lung cancer: clinical presentation, epidemiology, … · tumors of the lower respiratory tract 4...

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

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CLINICAL PRESENTATION

Lung cancer presents in different ways, largely depending on the location and size of the tumor and whether it remains localized to the lung or is metastatic (Table 1-1). One third of lung cancer patients present with early stage disease and the rest with advanced disease. Pa-tients with early stage tumors may have mini-mal or no symptoms; lung cancer screening has led to the increased detection of such cancers, resulting in a greater than 20 percent reduction in mortality (1). Patients with advanced disease can present with symptoms related to invasion or compression of major structures, such as the

Table 1-1

LUNG CANCER PRESENTING SYMPTOMSa

Category Symptom Pathogenesis

Primary tumor Cough Airway obstruction, atelectasis, infection, airway inflammation

Hemoptysis Airway inflammation 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.

vena cava, or metastasis to distant sites such as the bone or brain (Table 1-1).

Although the presentation of primary lung cancer varies with the location and size of the tumor mass, its extent of spread, and its cell type, there are many features of lung cancers that overlap. Five to 20 percent of patients are asymptomatic at the time of diagnosis. These patients usually have a chest radiographic im-aging procedure that reveals a small lung mass which gets sampled for pathology. However, over 80 percent of new lung cancer patients have one or more symptoms referable to their disease at the time of initial diagnosis, many of

Tumors of the Lower Respiratory Tract

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which are directly related to the presence of the primary tumor. The most common symptom is cough, which is usually related to irritation of bronchial structures by the neoplasm. A new cough or one that does not abate in a current or a former smoker should be evaluated promptly (2–4). Hemoptysis is also a frequent and char-acteristic presentation, especially for individuals with squamous cell carcinoma. Dyspnea is often present to some degree, especially with small cell carcinoma. It is usually related to the presence of the tumor as it obstructs airways or, less likely, spreads throughout much of the parenchyma; this may also result in wheezing. Chest pain, which is typically described as a dull ache that does not go away, may be related to invasion of soft tissue of the chest wall, ribs, or pleura. Recurrent or persistent infections, especially pneumonias, may be related to bronchial obstruction.

Spread of tumor within the thorax also causes clinical manifestations (Table 1-1) (2–4). One of the most dramatic is the superior vena cava syndrome. More often associated with small cell carcinoma, it is due to extrinsic compression of the superior vena cava by neoplasm. This results in edema of the face and upper extremity; the fluid accumulation is accentuated when the patient has been recumbent for some time. Cerebral edema may be a component, with associated headaches and other neurologic complications. Edema of the larynx may occur and rarely precipitates a medical emergency due to rapidly developing respiratory distress. Injury to the recurrent laryngeal nerve may lead to hoarseness. Neural damage to the phrenic nerve may produce dyspnea related to hemidiaphrag-matic paralysis. Local dissemination with the development of pleural or pericardial effusions contributes to shortness of breath, systemic manifestations, or reduced cardiac output.

Another striking group of symptoms related to local spread is the superior sulcus syndrome, or Pancoast tumor (3). This results from an apical neoplasm, usually nonsmall cell lung car-cinomas (NSCLCs), that grows directly into the ipsilateral proximal brachial plexus as it exits the neural foramina, especially the C8 and T1 branches. Initially, this leads to intense pain in the ipsilateral subscapular area or upper extrem-ity (especially the shoulder). With progression, the pain may radiate through the entire length

of the arm, especially along the lateral aspect, which may also manifest muscular atrophy and associated weakness. Occasionally, a Pancoast tumor directly extends to compress the spinal cord, producing paraplegia.

Another potential syndrome, which may be present at initial diagnosis or develop subse-quently, is oculosympathetic palsy, or Horner syndrome (3). This results from direct invasion of the paravertebral sympathetic ganglia. Clas-sic components of this complex are persistent miosis (and anisocoria), enophthalmosis, ptosis, and anhidrosis. Other manifestations of lo-cal tumor spread include dysphagia related to compression of the esophagus.

Metastases occur in any organ or body struc-ture and evoke clinical manifestations, and frequently, findings at the initial diagnosis are due to metastases (3). Major extranodal targets of lung cancer spread include the central nervous system (focal neurologic abnormalities, seizures, back pain, and headaches that classically are worse upon awakening from sleep) and bone me-tastases (vertebrae, ribs, and femur). The resultant usually lytic lesions are typically associated with unrelenting pain. Cachexia is associated with dis-seminated disease and a large tumor burden.

