PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
Small cell anaplastic cancer's favored site is mostly central or proximal lung root, reminiscent of the embryonic origin of the multipotential cells of lung buds, which form the anlage of lung endoderm.
PERSPECTIVE AND PATTERNS OF SPREAD
Small cell anaplastic (SCA) cancers are the most undifferentiated cancers. Their origin is mostly in central airways juxtaposed to the mediastinum. It is the most dedifferentiated and highly invasive lung cancer, entering into lymphatics and commonly presents as a large mediastinal nodal mass. Superior vena caval obstruction as a low-pressure thin wall is more vulnerable to compression than other mediastinal structures, such as the aorta, esophagus, and trachea. These cancers are notorious for being metastatic on presentation. The derepression of chromosomes leads to a variety of neuroendocrine and paraneoplastic syndromes including Cushing disease, severe lymphedema due to antidiuretic hormone excess, and neuromyopathic conditions. Their favored site is mostly central or proximal lung root, reminiscent of the embryonal origin of the multipotential cells of lung buds, which form the anlage of lung endoderm. Unlike most lung cancers, SCA cancer tends to infiltrate submucosally and distort the bronchus by extrinsic and submucosal compression. Their pattern of spread tends to create mediastinal masses (Fig. 18.2; Table 18.2).
Research advances in genetic and molecular biology have uncovered new markers that were recognized in the American Joint Committee on Cancer's (AJCC) fifth and sixth edition with their tabulation. However, the results were insufficient to recommend their incorporation into their staging system. In fact, in the seventh edition (2010) there is emphasis of molecular markers except to note “the marker needs to bear a strong relationship to patient prognosis” but not included in staging.
The dedifferentiation of SCA derepresses the cell, resulting in paraneoplastic syndromes that are expressed in 10% to 20% of cases.
PARANEOPLASTIC SYNDROMES
Extrapulmonary manifestations of lung cancer may be recognized before the lung cancer itself produces any symptoms. Approximately 2% of patients present with a paraneoplastic syndrome. These may be categorized as follows:
• Metabolic: Cushing's syndrome, hypercalcemia, excessive antidiuretic hormone, and carcinoid syndrome
• Neuromuscular: peripheral neuritis, cortical or cerebellar degenerations, and myopathy
• Dermatologic: acanthosis nigricans and dermatomyositis
• Skeletal: pulmonary hypertrophic osteoarthropathy, including clubbing of fingers
• Vacular: migratory thrombophlebitis and nonbacterial verrucous endocarditis
• Hematologic: anemia and disseminated intravascular coagulopathy*
PATHOLOGY
Of the many solid cancers, SCAs have been genetically classified as classic versus variants depending on their biologic characteristics. Frequently expressed mutations in tumor suppressor genes include 3P, RB, and TP53 (Fig. 18.1; Table 18.1).
*Preceding passage from Rubin P, Williams JP. Clinical Oncology: A Multi-Disciplinary Approach for Physicians & Students, 8th edition. Philadelphia, W. B. Saunders. 2001, p. 825.
Figure 18.1| Small cell carcinoma of the lung. This tumor consists of small oval to spindle-shaped cells with scant cytoplasm, finely granular nuclear chromatin, and conspicuous mitoses.
Figure 18.2 | Patterns of spread. The proximal location of the small cell cancer and its rapid dissemination via lymphatics is stressed. Although color coded, all T and N stages are referred to as “limited” if they are confined to the thorax. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern i.e. SIMLAP Table 18.2.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The common criteria of size in staging lung cancer do not apply to SCA. Pragmatically, all intrathoracic T stages and N categories are lumped together into “limited” stage intrathoracic disease. The “extensive” stage is applied to metastatic dissemination, which is all too common and, until shown otherwise, bone marrow invasion, liver, bone, and brain foci need to be excluded. For practical purposes, the staging is based on M0 versus M1 and the mainstay of treatment is systemic first because of the high likelihood of occult micrometastases.
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 (Fig. 18.3).
• The T classifications have been redefined:
• 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
Because of the magnitude of the T-category changes with shifts in both directions, that is both downstaging and upstaging, it is important to review the stage groupings of the sixth and seventh editions. The TNM Staging Matrix is color coded for identification of Stage Group once T and N stages are determined (Table 18.3).
SMALL CELL ANAPLASTIC CANCER
Figure 18.3 | TNM staging diagram. Small cell cancers have a tendency to metastasize early. They arise in central hilar locations with mediastinal invasion and they often present as large masses causing superior vena cava obstruction. Although shown in stages similar to other lung cancers, the typical stages are clustered as limited (M0), which includes all stages from IA, IB, to IIIA,B. Extensive applies to overt metastases M1 stage IV. Small cell cancer stage I/II/IIIA/B are color coded green/blue/red but are lumped together as M0 limited to thorax. Stage IV is metastatic black and referred to as extensive. Major stage group progression is dominated by the N stage progression.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
The orientation diagrams are at the T6-7 level and the key anatomic feature is their central locations as their point of origin akin to lung bud anlage. The isocenter for SCA is at the hilar area, which is at the thoracic T6-7 level (Fig. 18.4). The three main branches of each major bronchus are within the visceral pleura.
T-oncoanatomy
The rich lymphatic submucosal network ensures the cancer's rapid spread to the visceral pleura and crosses the mediastinal pleura. The three-planar views (Fig. 18.5) emphasize the right pulmonary mediastinal surfaces and the juxtaposed right mediastinum because mediastinal mass formation and invasion are common presentations.
