The Core Curriculum: Cardiopulmonary Imaging, 1st Edition (2004)

Chapter 7. Lung Cancer

Lung cancer is the most common fatal malignancy in humans. It is strongly associated with cigarette smoking and asbestos exposure; viral infections, pulmonary fibrosis, and radiation exposure play a less defined and/or less frequent role (1,2,3,4,5,6,7). Imaging plays a crucial role in detection, diagnosis, and staging.

Detection

Although history and physical examination may suggest a pulmonary process, they seldom result in a specific diagnosis of carcinoma of the lung. Sputum cytology is somewhat better in that it may reveal malignant cells. However, radiology alone allows direct noninvasive visualization of the pulmonary parenchyma and mediastinum.

The chest x-ray (CXR) is the cheapest, easiest, most convenient method for this examination. On the CXR, lesions are often detected when they are in the 1-cm size range, and smaller lesions may be detected. Unfortunately, smaller lesions are most likely to be seen if they are calcified, in which case they are probably benign. Frontal and lateral radiographs increase the likelihood of detecting important small lesions, and comparison with prior radiographs can also improve diagnostic accuracy and assessment of the lesion’s malignant potential. A nodule that has been present for more than 2 years or less than 2 months is unlikely to be malignant, depending on its size and growth rate.

The CXR is the cheapest, easiest, most convenient method for detecting lung cancer.

Interpretation of the CXR requires great care and awareness of locations that are more difficult to evaluate (and therefore require more scrutiny). Lesions that may be missed may occur in the lung apices, where overlapping ribs, clavicles, neck soft tissues, and variable pleural and parenchymal scarring from old granulomatous infections result in significant camouflage (Fig. 7.1). “Pseudo-lesions” also occur in this location, because calcification and/or ossification at the first costochondral junctions may simulate lung nodules. Apical lordotic chest radiography, with the patient leaning back and the x-ray beam angled upward, projects anterior structures cephalad, allowing better visualization of the lung apices.

The hila, with branching arteries and superimposed veins, may conceal an enlarged lymph node or obscure a nearby lung nodule. Hilar masses are sometimes better appreciated on the lateral radiograph (Fig. 7.2). The mediastinum may conceal an especially large mass, and lung lesions close to the mediastinum are also harder to detect because of overlap with the heart, aorta and its branches, and superior vena cava. Nodules in any part of the lung may be rendered invisible by surrounding parenchymal abnormality (Fig. 7.3). In addition, small nodules anywhere at the periphery of the lungs may be overlooked. Shallow oblique radiographs may be a very helpful first step in evaluating a suspicious opacity.

Figure 7.1 A nodule behind the medial right clavicle that could potentially be missed (arrow).

A particularly dangerous nodule location is in the posterior costophrenic sulci of the lungs, below the domes of the diaphragm (Fig. 7.4). In some patients a central endobronchial lesion will clearly be undetectable based on size alone, but careful assessment of secondary signs (such as postobstructive atelectasis, pneumonia, or air trapping) may still allow diagnosis (Fig. 7.5).

Figure 7.2 Hilar mass better seen on the lateral radiograph. A. Posteroanterior chest x-ray: slight enlargement of right lower hilum(arrow). B. Lateral chest x-ray: mass (M) more easily appreciated.

To broach the topic of malpractice, a discussion of missed lung cancer (as the flip side of lung cancer detection) is in order. Malpractice has well-defined legal elements (such as duty, breach of duty, negligence, and injury), but jurors are not legal scholars. Jurors may sympathize with young attractive plaintiffs who have obviously suffered from illness; the suffering may not be related to the radiologist in any way. The radiologist is particularly at risk because the images that reveal the radiologist’s “mistake” (important note: mistake does not equal malpractice) are generally available for review, and abnormalities seem to grow before your very eyes in retrospect.

Figure 7.3 The case of the missing lung nodule. A. Anteroposterior chest x-ray 3-6: pulmonary edema but no obvious nodule. B.Anteroposterior chest x-ray 3-8: right upper lobe collapse (C), with elevation of the minor fissure (arrows), but no obvious nodule. C.Anteroposterior chest x-ray 3-9: the nodule (N) is finally visible.

I offer the following ideas for defense of alleged radiologic malpractice in missed lung cancer:

1. Small lesions: It could not be diagnosed prospectively (usually easy to get supportive expert witness testimony, although it is also easy for the plaintiff to hire someone to testify that they could see this lesion).

2. Larger lesions: It did not affect the outcome (especially worth consideration with bad cell types like small cell and large cell carcinoma).

