described are listed in Table 1.

The following sections are included:

• Biological Basis of the Disease
• Epidemiology
• Clinical Presentation and Diagnosis
• Imaging
• Staging
• Surgical Treatment
• Chemotherapy
• Prognosis
• References

The following sections are included:

• Introduction
• Common Criteria for Pulmonary Metastasectomy
• International Registry of Lung Metastasis
• Oliogoprogression
• Surgical Techniques
• Conclusion
• References

Oligometastatic disease refers to a disease state in cancer that lies between localized and widely disseminated. Although the precise number of sites defining oligometastatic disease is debatable, a consensus definition of five sites or less has been described. A clinically meaningful characteristic of oligometastatic disease is that a patient with oligometastatic cancer may be curable with radical local therapies that eliminate all known sites of disease. The potential survival benefit of aggressive local treatments in the setting of oligometastatic cancer must be balanced against risk of toxicity and maximization of quality of life.

The following section is included:

• Index