Lung Cancer: Clinical Presentation, Epidemiology, 1 Tumor Staging, Classification, Histologic Grading, and Spread Through Air Spaces

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LUNG CANCER: CLINICAL PRESENTATION, EPIDEMIOLOGY, 1 TUMOR STAGING, CLASSIFICATION, HISTOLOGIC GRADING, AND SPREAD THROUGH AIR SPACES

CLINICAL PRESENTATION vena cava, or metastasis to distant sites such as Lung cancer presents in different ways, the bone or brain (Table 1-1). largely depending on the location and size of Although the presentation of primary lung the tumor and whether it remains localized to cancer varies with the location and size of the the lung or is metastatic (Table 1-1). One third tumor mass, its extent of spread, and its cell of lung cancer patients present with early stage type, there are many features of lung cancers disease and the rest with advanced disease. Pa- that overlap. Five to 20 percent of patients are tients with early stage tumors may have mini- asymptomatic at the time of diagnosis. These mal or no symptoms; lung cancer screening has patients usually have a chest radiographic im- led to the increased detection of such cancers, aging procedure that reveals a small lung mass resulting in a greater than 20 percent reduction which gets sampled for pathology. However, in mortality (1). Patients with advanced disease over 80 percent of new lung cancer patients can present with symptoms related to invasion have one or more symptoms referable to their or compression of major structures, such as the disease at the time of initial diagnosis, many of

Table 1-1 LUNG CANCER PRESENTING SYMPTOMSa

Category Symptom Pathogenesis Primary tumor Cough Airway obstruction, atelectasis, infection, airway infammation Hemoptysis Airway infammation or necrosis, tumor necrosis and cavitation Dyspnea Airway compression, lymphangitic spread, pleural effusion, thromboembolism, pericardial effusion Pain from invasion of chest wall or brachial plexus, Direct extension hoarseness from impingement of the recurrent laryngeal nerve, superior vena cava (SVC) syndrome, Horner syndrome (ptosis, miosis, anhidrosis) from invasion of the sympathetic chain and stellate gan- glion, pericardial tamponade Metastases Headache, bony pain, weight loss, anorexia, fatigue Sites: brain, bone, liver, adrenal gland, and lung Paraneoplastic Hyponatremia Syndrome of inappropriate antidiuretic syndromes Hypercalcemia Parathyroid hormone-related peptide Cushing syndrome (SCLC, carcinoid) Ectopic corticotropin Hypertrophic pulmonary osteoarthropathy Lambert-Easton myasthenic syndrome (SCLC) Encephalomyelitis-subacute sensory neuropathy (SCLC) aData from references 3 and 4.