3. The “Mayo Clinic” defense: In a study (8) of CXR screening for lung cancer at 4-month intervals, two or three experts in pulmonary disease (at least one a radiologist) reviewed radiographs specifically for evidence of lung cancer in high-risk patients (older males who were heavy smokers). When cancer was detected, in 45 of 50 peripheral lung cancers and in 30 of 42 central lung cancers the lesion could also be seen in retrospect on at least one earlier CXR; four were visible on radiographs dating back at least 2 years. Their conclusion: “Our results suggest that failure to detect a small pulmonary nodule on a single CXR should not constitute negligence or be the basis for malpractice litigation.”

4. The “Where’s Waldo?” defense: In an elegant letter to the editor of the journal Radiology (9), Dr. Ronald Hendrix pointed out the need for an analogy to explain to members of a lay audience how a well-qualified careful radiologist could ever miss a lesion that they now easily see on a radiograph. He likened this to the search for Waldo in the series of “Where’s Waldo?” books. As Dr. Hendrix pointed out, everyone understands how hard it can be to locate Waldo in a given illustration. However, once he has been found, Waldo is incredibly obvious when the same illustration is reviewed. Dr. Hendrix added that it is even harder to look for lung cancer (or any other radiographic finding) because, whereas Waldo is definitely present on every page of a “Where’s Waldo” book, a radiograph may be normal (in other words, it may contain no radiographic findings or Waldos).

Figure 7.4 Where is the nodule? A. Posteroanterior chest x-ray: no obvious nodule. B. Lateral chest x-ray: posterior right hemidiaphragmatic eventration (E), but no nodule. C. Computed tomography: right lower lobe nodule (N) below dome of right hemidiaphragm not seen on chest x-ray. D. Close-up of right lung base in A with adjusted viewing parameters: with hindsight and ample imagination, the nodule is possibly visible (arrows).

Figure 7.5 Effects of endobronchial lesion. A. Posteroanterior chest x-ray: slightly increased lucency of left lung compared with right, with fewer vessels per unit area in that lung, compatible with air trapping distal to an endobronchial mass. B. Computed tomography of lower lungs: lucency of left lung and sparsity of left lung vessels more clearly revealed. C. Anteroposterior chest x-ray 2 weeks after A: left lung collapse with bronchial cutoff (arrow).

I offer the following advice to potential radiologists: If you cannot stand to make mistakes (or more to the point, if you do not want proof of your errors to be part of the permanent medical record), choose another specialty.

Compared with the CXR, computed tomography (CT) is more sensitive for identifying lung nodules; unfortunately, this is accompanied by decreased specificity. Many small nodules detected only at CT are scars, intrapulmonary lymph nodes, or other nonspecific benign lesions. Unfortunately, some are early lung cancers. This is the crux of the issue currently being addressed by trials of CT for lung cancer screening.

Cancer screening would certainly seem to make sense for the leading cause of cancer-related deaths in the United States. However, the biological characteristics of a neoplasm influence the utility of screening for that neoplasm in an at-risk population. Screening evaluates individuals who manifest no signs of disease; in lung cancer, the at-risk population consists of heavy smokers. For effective screening, the following must apply:

1. Disease must be identifiable before symptoms develop.

2. Earlier treatment of the disease must be shown to have more effect than later treatment.

3. Benefits to the few treated for disease must outweigh the expense and harm to the screened population caused by the screening process.

4. To be considered effective, screening needs to demonstrate a decrease in the mortality of a given disease.

Certain biases need to be considered when evaluating the effectiveness of screening. Lead time bias refers to the fact that earlier detection of disease in a screened population compared with a control group makes it seem that patients live longer in the screened group, even if they die at the same age as control group patients with the same disease. Length time bias means that slowly growing tumors have a longer detectable preclinical phase than rapidly growing tumors and are therefore more likely to be identified at screening. Overdiagnosis bias is the failure to correct for preclinical disease that would not have produced signs or symptoms before the subject would have died of other causes. In general, a large number of subjects (more than 500) and a long observation time (usually more than 5 years) are required to validate the utility of screening.

Four large randomized trials (10,11,12,13) of lung cancer screening in the past 30 years (before the advent of CT screening) failed to detect a statistically significant decrease in lung cancer mortality. This subject is currently being reassessed with the addition of chest CT. CT screening for lung cancer certainly allows identification of disease before symptoms are present. However, it is not yet certain that this can be done cost-effectively, particularly because so many detected nodules turn out to be benign (14,15). In fact, the possibility that screening can even prove harmful has also been raised (16). It is probably best to describe lung cancer screening as a technique that is unproven but not yet discredited.

Lung cancer screening is currently best described as unproven but not yet discredited.

Diagnosis

Lung cancer often manifests as a single nodule or mass. Diagnosis or exclusion of lung cancer starts with an assessment of the radiographic features of the detected nodule or mass. A lesion is generally considered benign if it remains stable for at least 2 years. Thus, the single best test of a lesion’s malignant potential is comparison with old films. This simple fact is so often ignored that it must need more emphasis. Apart from its greater diagnostic accuracy, comparison with old films also results in lower expense (subject to the next rate increase from the U.S. Postal Service) and much less radiation than alternative imaging strategies for assessing a demonstrated lung nodule.

