PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
The adenocarcinomas (ADCs) arise from the intrapulmonary bronchi that branch like limbs of a tree in each lung, dividing into segmental and subsegmental bronchi.
PERSPECTIVE AND PATTERNS OF SPREAD
Adenocarcinomas (ADC) are the most common histopathologic type of lung cancer (Fig. 15.1), and they have gradually exceeded squamous cell cancers in incidence in the past two decades. The mucosal lining of the respiratory epithelium of the major bronchi is a pseudostratified ciliated columnar epithelium with goblet cells, which constitute 30% of the total cell population. They produce the mucinogen secretions and provide the mucin lubrication when released in an aqueous environment. These gland-forming ADC cells tend to give rise to four sub-types or variants ranging from well-differentiated ADCs with abundant mucous production to undifferentiated varieties that tend to lose their glandular arrangement (Table 15.1).
These cancers tend to be pulmonary in the more peripheral regions, arising in the lobar bronchi (Fig. 15.2; Table 15.2), which is also a major factor in determining their clinical presentation. They are the predominant female lung cancers (69%) and constitute 45% of male lung cancers. ADCs arise in lobar bronchi, which is the key determinant in their clinical presentation and pattern of spread. Because the lobar and segmental bronchi are the scaffolding for the lung, such cancers trigger segmental or lobar collapse or obstructive pneumonitis, which are more peripheral in location and do not extend beyond the lung hilus.
Cavitation produces a thickened wall with an air fluid level. The wall is irregular and its thickness is the key to whether it is benign or malignant. A wall thickness of 4 mm or less is 92% benign, between 5 to 10 mm it is 51%, and greater than 15 mm it drops to 5%. Cavitation is more common in squamous cell cancer and large cell anaplastic cancers; small cell anaplastic cancers do not cavitate.
PATHOLOGY
The precursor lesion for pulmonary adenocarcinoma is believed to be atypical alveolar hyperplasia (AAH), typically a coincidental finding in resected lung lobes. AAH is composed of proliferating type II pneumocytes and associated with bronchioloalveolar cancer. Genetic and cytologic features often overlap, making histologic distinction between bronchi-oloalveolar cancer and adenocarcinoma difficult. Only 1% to 5% of AAH cases progress to adenocarcinoma over a period of years.
The findings of a lung nodule that is more peripheral than central in location is a common presentation. The increased incidence in women of adenocarcinoma is 70% as opposed to men, where it is only 57%, and in both, it is more than 50%. Because of its peripheral location, extension to pleura is more common than squamous cell cancer.
Figure 15.1 | Adenocarcinoma of the lung. A papillary adenocarcinoma consists of malignant epithelial cells growing along thin fibrovascular cores.
Figure 15.2 | Patterns of spread. The primary cancer adenocarcinoma (ADC) invades in various directions, which are color coded for T stage: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red; and metastatic, black. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern i.e. SIMLAP Table 15.2.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
In their earliest stages, ADCs can be detected as pulmonary lesions T1 (3 cm) or T2 (>3 cm) that are intrapulmonary. The lung segments that collapse or consolidate do not extend beyond the hilar region medially. Such cancers lead to persistence or recurrence of symptoms and signs, namely, obstructive pneumonitis. The pathology does not extend beyond the visceral pleura laterally. Their stage categories have been consistent over the past decade and their associated findings are highlighted in Figure 15.3. The color code corresponds to a basic key, but T4 lesions are noted in red and black, with the malignant gradient being highest with mediastinal visceral invasions. The distinction between T3 and T4 occurred in the American Joint Committee on Cancer's (AJCC) fourth edition (1992). T3 cancers do not extend to the chest wall parietal pleura and are limited in extent to the visceral pleura. The stigmata of T4, unresectable cancer, are due to invasion of mediastinal viscera as heart, esophagus, and vital structures such as the great vessels, aorta, and vena cava.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• This staging system is now recommended for the classification of both non–small cell and small cell lung carcinomas and for carcinoid tumors of the lung.
• The T classifications have been redefined (Fig. 15.3):
• T1 has been subclassified into T1a (≤2 cm in size) and T1b (>2–3 cm in size)
• T2 has been subclassified into T2a (>3–5 cm in size) and T2b (>5–7 cm in size)
• T2 (>7 cm in size) has been reclassified as T3
• Multiple tumor nodules in the same lobe have been reclassified from T4 to T3
• Multiple tumor nodules in the same lung but a different lobe have been reclassified from M1 to T4
• No changes have been made to the N classification. However, a new international lymph node map defining the anatomical boundaries for lymph node stations has been developed.