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which are directly related to the presence of the of the arm, especially along the lateral aspect, primary tumor. The most common symptom is which may also manifest muscular atrophy and cough, which is usually related to irritation of associated weakness. Occasionally, a Pancoast bronchial structures by the neoplasm. A new tumor directly extends to compress the spinal cough or one that does not abate in a current or cord, producing paraplegia. a former smoker should be evaluated promptly Another potential syndrome, which may be (2–4). Hemoptysis is also a frequent and char- present at initial diagnosis or develop subse- acteristic presentation, especially for individuals quently, is oculosympathetic palsy, or Horner with squamous cell carcinoma. Dyspnea is often syndrome (3). This results from direct invasion present to some degree, especially with small cell of the paravertebral sympathetic ganglia. Clas- carcinoma. It is usually related to the presence of sic components of this complex are persistent the tumor as it obstructs airways or, less likely, miosis (and anisocoria), enophthalmosis, ptosis, spreads throughout much of the parenchyma; this and anhidrosis. Other manifestations of lo- may also result in wheezing. Chest pain, which cal tumor spread include dysphagia related to is typically described as a dull ache that does compression of the esophagus. not go away, may be related to invasion of soft Metastases occur in any organ or body struc- tissue of the chest wall, ribs, or pleura. Recurrent ture and evoke clinical manifestations, and or persistent infections, especially pneumonias, frequently, fndings at the initial diagnosis are may be related to bronchial obstruction. due to metastases (3). Major extranodal targets Spread of tumor within the thorax also causes of lung cancer spread include the central nervous clinical manifestations (Table 1-1) (2–4). One system (focal neurologic abnormalities, seizures, of the most dramatic is the superior vena cava back pain, and headaches that classically are syndrome. More often associated with small cell worse upon awakening from sleep) and bone me- carcinoma, it is due to extrinsic compression of tastases (vertebrae, ribs, and femur). The resultant the superior vena cava by neoplasm. This results usually lytic lesions are typically associated with in edema of the face and upper extremity; the unrelenting pain. Cachexia is associated with dis- fuid accumulation is accentuated when the seminated disease and a large tumor burden. patient has been recumbent for some time. Some patients present initially with a para- Cerebral edema may be a component, with neoplastic syndrome (Table 1-1) (3,4). The most associated headaches and other neurologic common one associated with lung cancer (espe- complications. Edema of the larynx may occur cially small cell carcinoma) is the syndrome of and rarely precipitates a medical emergency due inappropriate antidiuretic hormone (SIADH). to rapidly developing respiratory distress. Injury Tumor cells produce and release antidiuretic hor- to the recurrent laryngeal nerve may lead to mone (vasopressin), causing the body to retain hoarseness. Neural damage to the phrenic nerve water; a major consequence of this is hypona- may produce dyspnea related to hemidiaphrag- tremia which may cause a number of metabolic matic paralysis. Local dissemination with the disorders of varying severity including muscle development of pleural or pericardial effusions cramps and weakness, irritability, confusion, contributes to shortness of breath, systemic seizures, and even coma. Another paraneoplastic manifestations, or reduced cardiac output. syndrome related to neuroendocrine lung tumors Another striking group of symptoms related is Cushing syndrome, a result of the uncon- to local spread is the superior sulcus syndrome, trolled ectopic secretion of adrenocorticotropic or Pancoast tumor (3). This results from an hormone by the malignant cells. Rare neurologic apical neoplasm, usually nonsmall cell lung car- manifestations related to small cell carcinoma cinomas (NSCLCs), that grows directly into the are limbic encephalopathy, subacute cerebellar ipsilateral proximal brachial plexus as it exits degeneration, and subacute sensory neuropathy. the neural foramina, especially the C8 and T1 Only rarely are neuroendocrine tumors of the branches. Initially, this leads to intense pain in lung associated with the carcinoid syndrome. the ipsilateral subscapular area or upper extrem- Several paraneoplastic complications are much ity (especially the shoulder). With progression, more frequent with NSCLCs. A prominent one the pain may radiate through the entire length is humoral hypercalcemia of malignancy which,

