PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
The bronchioloalveolar cancers (BACs) arise from the most peripheral respiratory bronchi branching into an acinus and alveolar sacs allowing for its lepidic spread.
PERSPECTIVE AND PATTERNS OF SPREAD
The essential cell in the evolutionary process that enabled aquatic animals to leave the sea to become air breathers is the type II pneumocyte. The cry of the newborn recapitulates that stage in our ontogeny; it ensures that air has replaced the amniotic fluid in the alveolar acini. The malignant transformation of the type II pneumocyte provides the histogenesis into a bronchi-oloalveolar carcinoma (BAC). BACs have three distinct patterns of presentation that have been described as clinical pathologic entities: (i) cancers in peripheral pulmonary scars; (ii) multiple primary nodules; and (iii) diffuse and extensive pneumonitis. BACs account for 5% to 10% of all lung cancers, but its incidence has doubled in more recent series as its cellular characteristics are increasingly appreciated.
BACs are true cancers of the lung since they arise from the type II pneumocytes and grow alveolar walls. They only account for 1% to 5% of all cancers (Fig. 14.2 and Table 14.2). Because they arise in segmental bronchi, they can present as a segmental pneumonitis or atelectasis in contradistinction to adenocarcinomas that tend to arise in lobar bronchi, therefore producing lobar pneumonitis or atelectasis. Alternately, BACs can appear as peripheral nodules with a characteristic “pleural tuck sign.” Copious mucous sputum (bronchorrhea) is an unusual symptom and is a distinctive sign of BACs but only occurs in 5% to 10% of all presentations.
PATHOLOGY
The crucial point in understanding the concept of “lepidic” (scale-like) spread is the preexistence of a fine microcirculatory web in the alveoli walls of the terminal intrapulmonary airways or the alveolar acini and sacs (Fig. 14.1). The alveolar wall is lined by type I pneumocytes, which are singular, flat surface cells generated by the type II pneumocyte, which stores, manufactures, and secretes surfactant molecules. BACs arising in the terminal respiratory bronchiole may present as a peripheral pulmonary scar that extends to the pleural surface because a small subsegment of air sacs or alveoli collapses or becomes infiltrated by lepidic spread. Their histogenic features suggest they arise from the type II pneumocyte. (Table 14.1).
Figure 14.1 | Bronchioloalveolar carcinoma. Nonmucinous bronchioloalveolar carcinomas consist of atypical cuboidal to low columnar cells proliferating along the existing alveolar walls.
Figure 14.2 | Patterns of spread. The lepidic spread pattern of bronchioloalveolar cancer is a scale-like peripheral infiltration of acini and alveoli through alveolar wall pores without invasion of lymphatics or microcirculation. Color code simplified: T1, peripheral nodule (green); cancer in a peripheral scar (green); and T3, dissemination. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern i.e. SIMLAP Table 14.2.
The International Association for Study of Lung Cancer (IASLC) has meticulously defined pleural invasion:
• P0: Tumor falls short of invading elastic layer of pleura
• P1: Tumor extends through elastic layer
• P2: Tumor extends to surface of visceral pleura
• P3: Tumor extends to parietal pleura >T3
• Direct invasion across a fissure is classified as T2a
TNM STAGING CRITERIA
TNM STAGING CRITERIA
Lepidic spread refers to the noninvasive nature of BACs, which is an oxymoron. This is possible because of a special feature of terminal acini. Their clusters of alveolar sacs enable surface infiltration of the preexisting pulmonary capillary bed, namely the acini that communicate through the “pores of Kohn” between their alveolar walls. This allows BACs to spread without the need for generating their own tumor neovascular bed and blood supply. If these lepidic features are not evident—that is, stromal, vascular, or pleural invasion is seen—then the cancer needs to be reclassified as adenocarcinoma. Mixed subtypes require that each subtype present be specified.