• The M classifications have been redefined:
• The M1 has been subdivided into M1a and M1b
• Malignant pleural and pericardial effusions have been reclassified from T4 to M1a
• Separate tumor nodules in the contralateral lung are considered M1a
• M1b designates distant metastases
The TNM Staging Matrix is color coded for identification of Stage Group once T and N stages are determined (Table 15.3).
ADENOCARCINOMA
Figure 15.3 | TNM staging diagram. Adenocarcinomas are peripheral arising in segmental bronchi and tend to be associated with atelectasis or obstructive pneumonitis. Vertical presentation of stage groupings, which follow the same color code for cancer advancement, are organized in horizontal lanes: Stage 0, yellow; I, green; II, blue; IIIA, purple; IIIB, red; and metastatic stage IV, black. Definitions of TN are on the left and stage groupings is on the right. Major stage group progression is dominated by the N stage progression.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
The isocenter chosen relates to the branching lobar and segmental bronchi. The three-planar levels are chosen at thorax T3-4 level. The plane at this level divides the superior and inferior mediastinum. It is central to understanding the thoracic anatomy (Fig. 15.4).
T-oncoanatomy
The bronchial tree in which ADCs arise branches throughout the pulmonary parenchyma undergoing 10 orders of division. The trachea, which lies in the superior mediastinum, divides into right and left main stem bronchi that extend into the right and left lungs. At that point, they divide into lobar bronchi for the upper, middle, and lower lobes on the right, and the upper and lower lobes on the left. Each lobar bronchus divides into segmental bronchi (Fig. 15.5).
The lobes of the lung are divided into bronchopulmonary segments (10 per lung) and are defined by the branching of the segmental bronchi. The mucosa lining the bronchus is the usual site of origin for cancer of the lung, although cancer also may arise in the more peripheral areas of the bronchiolar tree.
Of particular interest are both the symmetry and asymmetry that exist between various portions of the left and right lungs and the bronchial trees. The projection of the lower lobe lesions in the upper half of the lung emphasizes the need to understand this complex anatomy. It is important to be familiar with the lung lobes in different projections when viewed anteriorly and posteriorly as well as their lateral and medial faces to recognize obstructive pneumonitis on chest films.
The right lung has three lobes and the left lung has two lobes. The middle lobe in the right side arises from the lower lobe bronchus, whereas the lingula, or the left side, which corresponds to the middle lobe, arises from the upper lobe bronchus. Major and segmental bronchi are presented in Figure 15.5A.
• Coronal: Anterior view demonstrates the lobar and segmental anatomy of the bronchial tree. Note the asymmetry of right and left lungs with the middle lobe on the right being equivalent to the lingula except the middle lobe bronchus arises from the lower lobe bronchus and the lingual from the upper lobe.
• Transverse (Fig. 15.5): This T3-4 level is at the plane dividing the mediastinum. Note broadening of the trachea at the carina, the azygos vein arching into the superior vena cava on the left and the arch of the aorta, and the entry of its three major arteries—the brachiocephalic, common carotid, and subclavian. The thoracic duct is in the left.
Figure 15.4 | Orientation of T-oncoanatomy. A. Coronal. B. Sagittal. The anatomic isocenter for three-planar oncoanatomy is placed at the thoracic vertebral level T3-4.
Figure 15.5 | T-oncoanatomy. The Color Code for the anatomic sites correlates with the color code for the stage group (Fig. 15.3) and patterns of spread (Fig. 15.2) and SIMLAP tables (Table 15.2). Connecting the dots in similar colors will provide an appreciation for the 3D Oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
The intrapulmonary lymph nodes are designated by their relationship to the bronchial tree and are referred to as lobar nodes bronchi on interlobar lymph nodes, which then drain to hilar nodes (Fig. 15.6). The tabulation of regional nodes is noted in Table 15.4.