2 Lung Cancer: Presentation, Epidemiology, Staging, Classifcation, Grading, and Spread

among lung cancers, is specifc for squamous cell Table 1-2 carcinoma. The tumor cells produce and secrete AGENTS, OCCUPATIONS, AND OCCUPATIONAL parathyroid hormone-related proteins into the PROCESSES CLASSIFIED AS HUMAN LUNG circulation, which enhances osteoclastic bone CARCINOGENS (GROUP 1) BY THE INTERNATIONAL resorption. Patients have weakness, coma, con- AGENCY FOR RESEARCH ON CANCERa fusion, polydipsia, polyuria, constipation, and Acheson process (synthesis of graphite and silicon carbide) nausea. Typically associated with lung adenocar- Aluminum production cinoma is hypertrophic osteoarthropathy (2,3). This includes clubbing of the digits, especially Arsenic and inorganic arsenic compounds the fngers; ossifying periostitis involving the Asbestos (all forms) distal parts of tubular bones, especially the tibia, Beryllium and beryllium compounds fbula, ulna, radius, and the bones of the wrist Bis(chloromethyl) ether; chloromethyl methyl ether and ankles; and arthralgias. This is characterized (technical grade) by progressive ossifcation of newly developed Cadmium and cadmium compounds subperiosteal vascularized connective tissue. Chromium (VI) compounds Clubbing is a related widening of the distal Coal, indoor emission from household combustion phalanx and elevation of the nail. Coal gasifcation EPIDEMIOLOGY Coal-tar pitch (occupations that involve electrode Lung cancer is the most common cause of manufacture, roofng and paving) cancer incidence and mortality worldwide as it Coke production has been for the past few decades (5–7). It was Diesel engine exhaust estimated in 2012 that there were 1.8 million Hematite mining (underground) new cases (12.9 percent of all cancers) and it is Iron and steel founding the cause of almost 20 percent (19.4 percent) of MOPP (vincristine-prednisone-nitrogen mustard-procar- all cancer deaths, with 1.59 million deaths in bazine mixture) 2012 (5,7–9). The highest estimated rates are in Nickel compounds North America (33.8 per 100,000) and Northern Europe (23.7 per 100,000). The incidence rates Outdoor air pollution in women are lower, mainly due to smoking Painting habits (8,9). Lung cancer became the most Particulate matter in outdoor air pollution common cause of cancer death in men in the Plutonium mid 1950s and in women in 1987. Radon-222 and its decay products In the United States the death rate for lung Rubber production industry cancer has fallen 45 percent from 1990 to 2015 among males and 19 percent from 2002 to 2015 Silica dust, crystalline among females due to decreases in smoking Soot (as found in occupational exposure of chimney from tobacco control and increased awareness sweeps) of the health risk of smoking (6). While this Sulfur mustard trend is observed in economically developed Tobacco smoke, second hand countries, in low- and middle-income countries, Tobacco smoking the lung cancer incidence and mortality rates Welding fumes continue to increase rapidly (10). X radiation, gamma radiation Smoking is the most common cause of lung a cancer. Nevertheless, in the United States, more Data from reference 10. than half of patients with lung cancer are never smokers or former smokers. Since there are approximately 20,000 cases of lung cancer in never cancers of the ovary, uterus, or lymphoma (6). smokers that occur in the United States each year, The International Agency for Research on Can- even this number ranks among the most com- cer (IARC) has reported a variety of additional mon 10 cancers by incidence, exceeding that of potential causes of lung cancer (Table 1-2).

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Figure 1-1 TRENDS IN LUNG CANCER DEATH RATES AND PREVALENCE OF CURRENT CIGARETTE SMOKING BY SEX, 1930-2013, UNITED STATES Top: Males Bottom: Females. (Figure 28- 5a,b from Thun MJ, Hemley SJ, Travis WD. Lung Cancer. In: Thun MJ, Linet MS, Cerhan JR, Haiman CA, Schottenfeld D, eds. Cancer: epidemiology and prevention, 4th ed. New York: Oxford University Press; 2018:519-542.)

The age-standardized lung cancer death rate in risk in those who stopped smoking because for men and women in the United States de- the age-standardized rates are weighted toward creased from 1930 to 2013, largely due to the older ages (10). decreasing smoking prevalence shown by the The incidence of lung cancers classifed as sex-specifc trends in fgure 1-1. Age-standard- adenocarcinomas has increased from less than ized lung cancer death rates increased continu- 5 percent of all lung cancers in the 1950s and ously for several decades despite the decreasing 1960s to approximately 70 percent in both sexes prevalence of current cigarette smoking. The in 2012 (10). During this time there were marked lag appears to be longer than would be expected decreases in the incidence of squamous cell and since lung cancer risk decreases within 5 years small cell carcinomas (fg. 1-2) (10). Similarly, after smoking cessation compared to the risk analysis of the National Cancer Institute (NCI) among continuing smokers; this reduced risk Surveillance, Epidemiology, and End Results depends on the cancer cell type (10–12). It (SEER) data showed the frequency of large cell is thought that the “overshoot” is due to the carcinoma also decreased markedly beginning continuing increase in lung cancer risk among around 1990 (fg. 1-3), about the time immu- continuing smokers in the birth cohorts with nohistochemistry for TTF-1 was introduced the heaviest lifetime history of smoking (13). into clinical practice; this appears to have led The increase in risk in older patients who practicing pathologists to reclassify most large continue to smoke is obscured by reductions cell carcinomas as adenocarcinomas (14).

