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Small Cell Lung Carcinoma: Staging, Imaging, and Treatment Considerations1 Brett W. Carter, MD Bonnie S. Glisson, MD Mylene T. Truong, MD Jeremy J. Erasmus, MD Abbreviations: AJCC = American Joint Committee on Cancer, ES-SCLC = extensive-stage SCLC, FDG = 2-[fluorine-18]fluoro-2-deoxyd-glucose, IASLC = International Association for the Study of Lung Cancer, LS-SCLC = limited-stage SCLC, SCLC = small cell lung carcinoma, SUVmax = maximum standardized uptake value, TNM = tumor-node-metastasis, TRT = thoracic radiation therapy, TTF-1 = thyroid transcription factor 1, VALSG = Veterans Administration Lung Cancer Study Group, WHO = World Health Organization RadioGraphics 2014; 34:1707–1721 Published online 10.1148/rg.346140178 Content Codes: From the Department of Diagnostic Radiology, Division of Diagnostic Imaging (B.W.C., M.T.T., J.J.E.), and Department of Thoracic/ Head and Neck Medical Oncology, Division of Cancer Medicine (B.S.G.), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1478, Houston, TX 77030. Received April 12, 2014; revision requested June 9 and received June 27; accepted July 3. For this journal-based SA-CME activity, the author B.W.C. has provided a disclosure (see p 1720); all other authors, the editor, and the reviewers have disclosed no relevant relationships. Address correspondence to B.W.C. (e-mail: bcarter2@ mdanderson.org). 1

SA-CME LEARNING OBJECTIVES After completing this journal-based SACME activity, participants will be able to: ■■Describe the staging of small cell lung carcinoma using the Veterans Administration Lung Cancer Study Group and American Joint Committee on Cancer TNM staging systems. ■■Discuss

the roles of CT and PET/CT in evaluating patients with small cell lung carcinoma. ■■Correlate

imaging findings with the clinical staging criteria for small cell lung carcinoma and discuss the implications for treatment planning and patient survival. See www.rsna.org/education/search/RG.

Small cell lung carcinoma (SCLC) is the most common primary pulmonary neuroendocrine malignancy and is characterized by a rapid doubling time and high growth fraction. Approximately 60%–70% of patients present with metastatic disease at the time of diagnosis, and their prognosis is poor. However, improved survival has been demonstrated when SCLC is diagnosed early and specific treatment strategies are used. A modified version of the Veterans Administration Lung Cancer Study Group (VALSG) staging system has traditionally been used to categorize SCLC as limited-stage or extensive-stage disease to guide therapy. However, the International Association for the Study of Lung Cancer has recommended that the current seventh edition of the American Joint Committee on Cancer tumor-node-metastasis staging system for lung cancer replace the VALSG system for staging of SCLC. Appropriate staging and patient management require knowledge of imaging manifestations of SCLC across multiple imaging modalities, the strengths and weaknesses of specific examinations, the correlation of these findings with the staging criteria used in clinical practice, and the impact of appropriate staging on patient treatment and survival. Computed tomography (CT) is primarily used to evaluate the primary tumor and the extent of intrathoracic disease. In recent years, however, 2-[fluorine-18]fluoro-2-deoxy-d-glucose positron emission tomography/CT has proved to be more accurate than conventional imaging in the staging of SCLC and can be used to guide therapy and assess treatment response. ©

RSNA, 2014 • radiographics.rsna.org

Introduction

The 2004 World Health Organization (WHO) classification scheme divides lung cancer into two major histologic categories: non–small cell lung carcinoma (non-SCLC) and SCLC (1,2). SCLCs account for 13%–15% of all lung cancers and are the most common primary pulmonary neuroendocrine neoplasm (3,4). Cigarette smoking is responsible for approximately 95% of cases, and of all the histologic subtypes of lung cancer, SCLC has the strongest association with cigarette smoking (5). SCLC is more aggressive than non-SCLC and is characterized by a rapid doubling time, high growth fraction (the ratio of proliferating cells to total cells), and greater propensity for early development of widespread metastases. At initial diagnosis, approximately 60%–70% of patients have metastatic disease (6). SCLC is usually categorized according to a modified version of the Veterans Administration Lung Cancer Study Group (VALSG) staging system as either limited-stage SCLC (LS-SCLC) or extensive-stage SCLC (ESSCLC) (7). However, the International Association for the Study of Lung Cancer (IASLC) has recommended that the current seventh edition of the America n Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for lung cancer replace

IMAGING OF UNCOMMON PRIMARY INTRATHORACIC MALIGNANCIES

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the modified VALSG system (8). Accurate staging of patients with SCLC helps guide individual treatment strategies, since patients with LS-SCLC are candidates for curative-intent chemotherapy– radiation therapy, a small percentage of whom experience long-term survival. In this article, we review the pathophysiology and natural history of SCLC and discuss the role of computed tomography (CT) and 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/CT in the evaluation and staging of patients with the disease.