When old films are unavailable, the lesion can be assessed for benign radiographic features. Calcification may be helpful if there is a benign pattern of calcification (diffuse, central, “popcorn,” or concentric) (Fig. 7.6); other patterns of calcification are unrevealing as to a lesion’s malignant potential (Fig. 7.7). Another suggestive finding of benign disease is “rabbit ears” (a feeding artery and draining vein) in a pulmonary arteriovenous malformation (Fig. 7.8). Thin-section CT may be more helpful in this setting, because it may demonstrate calcification that escapes CXR detection (Fig. 7.9), and it can also reveal fat within a lesion (diagnostic of hamartoma) (Fig. 7.10). There has been some enthusiasm for CT assessment of nodule enhancement, with lung cancers enhancing more than benign nodules. Early CT follow-up of a lesion (sometimes in just a few weeks) has also been applied to this issue.

Most of these approaches (apart from comparison with old films) have been superseded by positron emission tomography (PET). PET is the imaging equivalent of comparison with old films, in that it allows assessment of the activity of a lesion, not just its morphology (Fig. 7.11). We still generally attempt thin-section CT in the assessment of a nodule, but if there is any remaining doubt, PET is generally the next step. We use it increasingly frequently in the assessment of lung nodules, with three caveats:

1. A lesion must be 7 mm or greater in size for accurate PET assessment.

2. Bronchoalveolar carcinoma may be PET negative.

3. PET has false positives (inflammatory lesions, a particular problem in some parts of the country with abundant fungi such as histoplasmosis or coccidioidomycosis) and false negatives (well-differentiated carcinomas, particularly adenocarcinoma).

Assessment of a lesion’s activity (via PET or comparison with old films) is the crux of imaging a lung nodule or mass.

Figure 7.6 Hamartoma with popcorn calcification (arrows).

Figure 7.7 Calcified non–small cell lung cancer. A. Computed tomography through right lower lobe mass: irregular calcifications throughout (arrows)B. Computed tomography through subcarinal lymph node metastases: similar calcifications (arrow).

 

An important aspect of lung cancer diagnosis is a consideration of the typical CXR appearances of different cell types. The radiographic presentations are emphasized, along with a discussion of the demographics and other features of the various cell types. This is an approach whose merits have been championed by Dr. Michael McCarthy.

Figure 7.8 Pulmonary arteriovenous malformation. A. Posteroanterior chest x-ray: feeding artery and draining vein (arrows) resemble “rabbit ears.” B. Digital subtraction angiography: vascular nature of lesion (L) confirmed.

Figure 7.9 Thin-section computed tomography confirmation of nodule calcification. A. Routine computed tomography viewed at lung windows: 1 cm middle lobe nodule (arrow)B. Soft tissue window photography of A: no calcification visible. C. Scan 1 mm thick: nodule is a calcified granuloma (arrow).

Figure 7.10 Hamartoma. Thin-section computed tomography demonstrates fat within the lesion (marked by cursor).

Figure 7.11 Adenocarcinoma of lung. A. Posteroanterior chest x-ray: poorly visible left lung nodule (arrow)B. Projection and (C) axial positron emission tomography images: easily visible focus of uptake (arrows). (Courtesy of Dr. Chuong Bui, Ann Arbor, MI.)

Solitary Pulmonary Nodule

Solitary pulmonary nodule (SPN) refers to a single nodular lesion in the lung, but the literature is inconsistent with regard to the upper size limit that is included. Most authors use 4 cm as a cutoff, above which the abnormality is considered a mass. Lung cancers and granulomas account for at least 80% of SPNs in most series. In Siegelman et al.’s classic article (17) on CT of the SPN, the literature review indicated that 54% of SPNs were granulomas and 28% were bronchogenic carcinomas or other primary malignancies. Combining two large recent series, 49% of 955 SPNs were malignant. In six of nine series from the early 1960s, more than 40% of SPNs were malignant.

In lung cancer, the model for this radiographic presentation is adenocarcinoma; other cell types that may manifest this pattern are squamous cell carcinoma and bronchoalveolar carcinoma. Adenocarcinoma is now the most common cell type of lung cancer, accounting for 30% to 35% of such cancers. It is associated with cigarette smoking but less strongly than squamous cell and small cell carcinoma. It is the typical cell type when cancer develops at the site of a previous scar (“scar carcinoma”) and may also occur in the setting of pulmonary fibrosis.

Most malignant SPNs are adenocarcinoma, and more than half of adenocarcinomas present as SPNs. Adenocarcinoma has an upper lobe predilection, occurring there in almost 70% of cases (Fig. 7.12). Early lymphogenous and hematogenous spread is typical of adenocarcinoma, although not invariably seen (Fig. 7.13), but cavitation is uncommon.