4 Lung Cancer: Presentation, Epidemiology, Staging, Classifcation, Grading, and Spread

Figure 1-2 TRENDS IN AGE- STANDARDIZED INCIDENCE OF LUNG CANCER Surveillance, Epidemiology, and End Results (SEER) study of nine areas of the United States by gender and histology, 1973-2012, showing white males (top) and white females (bottom). (Figure 28-9a,b from Thun MJ, Hemley SJ, Travis WD. Lung Cancer. In: Thun MJ, Linet MS, Cerhan JR, Haiman CA, Schottenfeld D, eds. Cancer: epidemiology and prevention, 4th ed. New York: Oxford University Press; 2018:519-542.)

STAGING for the Study of Lung Cancer (IASLC) staging Staging is the determination of the extent of a classifcation were based on a rigorous analysis patient’s cancer that is frequently related directly of over 100,000 patients (17,18). Historically, to prognosis and to the therapy offered. Staging the TNM system was used for staging NSCLC, depends on the size of the tumor, the degree of its but now it is also recommended for small cell locoregional spread, and whether it has dissemi- carcinoma and carcinoid tumors (18,19). nated beyond local structures. The most widely In most cases, pathologic staging is straight- used staging system is that of the American Joint forward and the TNM rules are easily applied Committee on Cancer (AJCC), used mostly in (Tables 1-3, 1-4). A guide to uniform classifca- the United States, which is compiled and revised tion of situations beyond the standard descrip- in conjunction with the International Union tors is summarized in Table 1-5. In a minority of for Cancer Control (UICC), which is more of an cases the interpretation of staging characteristics international standard (15,16). Both the 7th and is not completely clear. In such cases, the gen- 8th editions of the International Association eral rule of the TNM system number 4 should

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Figure 1-3 TRENDS IN LUNG CANCER INCIDENCE RATES Age-adjusted 2000 United States standard from 1977- 1981 to 2006-2010 in the SEER 9 registries by histologic type. (Figure 1 from Lewis DR, Check DP, Caporaso NE, Travis WD, Devesa SS. US lung cancer trends by histologic type. Cancer 2014;120:2883-92.)

be applied: “If there is doubt concerning the (Table 1-3). In situ carcinoma is classifed as Tis correct T, N, or M category to which a particular (AIS) for adenocarcinoma in situ and Tis (SCC) case should be allotted, then the lower (i.e., less for squamous cell carcinoma in situ (Table 1-3). advanced) category should be chosen. This will T1. Tumors <3 cm surrounded by lung or also be refected in the stage” (20). visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar T Staging bronchus (i.e., not in the main bronchus) are T descriptors include tumor size, endobron- classifed as T1 (fg. 1-4A). T1 is divided into chial location, atelectasis/pneumonitis, and T1mi for minimally invasive adenocarcinoma invasion of anatomic structures around the (lepidic predominant, <3 cm total size, <0.5 lung (Table 1-3, fg. 1-4) (17). In the 8th TNM cm invasive size, and lacking vascular, pleural classifcation, T categories are proposed at 1-cm invasion, and spread through air spaces [STAS], intervals up to 5 cm (15,16,21,22). TX is used see below and chapter 4 for more specifcs), T1a when the primary tumor cannot be assessed or for tumors that are <1 cm, T1b for tumors that if tumor is proven by the presence of malignant are >1cm but <2cm; and T1c for tumors that are cells in the sputum or bronchial washings but >2 cm but <3 cm (Tables 1-3, 1-6; fg. 1-4A). not visualized by imaging or bronchoscopy. T0 is T2. T2 tumors are >3 cm but <5 cm in greatest used when there is no evidence of primary tumor dimension or tumors with any of the following