True solitary BACs carry an excellent prognosis, with a 70% 5-year survival. Another feature is its presentation as multiple primaries that are metachronous or synchronous. According to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer criteria as originally proposed by Martini and Melamed: The two tumors need to be the same histologic type but in separate lobes without evidence of nodal metastasis within a common nodal drainage, that is, interlobar nodes common to upper and lower lobes. The third scenario is the pneumonitic presentation, which can be multifocal and rapidly fills intrapulmonary acinar airways, resulting in an “air bronchogram.” Multiple nodules in the same lobe as the primary are considered to be metastatic and staged as T4. Survival for this multifocal disseminated form of cancer is nil.
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. 14.3).
• 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 TMN Staging Matrix is color coded for identification of Stage Group once T and N stages are determined (Table 14.3).
Stage Summary Matrix TABLE 14.3
BRONCHIOLOALVEOLAR CANCER
Figure 14.3 | TNM stage grouping. Bronchioloalveolar cancers are usually detected as peripheral cancers with scarring and subsegmental collapse. They are considered non-invasive but multicentric as in T3 and Tany. When invasion occurs as in T4, it is considered to be an adenocarcinoma or mixed type. Color coding: Stage 0, yellow; I, green; II, blue; IIIA, purple; IIIB, red; IV, black (metastatic). Definitions of TN on left and stage groupings on right. Although shown, stromal, vascular and pleural invasion require reclassification as adenocarcinoma.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
The respiratory bronchioles and their acini and alveoli constitute the breeding ground for BACs. Although the axial orientation is at the T2-3 level, a microscopic or macroscopic view of the intrapulmonary airways is required to appreciate the very fine bronchiole divisions as they become subsegmental, intrasegmental, lose the cartilage in their walls, and terminate as respiratory bronchioles. These respiratory bronchioles end in acini with alveolar sacs and alveoli. The intrapulmonary fine capillary meshwork is optimally designed for a lepidic cancer spread pattern due to the preconfigured microvasculature of the alveoli that BACs adopt as they extend through the pores of Kohn (Fig. 14.4).
T-oncoanatomy
The T-oncoanatomy is displayed in 3 planar views. A. Coronal, B. Sagittal, C. Transverse Axial (Fig. 14.5). The peripheral pleural anatomy of the lung is the geographic zone for the BACs. The presentation of the bronchopulmonary segmental anatomy follows:
• Coronal: Anterior and posterior views demonstrate the lobar and segmental anatomy of the lungs. 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.
• Sagittal: Note superior segment of lower lobes appears in the upper part of the lung fields. Both the middle lobe and lingual are anterior and medial and can be obscured by the cardiac silhouette if partially collapsed.
• Axial transverse: At the T2-3 level and sternoclavicular joints, this shows the great vessels, trachea, esophagus, and upper lobe segments. Midline structures are bronchiocephalic arterial trunk, trachea, and esophagus with thoracic duct and nodes to left.
Figure 14.4 | Orientation of T-oncoanatomy. A. Coronal. The anatomic isocenter is in the peripheral region of the lung. B. Sagittal. The anatomic isocenter is at transverse thoracic vertebral level T2-3 at thoracic inlet.
Figure 14.5 | T-oncoanatomy. The Color Code for the anatomic sites correlates with the color code for the stage group (Fig. 14.3) and patterns of spread (Fig. 14.2) and SIMLAP tables (Table 14.2). Connecting the dots in similar colors will provide an appreciation for the 3D Oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
The parallelism of the branching intrapulmonary bronchiole tree and the intrapulmonary nodes are presented according to the International Anatomical Terminology designation and contrasted with AJCC numbering of lymph node stations. The interstitial pulmonary lymphatics are usually visible under certain abnormal pathophysiologic circumstances. The most peripheral lymph nodes are intrapulmonary segmental or subsegmental lymph nodes (Fig. 14.6; Table 14.4).
If intrapulmonary lymph nodes are involved, the diagnosis is changed to adenocarcinoma. By definition, BAC does not spread by way of lymphatics.
M-ONCOANATOMY
By definition, BACs can only invade the lung by so-called lepidic spread, wherein local segmental collapse occurs or an extensive pneumonitic invasion appears. This unique obliteration of intrapulmonary airways is lethal when it is extensive, multifocal, and mimics bronchiolitis obliterans. The destruction of multiple separate synchronous primaries versus metastatic spread is often applied to BACs. The key anatomic fact is that the two lesions cannot share the same lymph node drainage, and no lymph nodes should be involved (see Fig. 14.7).