REGIONAL LYMPH NODES
The regional lymph nodes extend from the supraclavicular region to the diaphragm. During the past three decades, three different lymph node maps have been used to describe the regional lymph node potentially involved by lung cancers. The first map was endorsed by the Japan Lung Cancer Society. The second map, the Mountain Dresler modification of the American Thoracic Society (MDATS) lymph node map, is used in North America and Europe. The nomenclature for the anatomical locations of lymph nodes differs between these two maps. Recently the International Association for the Study of Lung Cancer (IASLC) proposed a lymph node map (Figure 15.6B) that reconciles the discrepancies between these two previous maps. The IASLC lymph node map is now the recommended means of describing regional lymph node involvement for lung cancers.
There are no evidence-based guidelines regarding the number of lymph nodes to be removed at surgery for adequate staging. However, adequate N staging is generally considered to include sampling or dissection of lymph nodes from stations 2R, 4R, 7, 10R, and 11R for right-sided tumors, and stations 5, 6, 7, 10L, and 11L for left-sided tumors. Station 9 lymph nodes should also be evaluated for lower lobe tumors. The more peripheral lymph nodes at stations 12–14 are usually evaluated by the pathologist in lobectomy or pneumonectomy specimens but may be separately removed when sublobar resections (e.g., segmentectomy) are performed. There is evidence to support the recommendation that histological examination of hilar and mediastinal lymphenectomy specimen(s) will ordinarily include 6 or more lymph nodes/stations. Three of these nodes/stations should be mediastinal, including the subcarinal nodes and three from N1 nodes/stations.*
M-ONCOANATOMY
Drainage into the subclavian vein, if invaded, then via the superior vena cava and pulmonary artery drain into the lung. Cancer invasion of chest wall drains into intercostal veins, then the azygos vein, and then the superior vena cava, which leads to lung dissemination. Adenocarcinoma dissemination of metastases is the most common lung cancer and is presented as the prototype for metastases into other organs (Fig. 15.7).
The M-oncoanatomy emphasizes the pulmonary venous drainage, which is oxygenated, drains the pulmonary parenchymal cancers and disseminates cells to many remote anatomic states by way of the left side of the heart. Virtually every remote organ site can be involved and include liver, adrenal, bones, and brain.
*Preceding passage from Edge SB, Byrd DR, and Compton CC, et al. AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, pp. 254–255.
Figure 15.6 | A. N-oncoanatomy. Interlobar bronchial nodes and hilar nodes are sentinel nodes within visceral pleura. B. M-oncoanatomy. International Association for the Study of Lung Cancer (IASLC). Labels correlate with Table 15.4.
Figure 15.7 | Incidence and distribution of metastases. Adenocarcinoma is the most common lung cancer and is presented as a prototype for lung cancers. The incidence and distribution of distant metastases are noted as percentages and correlate with Table 12.6.
STAGING WORKUP
RULES FOR CLASSIFICATION AND STAGING
Clinical Staging and Imaging
The TNM classification system is primarily for staging non–small cell lung cancers. The most important change dates back to the fourth edition of the American Joint Committee on Cancer (AJCC), where T3, resectable disease, was distinguished from T4, unresectable disease. Simultaneously, a greater reliance on more sophisticated imaging has occurred. It is with the sixth edition that computed tomography (CT) and positron emission tomography (PET) are allowed. The imaging modalities for detection and diagnosis apply to staging (see Table 15.5). Chest films and CT (preferably spiral) are essential steps in both the diagnosis and staging. PET combined with CT is utilized to overcome motion artifacts. Magnetic resonance imaging (MRI) is useful for mediastinal evaluation. Another advantage of CT over MRI for staging is that it allows for metastatic workup of lung, liver, adrenal, ribs, and vertebrae, especially for Pancoast cancers (Fig. 15.8).
Pathologic Staging
All pathologic specimens from clinical invasive procedures—bronchoscopy, mediastinoscopy, mediastinotomy, thoracentesis, and thorascopy—are applicable to pathologic stage. Thoracotomy and resection of primary and lymph nodes are the mainstay of pathologic staging. Margin status and any residual cancer need to be noted. Preferably, six nodes should be examined.
Surgical resection of primary and regional nodes needs to be carefully evaluated at bronchial stump for adequate margins. All resected nodes should be numbered according to AJCC system and assessed for tumor.
Oncoimaging Annotations
• Chest radiographs seldom detect primary lung cancers in their early stages.
• Spiral CT is useful in high-risk patients to detect nodule and infiltrates.