6 Lung Cancer: Presentation, Epidemiology, Staging, Classifcation, Grading, and Spread

Table 1-3 CATEGORIES, SUBCATEGORIES, AND DESCRIPTORS OF THE 8TH EDITION OF THE TNM CLASSIFICATION OF LUNG CANCERa

Category Subcategory Descriptors T – Primary Tumor TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy T0 No evidence of primary tumor Tis Carcinoma in situ: Tis(AIS): adenocarcinoma; Tis(SCIS): squamous cell carcinoma T1 Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus). The uncommon superfcial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classifed as T1a. T1mi Minimally invasive adenocarcinoma T1a Tumor 1 cm or less in greatest dimension T1b Tumor more than 1 cm but not more than 2 cm in greatest dimension T1c Tumor more than 2 cm but not more than 3 cm in greatest dimension T2 Tumor more than 3 cm but not more than 5 cm; or tumor with any of the following features. T2 tumors with these features are classifed T2a if 4 cm or less, or if size cannot be determined; and T2b if greater than 4 cm but not larger than 5 cm. Involves main bronchus regardless of distance to the carina, but without involving the carina Invades visceral pleura (PL1 or PL2) Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, either involving part of the lung or the entire lung T2a Tumor more than 3 cm but not more than 4 cm in greatest dimension T2b Tumor more than 4 cm but not more than 5 cm in greatest dimension T3 Tumor more than 5 cm but not more than 7 cm in greatest dimension or one that directly invades any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or associated separate tumor nodule(s) in the same lobe as the primary T4 Tumor more than 7 cm or one that invades any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) in a different ipsilateral lobe to that of the primary N – Regional Lymph Nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intra- pulmonary nodes, including involvement by direct extension N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) M – Distant Metastasis M0 No distant metastasis M1 Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fuid are negative for tumor, and the fuid is non-bloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor M1b Single extrathoracic metastasis in a single organ and involvement of a single distant (non-regional) node M1c Multiple extrathoracic metastases in one or several organs aData from references 15, 16, and 65.

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Table 1-4 features (fg. 1-4B): 1) involves the main bronchus regardless of the distance to the carina, but without STAGE GROUPING OF THE 8TH EDITION OF THE TNM CLASSIFICATION OF LUNG CANCERa involvement of the carina lung (this is assessed by clinicians not by pathologists), 2) invades the Stage T N M visceral pleura (PL1 or PL2, see below), and 3) asso- Occult carcinoma TX N0 M0 ciated with atelectasis or obstructive pneumonitis 0 Tis N0 M0 that extends to the hilar region either involving IA1 T1mi N0 M0 part of or the entire lung (this is assessed by cli- T1a N0 M0 nicians and radiology imaging, not by patholo- IA2 T1b N0 M0 IA3 T1c N0 M0 gists). T2a,b categories are summarized in Table IB T2a N0 M0 1-3 and fgure 1-4B. IIA T2b N0 M0 T3. Tumors are designated as T3 if they are IIB T1a, b, c N1 M0 5 to 7 cm in size, but also if they invade the T2a, b N1 M0 parietal pleura (PL3), chest wall (including su- T3 N0 M0 perior sulcus tumors), phrenic nerve, parietal IIIA T1a, b, c N2 M0 pericardium, or are separate tumor nodules in T2a, b N2 M0 the same lobe as the primary (fg. 1-4C). T3 N1 M0 T4. Tumors are designated as T4 if they are T4 N0 M0 T4 N1 M0 >7 cm or of any size that invades any of the IIIB T1a, b, c N3 M0 following: diaphragm, mediastinum, heart, T2a, b N3 M0 great vessels, trachea, recurrent laryngeal nerve, T3 N2 M0 esophagus, vertebral body, carina, or are separate T4 N2 M0 tumor nodule(s) in a different ipsilateral lobe to IIIC T3 N3 M0 that of the primary. Invasion of the mediastinal T4 N3 M0 pleura is no longer a T descriptor (fg. 1-4D). IV Any T Any N M1 The location of tumor <2 cm from the carina IVA Any T Any N M1a and the presence of total atelectasis/pneumonitis Any T Any N M1b are T2 descriptors, but both of these are not IVB Any T Any N M1c determined by the pathologist but rather by aData from references 15, 16, and 65.

Figure 1-4 TNM CLASSIFICATION A: Illustra- ted drawing of 8th edition TNM lung can cer man- i fes ta tions of T1a, T1b, and T1c. (All TNM fgures are courtesy of Dr. A. Frazier, Bal ti more, MD.)

8 Lung Cancer: Presentation, Epidemiology, Staging, Classifcation, Grading, and Spread

Figure 1-4, continued B: Illustrated drawing of T2a and T2b. C: Illustrated drawing of T3.