Most malignant solitary pulmonary nodules are adenocarcinoma, and adenocarcinoma usually presents as a solitary pulmonary nodule.

Lung cancer is generally morphologically distinct from pulmonary metastatic disease because the latter usually manifests as multiple nodules. In the setting of a previous extrapulmonary primary neoplasm, the relative likelihood that a new SPN is a solitary metastasis or a new lung cancer depends on the previous primary (Box 7.1). In a CXR-based series from the 1970s (18), the odds sometimes favored a new lung primary. This was true of head and neck carcinoma (15.8:1), bladder carcinoma (8.3:1), and cervical carcinoma (6:1). In fact, with some primaries all malignant SPNs were lung cancers (prostate, 26 patients; stomach, 7 patients; esophagus, 4 patients; pancreas, 3 patients). With other primaries a solitary metastasis was more likely. This applied to soft tissue sarcoma (17.5:1), osteosarcoma (6.7:1), melanoma (4.1:1), and testicular carcinoma (2:1). With many common primaries the odds were far from definitive but favored lung cancer slightly, such as with breast carcinoma (1.7:1), colon carcinoma (1.4:1), renal cell carcinoma (1.2:1), and endometrial carcinoma (1.1:1). A more recent study addressed this issue in patients with SPNs demonstrated at CT (19). In this series breast carcinoma moved more definitively into the lung cancer camp, but the other observations were reconfirmed.

Box 7.1: Solitary Pulmonary Nodule With Previous Primary Neoplasm

Probably lung cancer: head and neck, bladder, cervix, breast, prostate, stomach

Probably solitary metastasis: soft tissue sarcoma, osteosarcoma, melanoma, testicular carcinoma

Equivocal (lung cancer slightly favored): colon carcinoma, renal cell carcinoma, endometrial carcinoma

Figure 7.12 Adenocarcinoma as right upper lobe single pulmonary nodule (arrow).

Figure 7.13 Right upper lobe adenocarcinoma. Mass (M) is 10.2 cm in size, but clinically and pathologically there was no evidence of spread (T2N0M0). In contrast, the 1.5-cm nodule in Fig. 7.12 presented with a brain metastasis (T1N0M1).

Large Central Mass

The models for this appearance are squamous cell carcinoma and small cell carcinoma, but large cell carcinoma and adenocarcinoma sometimes manifest this way. Squamous cell carcinoma, formerly the most common cell type of lung cancer, still accounts for 30% of cases. It is the cell type most likely to produce a parathormone-like hormone. Squamous cell carcinoma typically arises endobronchially. It is known for relentless local growth and is relatively locally invasive. Hematogenous dissemination tends to occur late in the course of disease.

Squamous cell carcinoma often arises endobronchially and is known for relentless local growth.

Radiographically, squamous cell carcinoma most often presents with postobstructive findings of atelectasis or pneumonia (Fig. 7.14). Exophytic growth with or without (or else +/-) ipsilateral hilar lymph node metastases can result in the large central mass that we are discussing here, which is the second most common pattern of presentation (Fig. 7.15). Squamous cell carcinoma has significant heterogeneity of its radiographic appearance, with more than 25% presenting as a SPN. In fact, cavitation occurs in up to 20%, and squamous is by far the most common cell type in the presence of a cavitary lesion (Fig. 7.16). An important simulator of lower lobe cavitary neoplasm is illustrated in Fig. 7.17.

Figure 7.14 Endobronchial squamous cell carcinoma (arrow) presenting with collapse of the left upper lobe (C).

Figure 7.15 Squamous cell carcinoma as large central mass (M) on (A) posteroanterior chest x-ray and (B) computed tomography.

Small cell carcinoma accounts for 20% to 25% of lung cancers. It is the cell type most likely to be associated with paraneoplastic syndromes. This includes hormonal syndromes in 14% of small cell patients, especially syndrome of inappropriate antidiuretic hormone (Fig. 7.18), Cushing syndrome, and other syndromes of less certain origin like Eaton-Lambert syndrome, a sort of reverse myasthenia gravis (at least at electromyography).

The large central mass of small cell carcinoma is often bigger, more multifocal, and more mediastinal than the large central mass of squamous cell carcinoma (which tends to be centered in a hilum). Although 15% of small cell carcinomas are thought to arise peripherally, even in those patients hilar and mediastinal lymph node metastases often grow much more quickly than the lung lesion (Fig. 7.19). Tumor necrosis is common, but cavitation is rare. Because small cell carcinoma is often quite responsive to radiation and chemotherapy, the result can be disappearance of a mass in a relatively short period of time (Fig. 7.20).

Small cell carcinoma generally manifests predominantly in hilar and mediastinal lymph nodes.

Figure 7.16 Lymphoma with cavitary mass. A. Computed tomography of right lung base: cavitary right lower lobe nodule is squamous cell carcinoma (S). B. Abdominal computed tomography: mesenteric and left paraaortic lymphoma (L).

