TNM Staging Atlas with Oncoanatomy, 2e

CHAPTER 16. Large Cell Anaplastic Cancer

PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY

Large cell anaplastic cancers arise in more proximal bronchi and have a proclivity to invade mediastinal structures early.

PERSPECTIVE AND PATTERNS OF SPREAD

Large cell anaplastic (LCA) cancers are those cancers that are distinguished from small cell anaplastic cancers by numerous morphologic variants: large cell neuroendocrine, basaloid carcinoma, lymphoepithelioma-like and clear cell, or large cell with rhabdoid phenotype (Table 16.1Fig. 16.1). It is not a common cancer type, accounting for 5% to 10% of lung cancers, distinguished by its propensity to invade the mediastinum pleura and pericardium. A paradox to ponder is the resistance of the heart to direct invasion despite circulating cancer cells, especially from lung cancers, recognizing that the endocardium is never seeded and that myocardial nodulation is more often recognized and found only postmortem. Because most LCAs are undifferentiated, vascular infiltration occurs with rapid systemic dissemination to remote sites (Fig. 16.2Table 16.2).

Superior vena caval obstruction (SVCO) is a dreaded syndrome that can be rapid or slow in onset. It begins with facial edema, most apparent at the eyelids, plethora, headache or confusion (brain edema), and arm edema; caput medusa dilation of veins on chest wall and abdomen can occur.

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A rapid onset is an emergent situation, especially if there is difficulty breathing, suggesting tracheal compression. A slow onset and compensating altered blood flow patterns can be discerned clinically by compressing a prominent chest wall vein to determine if flow is in a caudal or cranial direction.

• SVCO above the azygos vein allows blood to flow inferiorly via hemiazygous vein into the vena cava.

• SVCO below the azygos vein allows blood to flow superiorly around the shoulder and to flow inferiorly via internal thoracic (mammary) and chest and abdominal wall veins into the inferior vena cava. Leg edema may result.

• SVCO and azygos vein obstructed shunts blood caudally from internal thoracic (mammary) veins to superior or inferior epigastric veins.

PATHOLOGY

LCA cancers with large pleomorphic nuclei spread in sheets, are often large and bulky masses, and can compress mediastinal structures as do small cell anaplastic (SCA) cancers. Variants are listed in Table 16.1.

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Figure 16.1 | Large cell carcinoma of the lung. This poorly differentiated tumor grows rapidly. The tumor cells are large and contain ample cytoplasm and prominent nucleoli.

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Figure 16.2 | Patterns of spread. The primary cancer invades in various directions, which are color coded for T stage: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red; and when 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 16.2.

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TNM STAGING CRITERIA

TNM STAGING CRITERIA

As thoracic surgery improved, the need for defining criteria of unresectability became evident. The distinction between T3 and T4 entered the American Joint Committee on Cancer (AJCC)/International Union Against Cancer staging in its fourth edition (1982), as did more researched biologic and molecular markers to distinguish small cell anaplastic cancers from its variants. T4 stage applies to any tumor regardless of size that invaded any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or malignant effusion with positive cells identified after both pleural and pericardial taps.

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. 16.3).

• 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 16.3).

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LARGE CELL ANAPLASTIC CANCER

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Figure 16.3 | TNM staging diagram. Large cell anaplastic cancers are variants and aggressive cancers with invasive qualities often with neuroendocrine effects. Vertical presentation of stage groupings, which follow the same color code for cancer advancement, is 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 grouping is on the right. Major stage group progression is dominated by the N stage progression.

T-ONCOANATOMY

ORIENTATION OF THREE-PLANAR ONCOANATOMY

LCA cancers can arise throughout the bronchial tree, and its isocenter has been assigned to thoracic T4-5 level posteriorly and to the fourth rib articulation with the sternum at the level of the horizontal fissure on the right and the cardiac contour on the left (Fig. 16.4).

T-oncoanatomy

T-oncoanatomy focuses on the left side of the mediastinum featuring the ascending aorta and descending aorta. The major nerves coursing into the thorax are the focus of the three-planar views, indicating where they are vulnerable to compression or invasion (Fig. 16.5).

• Coronal: At the thoracic inlet the vagus nerve (cranial nerve X) enters the chest, but the recurrent laryngeal loops around the right subclavian; whereas on the left it loops around the aortic arch. Compression on the right is anticipated with metastatic right supraclavicular and scalene nodes. On the left, the more common event is for mediastinal nodes to invade the recurrent laryngeal at the aortic pulmonary window. The anterior and posterior pulmonary plexuses receive sympathetic contributions from the right and left sympathetic trunks (second to fifth thoracic ganglia) and parasympathetic contributions from the right and left vagus nerves. The right and left vagus nerves pass inferiorly from the posterior pulmonary plexus to contribute fibers to the esophageal plexus. Branches from the pulmonary plexuses continue along the bronchi and pulmonary vasculature to the lungs. The phrenic nerve passes anterior to the root of the lung to the diaphragm.