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Figure 1-4, continued D: Illustrated drawing of T4.

a clinician. Invasion of diaphragm is now a introduced in the 2011 IASLC/American Tho- T4 descriptor and invasion of the mediastinal racic Society (ATS)/European Respiratory Society pleura is no longer regarded as a T descriptor (ERS) classifcation, and now are offcially rec- due to its infrequent use. ognized in the 2015 World Health Organization These T categories demonstrate prognos- (WHO) classifcation of lung tumors (23,24). tic signifcance for both cT (clinical) and pT The pathologic details of these entities are pro- (pathologic) classifcation (fg. 1-5A,C). For both vided in chapter 4. To address these entities in clinical (by computerized tomography [CT]) the 8th edition TNM staging classifcation, the and pathologic staging, tumor size should be T descriptor Tis (AIS) was introduced to distin- measured according to the single maximum guish AIS it from squamous cell carcinoma in dimension (22). situ or Tis (SCIS) (Table 1-3). Likewise, T1mi was New components of the T descriptors include introduced for staging of MIA. the concepts of adenocarcinoma in situ (AIS), The 8th TNM staging system recommends minimally invasive adenocarcinoma (MIA), using invasive size as the size T descriptor and lepidic-predominant adenocarcinoma, rather than total size for nonmucinous lung

10 Lung Cancer: Presentation, Epidemiology, Staging, Classifcation, Grading, and Spread

Table 1-5 GUIDE TO UNIFORM CLASSIFICATION OF SITUATIONS BEYOND THE STANDARD DESCRIPTORSa

Situation Classifcation Direct invasion of an adjacent lobe, across the fssure or directly if the fssure is incomplete, unless T2a other criteria assign a higher T Invasion of phrenic nerve T3 Paralysis of the recurrent laryngeal nerve, superior vena caval obstruction, or compression of the trachea T4 or esophagus related to direct extension of the primary tumor Paralysis of the recurrent laryngeal nerve, superior vena caval obstruction, or compression of the trachea N2 or esophagus related to lymph node involvement Involvement of great vessels: aorta, superior vena cava, main pulmonary artery (pulmonary trunk), intra- T4 pericardial portions of the right and left pulmonary artery, intrapericardial portions of the superior and inferior right and left pulmonary veins Pancoast tumors with evidence of invasion of the vertebral body or spinal canal, encasement of the sub- T4 clavian vessels, or unequivocal involvement of the superior branches of the brachial plexus (C8 or above) Pancoast tumors without the criteria for T4 classifcation T3 Direct extension to parietal pericardium T3 Direct extension to visceral pericardium T4 Tumor extending to rib T3 Invasion into hilar fat, unless other criteria assign a higher T T2a Invasion into mediastinal fat T4 Discontinuous tumor nodules in the ipsilateral parietal or visceral pleura M1a Discontinuous tumor nodules outside the parietal pleura in the chest wall or in the diaphragm M1b or M1c aData from reference 15. adenocarcinomas with a lepidic component than round tumors) (fg. 1-7); 3) determining (by pathology) and a part solid appearance (by total size when tumors are removed in multiple CT). Nevertheless, both total size and invasive/ parts by the surgeon; 4) determining total size solid size should be reported in radiology and when the entire specimen does not reach the pathology reports (fg. 1-6) (22). Some of these pathology laboratory (if tumor procurement in tumors will be classifed as lepidic-predominant the operating room signifcantly alters tumor adenocarcinomas (Table 1-6, fg. 1-6, see chap- size); 5) determining whether there is one or ter 4). In nonmucinous lung adenocarcinomas two nodules when there may be a connection with a lepidic component, if the size of the between two apparent nodules seen only by CT invasive component cannot be measured in a that is missed by gross exam; and 6) correcting single discrete focus, it should be estimated by errors recorded in the gross description sections multiplying the total size times the percentage of the pathology report regarding tumor size of the invasive components (22). measurements resulting either from mistaken measurements or typographical errors. Use of Radiologic-Pathologic Lepidic tumors are frequently ill-defned and Correlation to Determine Tumor Size diffcult to identify grossly, so the total size of CT is a useful technique for assessing tumor such tumors is often underestimated and bet- size in lung cancer. There are several settings in ter appreciated by CT review. Often, the size which this is helpful: 1) determining total versus measured grossly corresponds to the solid or invasive size in lepidic-predominant tumors invasive size rather than the total size (fg. 1-6). (fg. 1-6); 2) resolving discrepancies with CT When these tumors are processed for histology, versus gross measurements, particularly with if the tumor is not infated, the alveolar walls tumors that are oddly shaped (elongated rather can collapse, further complicating estimation of