Figure 7.17 Apparent left basilar cavity. A. Posteroanterior chest x-ray: air–fluid level (arrows) in left basilar abnormality. Any “cavity” not clearly separable from the diaphragm should be considered a bowel loop until proven otherwise. B. Barium swallow: diaphragmatic hernia containing a portion of stomach.

Figure 7.18 Small cell carcinoma in patient with syndrome of inappropriate antidiuretic hormone. Multiple mediastinal lymph node masses (M) and left pleural effusion (E).

 

Large Peripheral Mass

The model for a large peripheral mass is large cell carcinoma. It is sometimes a presentation of squamous cell carcinoma and adenocarcinoma. Large cell carcinoma accounts for 10% to 15% of lung cancers. This rapidly growing neoplasm tends to early lymphogenous and hematogenous spread, with resultant poor 5-year survival rates. It is the most common cause of a malignant peripheral mass larger than 6 cm in size.

Figure 7.19 Small cell carcinoma with rapid growth of lymph node metastases. A. Computed tomography 1-13: lung nodule (N) is small cell carcinoma. B. Computed tomography 1-13: no abnormal thoracic lymph nodes. C. Computed tomography 3-26: marked interval enlargement of right hilar, paratracheal, and subcarinal lymph nodes (N).

Figure 7.20 Small cell carcinoma with rapid response. A. Posteroanterior chest x-ray 12-22: central left lung mass (M) with left upper lobe collapse. B. Computed tomography confirms small cell carcinoma involving left hilar and subcarinal lymph nodes (N). C. Posteroanterior chest x-ray 1-16: after radiation and chemotherapy, 25-day follow-up chest x-ray is normal.

Slightly more than half of large cell carcinomas appear as a peripheral mass (Fig. 7.21). Most of the remainder are large central masses. As with small cell carcinoma, necrosis is common, but cavitation is rare.

Figure 7.21 Large cell carcinoma as large peripheral mass (M). A. Posteroanterior and (B) lateral chest x-ray.

Figure 7.22 Multiple bronchoalveolar carcinomas? A. Posteroanterior chest x-ray 1987: right lower lobe mass (A). B. Computed tomography 1987: mass contains air bronchograms or cavitation (arrows)C. Computed tomography 1989: two left lower lobe nodules(arrows)D. Posteroanterior chest x-ray and (E) computed tomography 1992: chronic right lower lung airspace disease (A). These are all manifestations of bronchoalveolar carcinoma in the same patient, a common pitfall that sometimes causes radiologists to overestimate the frequency of disease “in their own experience.”

 

Peripheral Infiltrate

The model for this mode of presentation is bronchoalveolar carcinoma. Adenocarcinoma may instead manifest this way, which is not surprising given that bronchoalveolar carcinoma is a subtype of adenocarcinoma (but with distinctive pathologic and radiographic findings). Bronchoalveolar carcinoma is responsible for 2% to 5% of lung cancers, although recent articles suggest that it is increasing in incidence. My own experience at Multidisciplinary Thoracic Oncology Conference emphatically corroborates the trend of rising incidence (Fig. 7.22). Bronchoalveolar carcinoma arises from bronchiolar epithelium and type 2 alveolar cells. This cell type has no relationship to cigarette smoking, but there is a relationship to pulmonary fibrosis in general and scleroderma lung in particular.

Bronchoalveolar carcinoma accounts for 2% to 5% of lung cancers and appears to be increasing in incidence.

Bronchoalveolar carcinoma has a variable growth rate, but it is sometimes quite indolent. SPN is the most common presentation of bronchoalveolar carcinoma, and disease has been documented to progress from SPN to focal or diffuse alveolar disease. Peripheral infiltrate is the second most common manifestation of bronchoalveolar carcinoma. Air bronchograms are typically a prominent finding, as opposed to postobstructive alveolar disease distal to a central obstructing lesion. When infiltrate is present the patient may demonstrate bronchorrhea, a symptom suggestive of this diagnosis. Indolent growth results in a relatively good prognosis when SPNs are bronchoalveolar carcinoma; once disease spreads in the lungs (a typical pattern of dissemination), the prognosis is grim.

Multiple Pulmonary Nodules

This pattern, more typical of metastatic disease from an extrathoracic primary, is also seen with bronchoalveolar carcinoma. Less frequently, adenocarcinoma may present in this fashion. Multiple nodules are the presenting radiographic appearance in up to 10% of patients with bronchoalveolar carcinoma. This pattern was initially thought to reflect multifocal origin of disease, but it is now believed to be secondary to aerogenous and/or hematogenous spread from one focus (Fig. 7.23). Disease is occasionally cavitary. Although it can be difficult to distinguish between prominent air bronchograms and cavitation in some patients (Fig. 7.22B), in others there is no such difficulty (Fig. 7.24). Bronchoalveolar carcinoma is the second most likely cell type to explain a cavitary mass (after squamous cell carcinoma) (Box 7.2).