• PET imaging with18 FDG (fluorodeoxyglucose) appears to be of value in discriminating malignant versus benign nodules.
• CT can detect mediastinal adenopathy, but histologic verification is essential to ascertain if it is malignant.
• Determining N2 versus N3 mediastinal nodes is important; it establishes resectability.
• MRI can be of value in assessing mediastinal invasion, chest wall and rib erosion, and compromised large vein involvement.
• ADCs are the most common lung cancers and often involve lobar bronchi with associated atelectasis extending to hilus.
• CT cannot distinguish mass from associated lobar collapse or pneumonitis.
• Irregular cavitation of abscess wall suggests cancer and is more frequently associated with squamous cell cancer.
• Most often present as peripheral nodules that can extend to pleura with some puckering.
Also of interest are biological and genetic markers that are of prognostic value based on meta analysis data of the International Association for Study of Lung Cancer (IASLC).
PROGNOSIS AND CANCER SURVIVAL
PROGNOSIS
Also of interest are biological and genetic markers that are of prognostic value based on meta analysis data of the IASLC.
Figure 15.8 | Axial CTs of T3 and T4 level correlate with the T-oncoanatomy transverse section (Figure 15.5B). Oncoimaging with CT is commonly applied to staging lung cancers, often combined with PET to determine true extent of primary cancer and involved lymph nodes. A. Mediastinal window. 1, tracheal carina; 2, ascending aorta; 3, descending aorta; 4, superior aspect left pulmonary artery; 5, superior pericardial recesses; 6, thymus; 7, superior vena cava; 8, trunchus anterior (RUL artery); 9, normal lymph node; 10, esophagus; 11, azygos vein. B. Lung window. 1, right main bronchus; 2, tracheal carina; 3, left main bronchus; 4, RUL bronchus; 5, post segment RUL bronchus; 6, post vein RUL; 7, anterior segment RUL bronchus; 8, anterior segment RUL art; 9, trunchus anterior (RUL artery); 10, apical-posterior segment LUL bronchus; 11, LUL artery; 12, pulmonary vein; 13, anterior junction line.
CANCER STATISTICS AND SURVIVAL
According to American Cancer Society facts and figures 2010, the age adjusted Cancer Death Rates for the more common cancers is striking in that cancer of lung and bronchus is the only cancer site that increases over the last 2 decades where as others decrease or plateau. (ACS Figure P3)
The number of new cases in the USA, exceed 220,000 new cases and result in approximately 157,000 deaths almost equally divided between genders with males exceeding females in incidence and mortality rates. Lung cancer constitutes of 15% of all cancer in males and is the second most common cancer, exceeded only by prostate cancer. Similarly in females, it constitutes 14% of all cancer cases and second only to breast cancer.
• Lung cancer remains the most lethal of all cancers accounting for 29% of male cancer deaths vs. 26% for female deaths.
• Smoking cigarettes remains the major risk factor and increases with quantity and duration. Other risk factors are second hand smoke, occupational or environmental exposure to radon, asbestos, and certain metals (chromium, cadmium, and arsenic).
• The value of CT screening in detecting early stage cancer in high risk patients is encouraging and is still undergoing clinical trial investigation.
• The 1 year survival for lung cancer increased from 35% in the seventies to 42% in 2000–2005.
• Generally the five-year survival for NSCLC is 13% vs. 6% SCLC.
• Survival, according to stage: localized is 53%, regional nodes is 24% and for metastatic distant disease is 4%.
• According to the IASLC lung database, a series of survival curves, plotted by stage group demonstrates the median survival for combination of clinical and pathologic staging, and illustrates the decrement of survival with stage (Fig. 25.5). Histopathology is a major factor and (Fig. 25.4) NSCLC vs. SCLC demonstrates the increasing mortality as anticipated.
The impact of both stage and histopathology is well demonstrated in Table 14.7 illustrating the five-year relative survival rates for different lung cancers. Although five-year survival rates have improved with early detection and surgery in localized stages and current radiation chemotherapy regimens, the outcome for each subset is presented in the graph.
Figure 15.9 | Survival in all non–small cell lung cancer by TNM stage (with “best” based on a combination of clinical and pathologic staging). Used with the permission of the American Joint Committee on Cancer (AJCC) Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh edition (2010) published by Springer SBM, LLC, p 114.