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Figure 1-5 TNM CLASSIFICATION Top: Survival according to the 8th edition T categories showing pathologically staged T1-4 N0M0R0 lung cancers. Bottom: Clinically staged T1- T4 N0M0 tumors. (Figs. 2A, and 2B from Rami-Porta R, Bolejack V, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classifcation for lung cancer. J Thorac Oncol 2015;10:990-1003.)

total tumor size, even histologically. CT correla- Pleural Invasion tion is helpful when lepidic tumors are too large to ft onto a single slide and multiple blocks Visceral pleural invasion (VPI) is classifed as are required (fg. 1-6). In many cases, review of PL0 when there is no invasion beyond the elastic these CT scans can help estimate the size of the layer, PL1 when invasion is beyond the elastic solid component, which can inform histologic layer, PL2 when invasion reaches the visceral pleu- assessment of the percentage of invasive versus ral surface, and PL3 with invasion of the parietal lepidic patterns. pleura or chest wall (fg. 1-8) (25). PL1 and PL2 are Since most radiologists measure tumor size classifed as T2, and PL3 is classifed as T3. Some only in the axial plane by CT, if an elongated literature suggests that there is no difference in tumor has the short axis in the axial or coronal survival for patients with PL1 and PL2 tumors, but plane, the maximum dimension of the tumor analysis of the large IASLC Lung Cancer Staging may be greatly underestimated (fg. 1-7A). In database indicates that survival for patients with such cases, accurate determination of the total PL2 tumors is worse than that for PL1 tumors tumor size by CT may require evaluation of (17). PL1 and PL2 are still maintained as T2 fac- both coronal and sagittal images (fg. 1-7B–D). tors in the 8th edition TNM classifcation.

12 Lung Cancer: Presentation, Epidemiology, Staging, Classifcation, Grading, and Spread

Table 1-6 8TH EDITION TNM CLASSIFICATION OF SMALL GROUND-GLASS/LEPIDIC ADENOCARCINOMAa

High-Resolution CT Images

cTc Solid part 0 cm 0 cm <0.5 cm 0.6-1.0 cm 1.1-2.0 cm 2.1-3.0 cm Total tumor size <0.5 cm 0.6-3.0 cm <3.0 cm 0.6-3.0 cm 1.1-3.0 cm 2.1-3.0 cm including GG Pathologic differ- AAH, AIS, MIA, LPA MIA, LPA, AIS LPA, Invasive LPA, Invasive AD ential diagnosis AIS, MIA AD, MIA Invasive AD Clinical stage cTis cT1 mi cT1a cT1b cT1c pT Invasive part 0 cm 0 cm <0.5cm 0.6-1.0 cm 1.1-2.0 cm 2.1-3.0 cm Total tumor size Usually <3.0 cm <3.0 cm 0.6-3.0 cm 1.1-3.0 cm 2.1-3.0 cm including lepidic <0.5 cm growth part Pathology AAH AIS MIA Lepidic predom- Invasive AD Invasive AD inant AD or in- with a lepidic with lepidic vasive AD with component component lepidic component or lepidic predominant AD Pathologic Stage pTis pT1mi pT1a pT1b pT1c aModifed from fgure 1 in reference 22. A pathologic differential diagnosis is listed for each of the proposed possibilities on CT scans. Final pT staging of these tumors requires complete pathologic examination in resected specimens. Tis (AIS)cT: These lesions typically show pure GG nodules (GGNs) measuring 3 cm or less; however, pure GGNs can also be minimally invasive AD (MIA) or invasive AD. pT: These tumors show pure lepidic growth without invasion, measuring 3 cm or less. T1mi;cT: MIA usually shows a GG predominant nodule 3 cm or smaller with a solid component that should appear 0.5 cm or smaller. Although some MIAs have a larger solid component on CT scans because of other benign components such as a scar or organizing pneumonia, these cases can only be diagnosed by pathologic examination. pT: MIA histologically shows an LPA nodule measuring 3 cm or less with an invasive component measuring 0.5 cm or less. T1a;cT: GG predominant nodules measuring 3.0 cm or less with a solid component measuring 0.6 to 1.0 cm. pT: When an LPA measuring 3.0 cm or less has an invasive component measuring 0.6 to 1.0 cm, it is classifed as pT1a. T1b;cT: GG predominant nodules measuring 3.0 cm or less with a solid component measuring 1.1to 2.0 cm. pT: When an LPA measuring 3.0cm or less has an invasive component measuring 1.1 to 2.0 cm, it is classifed as pT1b. T1c;cT: GG predominant nodules measuring 3.0 cm or less with a solid component measuring 2.1 to 3.0 cm are classifed as T1c. pT: When an invasive AD with a lepidic component measuring 3.0 cm or less has an invasive component measuring 2.1 to 3.0 cm, it is classifed as T1c.