Some patients present initially with a para-neoplastic syndrome (Table 1-1) (3,4). The most common one associated with lung cancer (espe-cially small cell carcinoma) is the syndrome of inappropriate antidiuretic hormone (SIADH). Tumor cells produce and release antidiuretic hor-mone (vasopressin), causing the body to retain water; a major consequence of this is hypona-tremia which may cause a number of metabolic disorders of varying severity including muscle cramps and weakness, irritability, confusion, seizures, and even coma. Another paraneoplastic syndrome related to neuroendocrine lung tumors is Cushing syndrome, a result of the uncon-trolled ectopic secretion of adrenocorticotropic hormone by the malignant cells. Rare neurologic manifestations related to small cell carcinoma are limbic encephalopathy, subacute cerebellar degeneration, and subacute sensory neuropathy. Only rarely are neuroendocrine tumors of the lung associated with the carcinoid syndrome.

Several paraneoplastic complications are much more frequent with NSCLCs. A prominent one is humoral hypercalcemia of malignancy which,

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Lung Cancer: Presentation, Epidemiology, Staging, Classification, Grading, and Spread

among lung cancers, is specific for squamous cell carcinoma. The tumor cells produce and secrete parathyroid hormone-related proteins into the circulation, which enhances osteoclastic bone resorption. Patients have weakness, coma, con-fusion, polydipsia, polyuria, constipation, and nausea. Typically associated with lung adenocar-cinoma is hypertrophic osteoarthropathy (2,3). This includes clubbing of the digits, especially the fingers; ossifying periostitis involving the distal parts of tubular bones, especially the tibia, fibula, ulna, radius, and the bones of the wrist and ankles; and arthralgias. This is characterized by progressive ossification of newly developed subperiosteal vascularized connective tissue. Clubbing is a related widening of the distal phalanx and elevation of the nail.

EPIDEMIOLOGY

Lung cancer is the most common cause of cancer incidence and mortality worldwide as it has been for the past few decades (5–7). It was estimated in 2012 that there were 1.8 million new cases (12.9 percent of all cancers) and it is the cause of almost 20 percent (19.4 percent) of all cancer deaths, with 1.59 million deaths in 2012 (5,7–9). The highest estimated rates are in North America (33.8 per 100,000) and Northern Europe (23.7 per 100,000). The incidence rates in women are lower, mainly due to smoking habits (8,9). Lung cancer became the most common cause of cancer death in men in the mid 1950s and in women in 1987.

In the United States the death rate for lung cancer has fallen 45 percent from 1990 to 2015 among males and 19 percent from 2002 to 2015 among females due to decreases in smoking from tobacco control and increased awareness of the health risk of smoking (6). While this trend is observed in economically developed countries, in low- and middle-income countries, the lung cancer incidence and mortality rates continue to increase rapidly (10).

Smoking is the most common cause of lung cancer. Nevertheless, in the United States, more than half of patients with lung cancer are never smokers or former smokers. Since there are ap-proximately 20,000 cases of lung cancer in never smokers that occur in the United States each year, even this number ranks among the most com-mon 10 cancers by incidence, exceeding that of

cancers of the ovary, uterus, or lymphoma (6). The International Agency for Research on Can-cer (IARC) has reported a variety of additional potential causes of lung cancer (Table 1-2).

Table 1-2

AGENTS, OCCUPATIONS, AND OCCUPATIONAL PROCESSES CLASSIFIED AS HUMAN LUNG

CARCINOGENS (GROUP 1) BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCERa

Acheson process (synthesis of graphite and silicon carbide)

Aluminum production

Arsenic and inorganic arsenic compounds

Asbestos (all forms)

Beryllium and beryllium compounds

Bis(chloromethyl) ether; chloromethyl methyl ether (technical grade)

Cadmium and cadmium compounds

Chromium (VI) compounds

Coal, indoor emission from household combustion

Coal gasification

Coal-tar pitch (occupations that involve electrode manufacture, roofing and paving)

Coke production

Diesel engine exhaust

Hematite mining (underground)

Iron and steel founding

MOPP (vincristine-prednisone-nitrogen mustard-procar- bazine mixture)

Nickel compounds

Outdoor air pollution

Painting

Particulate matter in outdoor air pollution

Plutonium

Radon-222 and its decay products

Rubber production industry

Silica dust, crystalline

Soot (as found in occupational exposure of chimney sweeps)

Sulfur mustard

Tobacco smoke, second hand

Tobacco smoking

Welding fumes

X radiation, gamma radiationaData from reference 10.