Figure 7.23 Bronchoalveolar carcinoma as airspace disease (A) and multiple nodules, some cavitary (arrow).

Figure 7.24 Bronchoalveolar carcinoma as large cavitary mass (M).

Staging

Staging differs significantly between small cell carcinoma and non–small cell lung cancer. Small cell carcinoma is generally considered inoperable, because more than 70% have metastasized at the time of diagnosis. It is staged as limited or extensive, depending on whether disease is confined to a single radiation port (limited) or not (extensive). In some patients with rather widespread disease confined to one radiation port, the resultant morbidity from the amount of lung that would have to be radiated leads to treatment of the patient as if disease had been extensive. The differentiation of limited versus extensive disease is mirrored in a difference in therapy (which is after all the intent of a staging scheme); patients with limited disease receive radiation and chemotherapy, whereas patients with extensive disease receive only chemotherapy. Patients with limited disease have a higher rate of disease remission and a higher cure rate, but overall this is still a terrible disease to have.

Box 7.2: Summary: Morphology of Lung Cancer

·      Solitary pulmonary nodule

o   Model: adenocarcinoma

o   Others: squamous, bronchoalveolar

·      Large central mass

o   Model: squamous, small cell

o   Others: large cell, adenocarcinoma

·      Large peripheral mass

o   Model: large cell

o   Others: squamous, adenocarcinoma

·      Peripheral infiltrate

o   Model: bronchoalveolar

o   Others: adenocarcinoma

·      Multiple pulmonary nodules

o   Model: bronchoalveolar

o   Others: adenocarcinoma

·      Cavity

o   Model: squamous

o   Others: bronchoalveolar

·      Postobstructive volume loss

o   Model: squamous

o   Others: small cell

Patients with limited small cell lung cancer receive radiation and chemotherapy, whereas those with extensive disease receive only chemotherapy.

In non–small cell lung cancer, the primary goal of staging is to determine resectability. Although advances in radiation and chemotherapy have resulted in significant improvements in response to therapy and even sometimes cure, surgical resection remains the best chance for cure. The staging scheme that is most widely used is the TNM system of the American Joint Committee on Cancer, revised in 1997 (20). This scheme is detailed in Table 7.1. In staging, the break between resectable and unresectable disease generally occurs between stages IIIA and IIIB. Thus, it is critical to detail the extent of mediastinal spread (differentiating ipsilateral mediastinal disease, stage IIIA, from contralateral mediastinal spread, stage IIIB) and to exclude more distant metastases (stage IV).

CXR evaluation is of limited utility in staging lung cancer. The problem is very low sensitivity. CXR evaluation is probably most helpful in the setting of thoracic skeletal metastases; CXR is sometimes better at demonstrating such lesions than CT. Mediastinal lymph node enlargement and contralateral lung nodules or hilar lymph nodes may also be suspected from the CXR, but CT evaluation will virtually always be far better.

The perceived value of CT staging has gone up and down over the past 20 years—not figuratively, but literally. In the 1970s CT was considered a poor staging tool, an apt reflection of the quality of scanners then available, the limited options for vascular enhancement, variable scanning techniques, and the more rudimentary knowledge of thoracic lymph node anatomy of that era. In the 1980s a number of studies (21,22) with better CT equipment, bolus administration of intravenous contrast, standardized contiguous scanning, and improved appreciation of nodal anatomy demonstrated that CT staging of mediastinal lymph nodes was highly sensitive (in the 90% range) but not specific (in the 65% range). Interestingly, CT at this time was not being uniformly applied to lung cancer patients for the purposes of staging. By the 1990s, several large studies (23,24) indicated that CT staging was not actually sensitive or specific (in the 50% range for both). Surprisingly, with CT’s reputation in shambles, virtually every patient diagnosed with lung cancer now undergoes CT staging.

Table 7.1: American Joint Committee Staging Scheme

Primary tumor (T)

Tx

Primary tumor cannot be assessed or tumor proven by presence of malignant cells in the sputum or bronchial washings but not visualized by bronchoscopy or CT.

T0

No evidence of primary tumor.

Tis

Carcinoma in situ.

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 bronchusa (i.e., not in main bronchus).

T2

Tumor with any of the following features of size or extent: a) More than 3 cm in greatest dimension. b) Involves main bronchus, 2 cm or more distal to the carina. c) Invades the visceral pleura. d) Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

T3

Tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumor), diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung.

T4

Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; separate tumor nodule(s) in the same lobe; or tumor with a malignant pleural effusion.b

Regional lymph nodes (N)

NX

Regional lymph nodes cannot be assessed.

N0

No regional lymph node metastases.