Classification of Pulmonary Neuroendocrine Neoplasms

The 2004 WHO tumor classification scheme includes four major types of pulmonary neuroendocrine tumors, which are grouped into three histologic grades. Low-grade malignant neoplasms include typical carcinoid tumor, intermediate-grade neoplasms include atypical carcinoids, and high-grade neoplasms include large cell neuroendocrine tumor and SCLC (3,9,10). In this article, however, we focus on SCLC.

Epidemiologic and Clinical Features

More than 95% of high-grade neuroendocrine carcinomas originate in the lung, whereas extrapulmonary tumors involving organs such as the nasopharynx, gastrointestinal tract, and genitourinary tract are exceptionally rare, with a prevalence of 0.1%–0.4% in the United States (11). The prevalence of SCLC in the United States peaked in the 1980s and has been declining since that time (4), decreasing from 17%–20% to 13%–15% over the past 30 years (4,12). Several factors may, at least in part, be responsible for this decline, such as a decrease in smoking rates, increased use of filtered cigarettes, and changes that have been made to the pathologic criteria for SCLC. SCLC typically affects patients between the ages of 60 and 70 years (13). Although SCLC has historically been seen more frequently in men than in women by a ratio of 2.6:1, its prevalence has remained the same since 2002 (4,14). The most common signs and symptoms reported at the time of presentation include cough, chest pain, hemoptysis, and dyspnea. Because patients typically have systemic disease at the time of diagnosis, symptoms such as weight loss, fatigue, and anorexia are often present. Patients with invasive or advanced disease may present with specific symptoms. For instance, 10% of patients report symptoms related to superior vena cava syndrome (9,13). Invasion of the esophagus and mediastinal structures (eg, the recurrent laryngeal nerve and trachea) can result in dysphagia and hoarseness, respectively.

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Extrapulmonary metastatic disease can manifest as bone pain, pruritus, jaundice, seizures, changes in mental status, and/or ataxia (9,13). Clinical symptoms can also be caused by tumor excretion of a bioactive substance such as a hormone, or can result from immune-mediated destruction of neural tissue caused by antibody- or cell-mediated immune responses (9). Numerous paraneoplastic disorders have been described in association with SCLC (2). The endocrine paraneoplastic syndrome most commonly associated with SCLC is the syndrome of inappropriate antidiuretic hormone secretion, which is characterized by excessive secretion of antidiuretic hormone and results in less concentrated urine, reduced plasma osmolarity, and euvolemic hyponatremia. Other endocrine paraneoplastic syndromes include Cushing syndrome secondary to ectopic adrenocorticotropic hormone and acromegaly due to ectopic growth hormone–releasing peptide. Neurologic paraneoplastic syndromes include autoimmune neuropathy (Eaton-Lambert syndrome), encephalomyelitis, and limbic encephalitis (9). In patients with these syndromes, neurologic symptoms typically precede the diagnosis of lung cancer by up to 2 years, are incapacitating, and progress rapidly, although improvement can occur after treatment of the lung cancer (15–18).

Histologic and Gross Pathologic Features

The diagnosis of SCLC may be established by examining tissue obtained at fine-needle aspiration biopsy or core biopsy. At light microscopy, SCLC is characterized by small blue round, oval, or spindle-shaped cells with scant cytoplasm, ill-defined borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli (Fig 1a) (2,6). Of the pulmonary neuroendocrine tumors, SCLC has the highest mitotic rate (>10 mitoses per 10 high-power fields; median, 80 mitoses per 10 high-power fields), and extensive necrosis is typically present. Nuclear molding is observed in well-preserved specimens, although crush artifact is more commonly encountered. The WHO recognizes two subtypes of SCLC: pure SCLC and combined SCLC (3,9). The majority of tumors are pure SCLCs; because only a limited amount of tissue is typically available for analysis, the combined subtype is rarely seen. Combined SCLC is characterized by the presence of a non-SCLC component such as adenocarcinoma, squamous cell carcinoma, large cell carcinoma, spindle cell carcinoma, or giant cell carcinoma (2,6). For a diagnosis of combined SCLC–large cell carcinoma to be made, at least