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The age-standardized lung cancer death rate for men and women in the United States de-creased from 1930 to 2013, largely due to the decreasing smoking prevalence shown by the sex-specific trends in figure 1-1. Age-standard-ized lung cancer death rates increased continu-ously for several decades despite the decreasing prevalence of current cigarette smoking. The lag appears to be longer than would be expected since lung cancer risk decreases within 5 years after smoking cessation compared to the risk among continuing smokers; this reduced risk depends on the cancer cell type (10–12). It is thought that the “overshoot” is due to the continuing increase in lung cancer risk among continuing smokers in the birth cohorts with the heaviest lifetime history of smoking (13). The increase in risk in older patients who continue to smoke is obscured by reductions

in risk in those who stopped smoking because the age-standardized rates are weighted toward older ages (10).

The incidence of lung cancers classified as adenocarcinomas has increased from less than 5 percent of all lung cancers in the 1950s and 1960s to approximately 70 percent in both sexes in 2012 (10). During this time there were marked decreases in the incidence of squamous cell and small cell carcinomas (fig. 1-2) (10). Similarly, analysis of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) data showed the frequency of large cell carcinoma also decreased markedly beginning around 1990 (fig. 1-3), about the time immu-nohistochemistry for TTF-1 was introduced into clinical practice; this appears to have led practicing pathologists to reclassify most large cell carcinomas as adenocarcinomas (14).

Figure 1-1

TRENDS IN LUNG CANCER DEATH RATES AND PREVALENCE OF CURRENT CIGARETTE SMOKING BY SEX,

1930-2013, UNITED STATESTop: MalesBottom: 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.)

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Figure 1-2

TRENDS IN AGE- STANDARDIZED INCIDENCE

OF LUNG CANCERSurveillance, 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

Staging is the determination of the extent of a patient’s cancer that is frequently related directly to prognosis and to the therapy offered. Staging depends on the size of the tumor, the degree of its locoregional spread, and whether it has dissemi-nated beyond local structures. The most widely used staging system is that of the American Joint Committee on Cancer (AJCC), used mostly in the United States, which is compiled and revised in conjunction with the International Union for Cancer Control (UICC), which is more of an international standard (15,16). Both the 7th and 8th editions of the International Association

for the Study of Lung Cancer (IASLC) staging classification were based on a rigorous analysis of over 100,000 patients (17,18). Historically, the TNM system was used for staging NSCLC, but now it is also recommended for small cell carcinoma and carcinoid tumors (18,19).

In most cases, pathologic staging is straight-forward and the TNM rules are easily applied (Tables 1-3, 1-4). A guide to uniform classifica-tion of situations beyond the standard descrip-tors is summarized in Table 1-5. In a minority of cases the interpretation of staging characteristics is not completely clear. In such cases, the gen-eral rule of the TNM system number 4 should


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be applied: “If there is doubt concerning the correct T, N, or M category to which a particular case should be allotted, then the lower (i.e., less advanced) category should be chosen. This will also be reflected in the stage” (20).

T Staging

T descriptors include tumor size, endobron-chial location, atelectasis/pneumonitis, and invasion of anatomic structures around the lung (Table 1-3, fig. 1-4) (17). In the 8th TNM classification, T categories are proposed at 1-cm intervals up to 5 cm (15,16,21,22). TX is used when the primary tumor cannot be assessed or if tumor is proven by the presence of malignant cells in the sputum or bronchial washings but not visualized by imaging or bronchoscopy. T0 is used when there is no evidence of primary tumor

(Table 1-3). In situ carcinoma is classified as Tis (AIS) for adenocarcinoma in situ and Tis (SCC) for squamous cell carcinoma in situ (Table 1-3).

T1. Tumors <3 cm surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus) are classified as T1 (fig. 1-4A). T1 is divided into T1mi for minimally invasive adenocarcinoma (lepidic predominant, <3 cm total size, <0.5 cm invasive size, and lacking vascular, pleural invasion, and spread through air spaces [STAS], see below and chapter 4 for more specifics), T1a for tumors that are <1 cm, T1b for tumors that are >1cm but <2cm; and T1c for tumors that are >2 cm but <3 cm (Tables 1-3, 1-6; fig. 1-4A).

T2. T2 tumors are >3 cm but <5 cm in greatest dimension or tumors with any of the following

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.)

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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 superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified 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 classified 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) fluid are negative for tumor, and the fluid 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 organsaData from references 15, 16, and 65.