• Sagittal plane: The lung bud anlage is superior imposed on the bronchial tree. The mediastinal structures that are commonly compressed include the low-pressure, thin-walled superior vena cava or brachiocephalic vein and their entrapment between metastatic matted mediastinal masses of nodes and arteries. Plugs of tumor, when entering the thoracic duct or metastatic lymph nodes, can also compress and block the lymphatic flow, which can lead to chylous or pseudochylous effusions. Similarly, pulmonary venous compression results in serous pleural effusions. It is critical in staging to send cytospins of pleural effusions for evaluation to determine if they are positive for cancer cells or whether they are cytologically negative.
• Coronal view: The medial aspects of the lung reflect the structures into the superior and inferior mediastinum by virtue of anatomic position. A rapidly growing neoplasm penetrates the mediastinal pleura and invades mediastinal lymphatics and nodes directly.
• Transverse view: The T6-7 level is a critical level to appreciate. The arch of the aorta is defined, the trachea is bifurcating, and the branches of the sympathetics and parasympathetics, particularly the cardiac branches, are streaming alongside the trachea to form the cardiac plexuses, which, when invaded, can lead to cardiac arrhythmias.
Figure 18.4 | Orientation of T-oncoanatomy. A. Anterior. B. Lateral. The isocenter for three-planar oncoanatomy is placed centrally at the lung root and transversely at the thoracic vertebral level T6-7.
Figure 18.5 | T-oncoanatomy. The Color Code for the anatomic sites correlates with the color code for the stage group (Fig. 18.3) and patterns of spread (Fig. 18.2) and SIMLAP tables (Table 18.2). Connecting the dots in similar colors will provide an appreciation for the 3D Oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
The mediastinal lymph nodes are the main focus of small cell cancers, which can and do spread into all sectors of the mediastinum. Each sector of the mediastinum has a vulnerable structure that can be invaded or compressed. Because of the central and proximal origin of SCA, they present with rapid extension to mediastinal surfaces. Small cell cancers arising in the upper and lower lobes involve mediastinal structures by juxtaposition. The right-sided posterior nodal masses can trap the thoracic duct as it enters the chest from the abdomen. True chylous effusions tend to be right sided. The right superior mediastinum mass can lead to superior vena caval obstruction. On the left side, the recurrent laryngeal nerve is most often compressed by nodes in the pulmonary aortic window and leads to hoarseness. Phrenic nerve invasion can lead to refractory hiccoughing due to spasmatic contractions of the diaphragm (Fig. 18.6A; Table 18.4).
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 18.6B) 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, 10, L, 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
The rapid entry into the arterial system allows for widespread remote and venous dissemination and leads to multiorgan metastases. The development of superior vena cava obstruction (SVCO) emphasizes collateral venous channels or caput medusa presentations on the chest wall, shoulders, and abdomen, depending on whether the azygos vein is at or below the level of obstruction. If azygos vein is patent inferior to the SVCO, then blood flows through the hemiazygos system to the collateral channels around the shoulder. If both azygos and superior vena cava are obstructed, however, blood takes the circuitous route of intervertebral venous plexus to the femoral, iliac veins, or hemiazygos vein to the lumbar veins and inferior vena cava then anterior abdominal veins or the inferior vena cava to the right heart. The anatomic distribution of distant metastases is shown in Figure 18.7.
*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.
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.
Figure 18.6 | A: N-oncoanatomy. Hilar and ipsilateral mediastinal nodes are the sentinel nodes that are often bulky and fused with the primary mass in lung. B: M-oncoanatomy. International Association for the Study of Lung Cancer (IASLC). Labels correlate with Table 18.4.
Figure 18.7 | Incidence and Distribution of Distant Metastases of Small Cell Anaplastic Lung Cancer correlates 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 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 (Table 18.5). Chest films and CT, preferably spiral CT, are essential 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 small cell cancers (Fig. 18.8).
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 needs to be noted. Preferably, six nodes should be examined.
Surgical resection of primary and regional nodes needs to be carefully evaluated at the 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.
• MRI of vertebrae may show bone marrow replacement by cancerous infiltrates of disseminated metastases.
• CT may often be unable to discriminate the primary from its mediastinal adenopathy.
• SVCO can be determined as cancer invasion versus compression by MRI rather than CT.
• Eighty percent of SCAs present on central tumors and have hilar or mediastinal lymph adenopathy and invasion (limited stage).
• Seventy percent to 90% of SCAs have dissemination outside the thorax (extensive stage) and frequently with paraneoplastic syndromes.
• Metastases to bone marrow are found in 50% and in brain in 10% to 15%.
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
The limited number of prognostic factors are listed in Table 18.6
Figure 18.8 | Axial CTs of T6 and T7 level correlate with the T-oncoanatomy transverse section (Figure 18.5C). 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, ascending aorta; 2, descending aorta; 3, main pulmonary artery; 4, right atrium; 5, right atrial appendage; 6, superior pulmonary vein; 7, lower lobe pulmonary artery; 8, RML artery; 9, lingular artery; 10, superior segment lower lobe artery; 11, azygos vein. B. Lung window. 1, lower lobe pulmonary artery; 2, lower lobe bronchus; 3, superior segment lower lobe bronchus; 4, RML bronchus; 5, medial segment RML bronchus; 6, lateral segment RML bronchus; 7, medial segment RML artery; 8, inferior segment lingula bronchus; 9, inferior segment lingula artery; 10, lingular vein; 11, superior segment lower lobe artery.
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 5 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. 18.9). Histopathology is a major factor and NSCLC vs. SCLC demonstrates the increasing mortality as anticipated.
The impact of both stage and histopathology is well demonstrated in T14.7 illustrating the 5 year relative survival rates for different lung cancers. Although 5 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 18.9 | Survival in all SCLC by TNM stage (according to “best” stage based on a combination of clinical and pathologic staging in the IASLC lung database). (From Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer, 2010:261, with permission.)