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Figure 1.  Microscopic features of SCLC. (a) High-power photomicrograph (original magnification, ×400; hematoxylin-eosin stain) of a core biopsy specimen from a right upper lobe lesion shows tumor cells with extensive mitoses and marked nuclear atypia. (b) High-power photomicrograph (original magnification, ×400; chromogranin stain) of the same specimen shows positive staining for chromogranin (brown).

10% of the tumor should be composed of large or giant cells. However, for other histologic subtypes such as adenocarcinoma, squamous cell carcinoma, or spindle cell carcinoma, the proportion of large or giant cells is inconsequential to the diagnosis (2,6). Immunohistochemical analysis for the diagnosis of SCLC typically includes a pancytokeratin antibody such as AE1/AE3, CD56, chromogranin (Fig 1b)–synaptophysin, thyroid transcription factor 1 (TTF-1), or Ki-67. If specimens are negative for pancytokeratin antibodies, other tumors such as lymphoma (CD45 and CD20), primitive neuroectodermal tumors (CD99), and melanoma (S100) must be excluded (9). Approximately 80% of SCLCs demonstrate TTF-1 positivity (19,20). The Ki-67 proliferation index ranges from 80% to 100% for SCLC and can be used to differentiate SCLC from carcinoid. Differentiation of SCLC from basaloid squamous cell cancer can be made at immunohistochemical analysis. For instance, expression of neuroendocrine markers and TTF-1 is seen in SCLC, whereas expression of p63 (4A4) and high-molecular-weight cytokeratins (CK5/6 or 34bE12) is present in basaloid squamous cell carcinoma. Over 90% of SCLCs are centrally located and tend to surround and constrict the major bronchi (21). Tumors may directly invade and metastasize to regional lymph nodes and may spread in a lymphangitic pattern in the lung. However, SCLC may occasionally arise as a relatively small bronchial tumor. Surgical resection of SCLC is rarely performed. However, in cases of resection, the tumor typically manifests as a circumscribed peripheral lung nodule measuring 2–4 cm with a tan, ne-

crotic cut surface (9). At CT, these peripheral tumors are typically spiculated, a finding that represents vascular, lymphatic, or intraalveolar invasion, with surrounding ground-glass opacity representing focal edema and hemorrhage and, less commonly, intraalveolar invasion (21).

Staging of SCLC

The VALSG staging system traditionally divided SCLC into LS-SCLC and ES-SCLC (Table 1) (7). Historically, LS-SCLC was characterized as tumoral involvement limited to one hemithorax (with or without local extension) with no distant extrathoracic metastatic disease. Regional and ipsilateral supraclavicular lymph nodes were considered LS-SCLC if they could be included in a single safe and adequate radiation port. All other cases were thought to represent ES-SCLC and included features such as malignant pleural and pericardial effusions, contralateral hilar or supraclavicular lymph nodes, and metastatic disease that could not be treated in a single radiation port. In 1989, however, the IASLC proposed changes to the VALSG system (Table 2), the most important of which grouped contralateral mediastinal or supraclavicular lymph nodes and ipsilateral pleural effusions (whether benign or malignant) under LS-SCLC (22). ESSCLC was classified as disease that went beyond LS-SCLC. At one institution, a retrospective study of 109 patients with SCLC indicated that the IASLC system had better prognostic value than the VALSG system (23). In clinical practice, specific features of the VALSG and IASLC systems have typically been combined. For example, LS-SCLC can include contralateral mediastinal and ipsilateral supraclavicular lymph node involvement. However, certain disease

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features such as contralateral supraclavicular or hilar lymph node involvement remain controversial, and clinical treatment is typically based on the ability to include these regions in a safe and adequate radiation port (24). The IASLC has recommended that the current seventh edition of the AJCC TNM staging system for lung cancer replace the VALSG system for the staging of SCLC (Table 3) (8). In this system, stages I–III correspond to LSSCLC and stage IV corresponds to ES-SCLC. In a study of approximately 10,000 patients identified in the California Cancer registry between 1991 and 2005, the AJCC TNM staging system was shown to better differentiate stage-specific survival in SCLC than the VALSG system (25). However, it should be noted that the TNM staging system does not frequently alter clinical management and is less powerful in the assessment of prognosis. Still, it is useful in identifying patients who may benefit from surgical resection. Therefore, incorporation of the TNM system into clinical research and cancer registries is important (26).