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Table 1-4

STAGE GROUPING OF THE 8TH EDITION OF THE TNM CLASSIFICATION OF LUNG CANCERa

Stage T N M

Occult carcinoma TX N0 M0 0 Tis N0 M0

IA1 T1mi N0 M0 T1a N0 M0 IA2 T1b N0 M0 IA3 T1c N0 M0 IB T2a N0 M0

IIA T2b N0 M0 IIB T1a, b, c N1 M0 T2a, b N1 M0 T3 N0 M0

IIIA T1a, b, c N2 M0 T2a, b N2 M0 T3 N1 M0 T4 N0 M0 T4 N1 M0 IIIB T1a, b, c N3 M0 T2a, b N3 M0 T3 N2 M0 T4 N2 M0

IIIC T3 N3 M0 T4 N3 M0

IV Any T Any N M1

IVA Any T Any N M1a Any T Any N M1b IVB Any T Any N M1caData from references 15, 16, and 65.

features (fig. 1-4B): 1) involves the main bronchus regardless of the distance to the carina, but without involvement of the carina lung (this is assessed by clinicians not by pathologists), 2) invades the visceral pleura (PL1 or PL2, see below), and 3) asso-ciated with atelectasis or obstructive pneumonitis that extends to the hilar region either involving part of or the entire lung (this is assessed by cli-nicians and radiology imaging, not by patholo-gists). T2a,b categories are summarized in Table 1-3 and figure 1-4B.

T3. Tumors are designated as T3 if they are 5 to 7 cm in size, but also if they invade the parietal pleura (PL3), chest wall (including su-perior sulcus tumors), phrenic nerve, parietal pericardium, or are separate tumor nodules in the same lobe as the primary (fig. 1-4C).

T4. Tumors are designated as T4 if they are >7 cm or of any size that invades any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or are separate tumor nodule(s) in a different ipsilateral lobe to that of the primary. Invasion of the mediastinal pleura is no longer a T descriptor (fig. 1-4D).

The location of tumor <2 cm from the carina and the presence of total atelectasis/pneumonitis are T2 descriptors, but both of these are not determined by the pathologist but rather by

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 figures are courtesy of Dr. A. Frazier, Bal ti more, MD.)

A

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Figure 1-4, continued

B: Illustrated drawing of T2a and T2b.C: Illustrated drawing of T3.


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D: Illustrated drawing of T4.

a clinician. Invasion of diaphragm is now a T4 descriptor and invasion of the mediastinal pleura is no longer regarded as a T descriptor due to its infrequent use.

These T categories demonstrate prognos-tic significance for both cT (clinical) and pT (pathologic) classification (fig. 1-5A,C). For both clinical (by computerized tomography [CT]) and pathologic staging, tumor size should be measured according to the single maximum dimension (22).

New components of the T descriptors include the concepts of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic-predominant adenocarcinoma,

introduced in the 2011 IASLC/American Tho-racic Society (ATS)/European Respiratory Society (ERS) classification, and now are officially rec-ognized in the 2015 World Health Organization (WHO) classification of lung tumors (23,24). The pathologic details of these entities are pro-vided in chapter 4. To address these entities in the 8th edition TNM staging classification, the T descriptor Tis (AIS) was introduced to distin-guish AIS it from squamous cell carcinoma in situ or Tis (SCIS) (Table 1-3). Likewise, T1mi was introduced for staging of MIA.

The 8th TNM staging system recommends using invasive size as the size T descriptor rather than total size for nonmucinous lung

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Table 1-5

GUIDE TO UNIFORM CLASSIFICATION OF SITUATIONS BEYOND THE STANDARD DESCRIPTORSa

Situation Classification

Direct invasion of an adjacent lobe, across the fissure or directly if the fissure 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 classification 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 M1caData from reference 15.

adenocarcinomas with a lepidic component (by pathology) and a part solid appearance (by CT). Nevertheless, both total size and invasive/solid size should be reported in radiology and pathology reports (fig. 1-6) (22). Some of these tumors will be classified as lepidic-predominant adenocarcinomas (Table 1-6, fig. 1-6, see chap-ter 4). In nonmucinous lung adenocarcinomas with a lepidic component, if the size of the invasive component cannot be measured in a single discrete focus, it should be estimated by multiplying the total size times the percentage of the invasive components (22).

Use of Radiologic-Pathologic Correlation to Determine Tumor Size

CT is a useful technique for assessing tumor size in lung cancer. There are several settings in which this is helpful: 1) determining total versus invasive size in lepidic-predominant tumors (fig. 1-6); 2) resolving discrepancies with CT versus gross measurements, particularly with tumors that are oddly shaped (elongated rather

than round tumors) (fig. 1-7); 3) determining total size when tumors are removed in multiple parts by the surgeon; 4) determining total size when the entire specimen does not reach the pathology laboratory (if tumor procurement in the operating room significantly alters tumor size); 5) determining whether there is one or two nodules when there may be a connection between two apparent nodules seen only by CT that is missed by gross exam; and 6) correcting errors recorded in the gross description sections of the pathology report regarding tumor size measurements resulting either from mistaken measurements or typographical errors.