N1

Metastases to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes involved by direct extension of the primary tumor.

N2

Metastases to ipsilateral mediastinal and/or subcarinal lymph node(s).

N3

Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph nodes.

Metastases (M)

MX

Distant metastases cannot be assessed.

M0

No distant metastases.

M1

Distant metastases present (includes synchronous separate nodule(s) in a different lobe).

Stage grouping

Occult

TX

N0

M0

Stage 0

Tis

N0

M0

Stage IA

T1

N0

M0

Stage IB

T2

N0

M0

Stage IIA

T1

N1

M0

Stage IIB

T2

N1

M0

T3

N0

M0

Stage IIIA

T3

N1

M0

T1

N2

M0

T2

N2

M0

T3

N2

M0

Stage IIIB

Any T

N3

M0

T4

Any N

M0

Stage V

Any T

Any N

M1

aThe uncommon superficial 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 T1.
bMost pleural effusions associated with lung cancer are due to tumor. However, there are a few patients in whom multiple cytopathologic examinations of pleural fluid are negative for tumor. In these cases, fluid is nonbloody and is not an exudate. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be staged T1, T2, or T3.
CT, computed tomography.
From Mountain CF. Revision in the international staging system for staging lung cancer. Chest 1997;111:1710–1717, with permission.

The fact is that CT remains the workhorse of lung cancer staging. Although it is not clear why CT sensitivity and specificity are no better than flipping a coin, most decisions regarding surgery, radiation, and chemotherapy are based on CT data. It may be that CT misses (such as metastases to normal-size lymph nodes) (25) would not change the therapeutic approach, even if they were appreciated beforehand. CT has the important advantage of evaluating numerous potential sites of metastatic disease throughout the lower neck, chest, and upper abdomen, and a few words about some of them follows:

·      Thoracic lymph nodes: 1 cm in short axis should be used as the threshold.

·      Lungs: CT is very sensitive for detecting small nodules but is not at all specific.

·      Adrenals: Many detected nodules are non-hyperfunctioning adenomas; dedicated adrenal CT can be helpful for distinguishing benign from malignant (26,27).

·      Liver: CT again is sensitive and somewhat able to characterize lesions (such as cysts and hemangiomas); small lesions may still be problematic, and hepatic magnetic resonance imaging can be helpful as a problem-solving tool.

·      Bones: CT is generally not very good at detecting or characterizing skeletal lesions, although careful attention to the bones sometimes yields critical information. Radionuclide bone scan is far preferable.

When CT detects a single questionable finding of potential importance for subsequent therapy, a variety of imaging tools may be called upon for more definitive diagnosis, as noted above (e.g., adrenal CT, hepatic magnetic resonance imaging, radionuclide bone scan). However, more and more the next step turns out to be PET (28). This is particularly helpful in a patient with several questionable findings or for further characterization of borderline or mildly enlarged thoracic lymph nodes. Currently, it seems that almost one-fourth of our lung cancer patients have PET as part of the staging process. However, a patient with no evidence of distant spread at CT will generally go directly to surgery without PET. The need for other imaging tests (such as head CT or magnetic resonance imaging) will depend on the cell type and the presence or absence of symptoms.

CT is the workhorse for lung cancer staging, but more and more patients are also undergoing PET.

The best measure of the final product of staging is probably the satisfaction of the thoracic surgeon. Surgeons in general do not like to operate on patients only to discover that the extent of disease is far greater than previously appreciated, necessitating surgical closure without cancer resection (apparently, only attorneys truly appreciate “open and shut cases”). Surgeons in general are not shy about expressing their opinions, and we have seldom encountered surgeons who were in particular shy about telling us when our radiographic interpretations were problematic. It probably bespeaks their satisfaction with the current imaging approach to diagnosis and staging of lung cancer that our surgeons have not complained of an increasing number of so-called staging thoracotomies.

With the current approach some limitations should be acknowledged. We are generally poor at detecting local extension of disease, such as chest wall or mediastinal invasion. Chest wall invasion generally does not change resectability, although it changes the extent of the surgical procedure. It is therefore probably best to suggest the possibility of pleural or chest wall involvement whenever there is extensive contact between tumor and pleura, localized pleural thickening, or gross abnormality of adjacent chest wall structures. As for mediastinal involvement, some patients with minimal contact between tumor and mediastinum cannot be resected (Fig. 7.25); in others, tumor that appears to invade mediastinum at imaging is easily peeled off the mediastinal pleura at surgery (Fig. 7.26). Not all examples of mediastinal invasion are so equivocal (Fig. 7.27). CT after introduction of pleural air (artificial pneumothorax) has been suggested to solve this vexing problem. However, pleural adhesions can simulate mediastinal invasion by neoplasm. Because surgical resection provides the best hope for cure of disease, it is probably best to give the patient the benefit of the doubt whenever uncertainty remains.