• If dissemination occurs, the diagnosis changes to adenocarcinoma.
Figure 14.6 | N-oncoanatomy. Sentinel nodes can be intrapulmonary nodes or interlobar bronchial nodes if involved, diagnosis becomes adenocarcinomas.
Figure 14.7 | M-oncoanatomy: If dissemination occurs, the diagnosis changes to adenocarcinoma. 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 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 14.5). Chest films and CT (preferably spiral) are essential steps in both the diagnosis and staging (Fig. 14.8). 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.
Pathologic Staging
All pathologic specimens from clinical invasive procedures—bronchoscopy, mediastinoscopy, mediastinotomy, thoracentesis, and thorascopy—are applicable.
The thoracotomy and resection of primary and lymph nodes are the mainstay of pathologic staging. 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
• Most BAC begin in peripheral nodules arising in respiratory bronchi with infiltration of the acini complex, resulting in a collapse of peripheral lung and producing a pleural tethering or tuck sign.
• Multifocal lepidic spread leads to sparing of segmental bronchi, producing an air bronchogram.
• Multiple primaries can occur in synchronous or metachronous fashion.
• Bronchi seen on an end of CT appear as small bubbles or popcorn sign.
• Presence of hilar or mediastinal nodes excludes BAC diagnosis.
PROGNOSIS AND CANCER SURVIVAL
CANCER STATISTICS AND SURVIVAL
According to Surveillance Epidemiology and End Results data based on 16,000 patients, the relative 5-year survival is 8% to 10% and 10-year survival 5% to 7%. Surprisingly, there is a small attrition for 5-year survivors; 70% are alive at 10 years. Female gender, good Karnofsky performance status, and cessation of smoking contribute to longer survival.
Staging is a major factor in survival, and these data are presented in Tables 14.6 and 14.7. For stage IA cancers, the 90% T1N0M0 patient decreases to 61% at 5 years and stage IB 70% at 1 year is almost halved at 5 years at 38%. The 50% 5-year survival for stage I decreases to 30%, indicating metastatic disease is highly likely. Stage IIIA represents the most favorable advanced disease patients, with 50% 1-year survival and, despite vigorous chemoradiation, only decreases to 10%. Surgically staged IIIA patients do better, as expected, with 25% alive at 5 years. BACs have the best 5-year survival rates (65%) as compared to other histologies (Table 14.7).
BAC is characterized by the nuclear anaplasia and pleomorphism of type II pneumocytes or clara cells. The spread pattern is in a monolayer over acinar alveoli and can, when extensive (T3, T4), interfere with gas exchange and result in a right to left intrapulmonary shunt. Five subtypes have been described. Types A and B have a 100% survival and are noninvasive. Type C is transitional into an adenocarcinoma and has an 80% survival rate. Types D and E have angiolymphatic invasion to lymph nodes and beyond with higher mortality rates similar to adenocarcinomas with regional nodal invasion survival of 25% to 30% and with distant metastases of 5%.
PROGNOSIS
The limited number of prognostic factors are listed in Table 14.6.
Figure 14.8 | Axial CTs of T2 and T3 level correlate with the T-oncoanatomy transverse section (Figure 14.5C). 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. 1, trachea; 2, esophagus; 3, right common carotid artery; 4, head of clavicle; 5, subclavian vein; 6, right subclavian artery; 7, left vertebral artery; 8, left subclavian artery; 9, left subclavian (axillary) artery; 10, internal jugular vein; 11, left common carotid artery. B. 1, trachea; 2, right common carotid artery; 3, right subclavian artery; 4, right brachiocephalic vein; 5, left subclavian artery; 6, left common carotid artery; 7, left brachiocephalic vein; 8, subclavian vein (unopacified); 9, subclavian artery; 10, pectoralis major muscle; 11, pectoralis minor muscle.