In cases where invasion of the visceral pleura always the outer layer, so it is simpler to focus on is uncertain, elastic stains are recommended as the single dominant elastic layer for assessment this results in a change in stage from IA1-3 to of visceral pleural invasion because it is readily IB in 19 percent of cases (25–27). While elastic identifable in most cases (fg. 1-9) (25). stains are useful, determination of visceral pleu- Three patterns are encountered with visceral ral invasion remains diffcult in some cases. The pleural invasion: 1) with no secondary changes visceral pleura usually shows a single dominant elicited, 2) with prominent elastic reduplica- elastic layer. Other, less dominant elastic layers tion and infammatory infltrates, and 3) with can be seen in the visceral pleura, and previous thick fbroblastic proliferation (28). Extensive literature has recommended documenting two reduplication of the elastic layers can make elastic layers, including an inner and an outer interpretation challenging. In cases with thick elastic layer (25). Two layers, however, are not fibroblastic proliferation, elastic stains are always seen and the dominant elastic layer is not particularly useful (fg 1-9). In some cases, it is

13 Tumors of the Lower Respiratory Tract

Figure 1-6 RADIOLOGIC PATHOLOGIC CORRELATION IN LEPIDIC-PREDOMINANT ADENOCARCINOMA This tumor grossly measured 1.8 cm. However, the CT shows a large part solid tumor with a predominant ground-glass component (A) that measures 4.2 cm total size (B) and 1.5 cm solid size (C). The gross measurement underestimated the total size and corresponded to the solid size on CT. Lepidic components are frequently underestimated on gross exam.

14 Lung Cancer: Presentation, Epidemiology, Staging, Classifcation, Grading, and Spread

Figure 1-6, continued Histologically, the tumor was lepidic predominant (D) with an extensive lepidic component (E) and a minor acinar invasive component (F).

diffcult to determine whether atypical cells on elastic fbers. In some cases, but less often than the pleural surface or invading into the pleura in the visceral pleura, an elastic stain is used in are tumor cells. Immunohistochemistry for this setting for PL3 assessment. The presence TTF-1 (fg. 1-10) or p40, paired with mesothelial of tumor invading into fat does not mean the markers such as WT-1 or calretinin, may help tumor has invaded chest wall fat because fatty in the assessment of visceral pleural invasion, metaplasia can occur within the visceral pleura particularly PL1 versus PL2 status. and tumor can invade into this fat and still be The information provided by elastic stains classifed as PL1 (fg. 1-11). In most cases, this is helps evaluate invasion of the parietal pleura for clear because there is intact surface connective PL3 status. In contrast to the visceral pleura, in tissue and smooth mesothelial surface lining. If this anatomic location there is no constant or there is any doubt about this, however, the tho- continuous elastic layer. Instead, if an elastic lay- racic surgeon should asked whether the parietal er is present, it consists of loose discontinuous pleural or chest wall soft tissues were removed.