Lepidic tumors are frequently ill-defined and difficult to identify grossly, so the total size of such tumors is often underestimated and bet-ter appreciated by CT review. Often, the size measured grossly corresponds to the solid or invasive size rather than the total size (fig. 1-6). When these tumors are processed for histology, if the tumor is not inflated, the alveolar walls can collapse, further complicating estimation of


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Figure 1-5

TNM CLASSIFICATIONTop: 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 classification for lung cancer. J Thorac Oncol 2015;10:990-1003.)

total tumor size, even histologically. CT correla-tion is helpful when lepidic tumors are too large to fit onto a single slide and multiple blocks are required (fig. 1-6). In many cases, review of these CT scans can help estimate the size of the solid component, which can inform histologic assessment of the percentage of invasive versus lepidic patterns.

Since most radiologists measure tumor size only in the axial plane by CT, if an elongated tumor has the short axis in the axial or coronal plane, the maximum dimension of the tumor may be greatly underestimated (fig. 1-7A). In such cases, accurate determination of the total tumor size by CT may require evaluation of both coronal and sagittal images (fig. 1-7B–D).

Pleural Invasion

Visceral pleural invasion (VPI) is classified as PL0 when there is no invasion beyond the elastic layer, PL1 when invasion is beyond the elastic layer, PL2 when invasion reaches the visceral pleu-ral surface, and PL3 with invasion of the parietal pleura or chest wall (fig. 1-8) (25). PL1 and PL2 are classified as T2, and PL3 is classified as T3. Some literature suggests that there is no difference in survival for patients with PL1 and PL2 tumors, but analysis of the large IASLC Lung Cancer Staging database indicates that survival for patients with PL2 tumors is worse than that for PL1 tumors (17). PL1 and PL2 are still maintained as T2 fac-tors in the 8th edition TNM classification.

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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 pT1caModified from figure 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 classified 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 classified 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 classified 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 classified as T1c.

In cases where invasion of the visceral pleura is uncertain, elastic stains are recommended as this results in a change in stage from IA1-3 to IB in 19 percent of cases (25–27). While elastic stains are useful, determination of visceral pleu-ral invasion remains difficult in some cases. The visceral pleura usually shows a single dominant elastic layer. Other, less dominant elastic layers can be seen in the visceral pleura, and previous literature has recommended documenting two elastic layers, including an inner and an outer elastic layer (25). Two layers, however, are not always seen and the dominant elastic layer is not

always the outer layer, so it is simpler to focus on the single dominant elastic layer for assessment of visceral pleural invasion because it is readily identifiable in most cases (fig. 1-9) (25).

Three patterns are encountered with visceral pleural invasion: 1) with no secondary changes elicited, 2) with prominent elastic reduplica-tion and inflammatory infiltrates, and 3) with thick fibroblastic proliferation (28). Extensive reduplication of the elastic layers can make interpretation challenging. In cases with thick fibroblastic proliferation, elastic stains are particularly useful (fig 1-9). In some cases, it is


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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.

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difficult to determine whether atypical cells on the pleural surface or invading into the pleura are tumor cells. Immunohistochemistry for TTF-1 (fig. 1-10) or p40, paired with mesothelial markers such as WT-1 or calretinin, may help in the assessment of visceral pleural invasion, particularly PL1 versus PL2 status.

The information provided by elastic stains helps evaluate invasion of the parietal pleura for PL3 status. In contrast to the visceral pleura, in this anatomic location there is no constant or continuous elastic layer. Instead, if an elastic lay-er is present, it consists of loose discontinuous

elastic fibers. In some cases, but less often than in the visceral pleura, an elastic stain is used in this setting for PL3 assessment. The presence of tumor invading into fat does not mean the tumor has invaded chest wall fat because fatty metaplasia can occur within the visceral pleura and tumor can invade into this fat and still be classified as PL1 (fig. 1-11). In most cases, this is clear because there is intact surface connective tissue and smooth mesothelial surface lining. If there is any doubt about this, however, the tho-racic surgeon should asked whether the parietal pleural or chest wall soft tissues were removed.


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

lung cancer: clinical presentation, epidemiology, … · tumors of the lower respiratory tract 4...

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