• Sagittal: The left side of the mediastinum is the “red side,” dominated by the arch and descending portion of the aorta and the left common carotid and subclavian arteries, which obscures the trachea from view. The left vagus nerve passes posterior to the root of the lung, sending its recurrent laryngeal branch around the ligamentum arteriosum inferior, then medial to the aortic arch. The phrenic nerve passes anterior to the root of the lung and penetrates the diaphragm more anteriorly than on the right side.

• Transverse: Note the juxtaposition of the ascending and descending aorta with the carina at the T4-5 level.

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Figure 16.4 | Orientation of T-oncoanatomy. The isocenter is shifted to the left lung and is at the T4-5 level to focus on the nerves entering the thorax and their course. A. Coronal. B. Sagittal.

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Figure 16.5 | T-oncoanatomy. The Color Code for the anatomic sites correlates with the color code for the stage group (Fig. 16.3) and patterns of spread (Fig. 16.2) and SIMLAP tables (Table 16.2). Connecting the dots in similar colors will provide an appreciation for the 3D Oncoanatomy.

N-ONCOANATOMY AND M-ONCOANATOMY

N-ONCOANATOMY

The first station lymph nodes are the intrapulmonary, pulmonary, and bronchopulmonary lymph nodes, which are contained within the visceral pleural reflection. There are three major collecting trunks: the superior, middle, and inferior trunks. These drain into 10 to 15 peribronchial nodes and then to hilar nodes. Second station lymph nodes are those in the mediastinum and may be paraesophageal, subcarinal, or paratracheal and pretracheal or retrotracheal in location. Involvement of scalene, cervical, supraclavicular, and axillary nodes is considered distant metastases (Fig. 16.6ATable 16.4).

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 16.6B) 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.

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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 vasculature of the lung is rich. The microcirculation is intimately organized into the alveolar matrix and originates from two separate circulations—the bronchial arteries and the pulmonary arteries. However, all the blood is gathered and returned by the pulmonary veins (Fig. 16.6B). The anatomic distribution of distant metastases is shown in Table 16.5.

There is a major difference between the bronchial and pulmonary arteries. The pulmonary arteries are essentially venous blood carrying the right heart output into the lungs for aeration. Similarly, the pulmonary vein, unlike other veins in the body, has well-oxygenated blood carrying blood from the lungs to the left heart for injection into the general circulation. The bronchial arteries rise from the aorta and, therefore, carry oxygenated blood. An important feature of staging is the difference between T3 and T4 cancers.

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.

*Preceding passage from Edge SB, Byrd DR, and Compton CC, et al. AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, pp. 254255.

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Figure 16.6 | A. N-oncoanatomy. The hilar and coronal nodes are the sentinel nodes. However, if lower lobe cancers invade the mediastinum directly, the posterior mediastinal nodes are at risk. If the diaphragm is invaded directly, posterior and inferior mediastinal nodes are the sentinel nodes. B. M-oncoanatomy. International Association for the Study of Lung Cancer (IASLC). Labels correlate with Table 16.4.

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Figure 16.7 | Incidence and distribution of distant metastases of Large Cell Anaplastic lung cancer correlates with Table 16.6.

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 16.5). Chest films and CT (preferably spiral) are essential steps in both 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, (Fig. 16.8).

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.

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.

• CT staging should include liver and adrenal glands by extending chest examinations. Most adrenal enlargements are benign and require biopsy or MRI to establish metastatic cancer.

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).

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PROGNOSIS AND CANCER SURVIVAL

PROGNOSIS

The limited number of prognostic factors are listed in Table 16.6.

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Figure 16.8 | Axial CTs of T4 and T5 level correlate with the T-oncoanatomy transverse section (Figure 16.5C). 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, left pulmonary artery; 5, right pulmonary artery; 6, superior vena cava; 7, left main bronchus; 8, esophagus; 9, normal subcarinal lymph node; 10, superior pulmonary veins; 11, azygos vein; 12, hemiazygos vein branch; 13, thymus. B. Lung window. 1, bronchus intermedius; 2, left main bronchus; 3, anterior segment LUL bronchus; 4, apical-posterior segment LUL bronchus; 5, major fissure; 6, minor fissure; 7, anterior junction line; 8, RUL; 9, RML; 10, RLL.

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 (F25.5). Histopathology is a major factor and (F25.4) 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.

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Figure 16.9 | Survival in all NSCLC by TNM stage (according to “best” based on a combination of clinical and pathologic staging). (From Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer, 2010, p. 261, with permission.)



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