Figure 7.25 Unresectable lung cancer because of mediastinal invasion. Despite an apparent fat plane (arrows), mass (M) could not be separated from mediastinum.

Figure 7.26 Resectable lung cancer. Despite apparent mediastinal involvement, mass (M) readily peeled away from mediastinum at surgery.

Figure 7.27 Gross mediastinal invasion, with involvement of superior vena cava (arrows).

References

1. Boucot KR, Cooper DA, Weiss W, et al. Cigarettes, cough and cancer of the lung. JAMA 1966;196:985–990.

2. Janerich DT, Thompson WD, Varela LR, et al. Lung cancer and exposure to tobacco smoke in the household. N Engl J Med1990;323:632–636.

3. Finkelstein MM. Mortality among employees of an Ontario asbestos cement factory. Am Rev Respir Dis 1984;129:754–761.

4. Bejui-Thivolet F, Liagre N, Chignol MC, et al. Detection of human papilloma virus DNA in squamous bronchial metaplasia and squamous cell carcinoma of the lung by in situ hybridization using biotinylated probes in paraffin-embedded specimens. Hum Pathol 1990;21:111–116.

5. Butler AE, Colby TV, Weiss L, et al. Lymphoepithelioma-like carcinoma of the lung. Am J Surg Pathol 1989;13:632–639.

6. Roumm AD, Medsger TA Jr. Cancer and systemic sclerosis: an epidemiologic study. Arthritis Rheum 1985;28:1336–1340.

7. Neuberger JS. Residential radon exposure and lung cancer: an overview of published series. Cancer Detect Prev 1991;15:435–443.

8. Muhm JR, Miller WE, Fontana RS, et al. Lung cancer detected during a screening program using four-month chest radiographs.Radiology 1983;148:609–615.

9. Hendrix RW. In defense of a missed lesion. Radiology 1995;195:578–579.

10. Frost JK, Ball WC, Levin ML, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins Study. Am Rev Respir Dis 1984;130:549–554.

11. Flehinger BJ, Melamed MR, Zama MB, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Memorial Sloan-Kettering study. Am Rev Respir Dis 1984;130:555–560.

12. Fontana RS, Sanderson DR, Taylor WF, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic study. Am Rev Respir Dis 1984;130:561–565.

13. Kubik A, Polak J. Lung cancer detection: results of a randomized prospective study in Czechoslovakia. Cancer 1986;57:2427–2437.

14. Patz EF Jr, Black WC, Goodman PC. CT screening for lung cancer: not ready for routine practice. Radiology 2001;221:587–591.

15. Miettinen OS, Henschke CI. CT screening for lung cancer: coping with nihilistic recommendations. Radiology 2001;221:592–596.

16. Reich J. Hazards of lung cancer screening. Chest 2001;119:659–660.

17. Siegelman SS, Zerhouni EA, Leo FP, et al. CT of the solitary pulmonary nodule. AJR Am J Roentgenol 1980;135:1–13.

18. Cahan WG, Shah HP, Castro EB. Benign solitary lung lesions in patients with cancer. Ann Surg 1978;187:241–244.

19. Quint LE, Park CH, Iannettoni MD. Solitary pulmonary nodules in patients with extrapulmonary neoplasms. Radiology 2000;217:257–261.

20. Mountain CF. Revision in the international staging system for staging lung cancer. Chest 1997;111:1710–1717.

21. Glazer GM, Orringer MB, Gross BH, et al. The mediastinum in non-small cell lung cancer: CT-surgical correlation. AJR Am J Roentgenol 1984;142:1101–1105.

22. Lewis JW Jr, Pearlberg JL, Beute GH, et al. Can computed tomography of the chest stage lung cancer? Yes and no. Ann Thorac Surg1990;49:591–596.

23. Webb WR, Gatsonis C, Zerhouni EA, et al. CT and MR imaging in staging non-small cell carcinoma: report of the Radiologic Diagnostic Oncology group. Radiology 1991;178:705–713.

24. McLoud TC, Bourgouin PM, Greenberg RW, et al. Bronchogenic carcinoma: analysis of staging in the mediastinum with CT by correlative lymph node mapping and sampling. Radiology 1992;182:319–323.

25. Gross BH, Glazer GM, Orringer MB, et al. Bronchogenic carcinoma metastatic to normal-sized lymph nodes: frequency and significance. Radiology 1988;166:71–74.

26. Korobkin M, Brodeur FJ, Yutzy GY, et al. Differentiation of adrenal adenomas from nonadenomas using CT attenuation values. AJR Am J Roentgenol 1996;166:531–536.

27. Korobkin M, Brodeur FJ, Francis IR, et al. Delayed enhanced CT for differentiation of benign from malignant adrenal masses.Radiology 1996;200:737–742.

28. Pieterman RM, van Putten JWG, Meuzelaar JJ, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 2000;343:254–261.