Patient Evaluation

The evaluation of patients with an initial diagnosis of SCLC includes a detailed history and physical examination, laboratory studies such as complete blood counts and chemical analyses, and pathologic review of tumor specimens. Because imaging is the principal method of staging SCLC and accurate staging of the disease is critical to formulating treatment strategies, careful selection of imaging studies is paramount. Contrast material–enhanced CT of the chest through the adrenal glands is the principal method of evaluating the primary tumor and determining the extent of disease. Imaging of the brain, ideally with magnetic resonance (MR) imaging, is recommended for all patients, since metastatic disease is reported to occur in 10%–15% of neurologically asymptomatic patients, including 12% of patients who would otherwise be considered as having LS-SCLC (27,28). In one study, all lesions detected at CT were seen in symptomatic patients, whereas 11% of lesions detected at MR imaging were seen in asymptomatic patients (28). Overall, the most common sites of metastases are bone (19%–38% of cases), liver (17%–34%), adrenal glands (10%– 17%), and brain (up to 14%) (29). FDG PET/ CT is typically performed in patients with SCLC. If FDG PET/CT is unavailable, bone scintigraphy with technetium-99m methylene diphosphonate and CT of the abdomen are recommended. Although bone marrow aspiration and biopsy have allowed detection of metastatic disease in 15%–30% of patients at the time of diagnosis,

radiographics.rsna.org Table 1: VALSG Staging System LS-SCLC  Confined to a single radiation port  Confined to the ipsilateral mediastinum  Ipsilateral mediastinal or supraclavicular lymph  nodes ES-SCLC  Not confined to a single radiation port  Contralateral mediastinal or supraclavicular  lymph nodes  Malignant pleural or pericardial effusion  Metastatic disease Table 2: Modified VALSG Staging System LS-SCLC  Confined to a single radiation port  Ipsilateral mediastinal or supraclavicular lymph  nodes  Contralateral mediastinal or supraclavicular  lymph nodes  Ipsilateral pleural effusions (benign or malignant) ES-SCLC  Not confined to a single radiation port  Metastatic disease

less than 5% of patients have bone marrow involvement as an isolated site of metastatic disease. Therefore, routine bone marrow studies are not recommended in patients with normal blood counts (30–32).

Imaging of SCLC General Features Because 90%–95% of SCLCs arise from lobar or main bronchi (33), the most common manifestation of SCLC is a large mass centrally located within the lung parenchyma (Fig 2) or a mediastinal mass involving at least one hilum (Fig 3) (21). Centrally located SCLCs can result in atelectasis of either a lobe or the entire lung. Although both the primary lung malignancy and mediastinal lymphadenopathy can sometimes be identified (Fig 4), confluent mediastinal lymphadenopathy can be present without visualization of a primary lung tumor (21,34,35).

Computed Tomography Most SCLCs are located within the central aspect of the chest and manifest as a mediastinal (92% of cases) or hilar (84%) lymphadenopathy (21). Contrast-enhanced CT can be useful in revealing the extent of mediastinal invasion (Fig 5). Encasement of mediastinal structures such

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Table 3: AJCC TNM Staging System for Lung Cancer Stage Primary tumor (T) TX T0 Tis T1

T1a T1b T2

T2a T2b T3

T4 Lymph nodes (N) NX N0 N1 N2 N3 Metastasis (M) M0 M1 M1a M1b

Description

Primary tumor cannot be assessed or is indicated by the presence of malignant cells in sputum or bronchial washings but not visualized at imaging or bronchoscopy No evidence of primary tumor Carcinoma in situ Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus) Tumor ≤2 cm in greatest dimension Tumor >2 cm but ≤3 cm in greatest dimension Tumor >3 cm but ≤7 cm in greatest dimension or has any of the following features: involves the main bronchus 2 cm or more distal to the carina, invades visceral pleura, or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung Tumor >3 cm but ≤5 cm in greatest dimension Tumor >5 cm but ≤7 cm in greatest dimension Tumor >7 cm in greatest dimension or directly invades the parietal pleura, chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium; tumor in the main bronchus