14 Staging of Lung Cancer with MDCT P. M. Boiselle

Staging of Lung Cancer with MDCT 205

CONTENTS

14.1 Introduction 205 14.2 T-Status 205

14.2.1 T-1 and T-2 Lesions 205 14.2.2 T-3 and T-4 Lesions 208 14.3 N-Status 210

14.3.1 N-2 and N-3 210 14.3.2 N-1 212 14.4 M-Status 212 14.5 Summary 213

References 213

14.1 Introduction

Lung cancer is the leading cause of cancer mortality in the United States, with deaths from this disease sur- passing the combined total of deaths from can cers of the breast, colon, and prostate combined (Green lee et al. 2000). Accurate staging of non small cell lung cancer (NSCLC) is of critical im por tance in order to determine which patients are most likely to benefi t from surgical resection, the only true hope for a cure from this disease (Jett et al. 1997). The International System for Staging Lung Cancer, in clud ing the TNM subsets and stage groupings (Ta bles 14.1 and 14.2), provides important information for estimating prog- nosis and planning appropriate therapy (Mountain 1997). For example, patients with Stage IA disease have a relatively high cure rate fol low ing surgical resection, whereas patients cat e go rized as having disease consis- tent with stages IIIB or IV have a much poorer progno- sis and are unlikely to benefi t from surgical resection.

The staging sys tem also provides helpful information for entering pa tients into appropriate clinical trials,

14 Staging of Lung Cancer with MDCT

P. M. Boiselle

P. M. Boiselle , MD

Director of Thoracic Imaging, Beth Israel Deaconess Medi- cal Center, Assistant Professor of Radiology, Harvard Medi- cal School, Department of Radiology, 330 Brookline Avenue, Bos ton, MA 02215, USA

comparing dif fer ent treatment regimens, and evalu- ating new prog nos tic factors (Mountain 2002).

Despite its recognized limitations, CT is con- sid ered the imaging study of choice for the initial stag ing evaluation of patients with NSCLC (McLoud 2002). The recent advent of MDCT affords sig nifi cant advantages over single-detector helical CT scan ners, including faster scanning, improved res o lu tion, better vascular enhancement and higher qual i ty mul- tiplanar reformation and 3-D re con struc tion images (Choi and Boiselle 2002). These ad van tag es have the potential to enhance the ability to accurately stage lung neoplasms. This chapter re views the potential contributions and relative lim i ta tions of MDCT with regard to assessing the T (pri ma ry tumor), N (nodal) and M (distant metastases) components of the Inter- national System for Staging Lung Cancer.

14.2 T-Status

14.2.1 T-1 and T-2 Lesions

MDCT scanners have the potential to enhance the detection of small lung cancers by allowing for the use of narrower collimation than is routinely em ployed with single detector CT scanners. For ex am ple, it has been shown that thin-collimation images are more sensitive than thick-collimation images for detecting small, subcentimeter lung nodules (Nishi et al. 2000).

Thin-collimation images also provide more ac cu rate

characterization of nodules than thick-col li ma tion

images, especially with regard to the iden ti fi ca tion of

calcifi cation within nodules and the as sess ment of

nodule margins. These are important factors for deter-

mining the likelihood that a nodule is either benign or

malignant (McLoud 2002). A unique feature of MDCT

is the ability to ret ro spec tive ly create images with a

collimation that is nar row er than the value that was

prospectively em ployed (Choi and Boiselle 2002). In

ipsilateral primary-tumor lobe of the lung Regional lymph nodes (N)

NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis

N1 Metastasis to ipsilateral peribronchial and or ip si lat er al hilar lymph nodes, and intrapulmonary nodes in volved by direct extension of the primary tumor

N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)

N3 Metastasis to contralateral mediastinal, con tralat er al hilar, ipsilateral or contralateral scalene, or su pr a clav ic u lar lymph node(s)

Distant metastasis (M)

MX Presence of distant metastasis cannot be assessed M0 No distant metastasis

M1 Distant metastasis present

* The uncommon superfi cial tumor of any size with its in va sive component limited to the bronchial wall, which may ex tend proximal to the main bronchus, is also classifi ed T1

†

Most pleural effusions associated with lung cancer are due to tumor. However, there are a few patients in whom multiple cytopathologic examinations of pleural fl uid show no tumor. In these cases, the fl uid in 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 ex- cluded as a staging element and the patient’s disease should be staged T1, T2, or T3. Pericardial effusion is clas si fi ed according to the same rules.

‡

Separate metastatic tumor nodule(s) in the ipsilateral nonprimary-primary lobe(s) of the lung also are classifi ed M1 (From Mountain 1997)

Table 14.2. Stage Grouping – TNM Subjects*

Stage TNM Subject c. Carcinoma in situ IA T1NOM0 IB T2NOM0 IIA T1N1M0 IIB T2N1M0 T3N0M0 IIIA T3N1M0 T1N2M0 T2N2M0 T3N2M0 IIIB T4N0M0 T4N1M0 T4N2M0 T1N3M0 T2N3M0 T3N3M0 T4N3M0 IV Any T Any N M1

* Staging is not relevant for occult carcinoma, designed TXN0M0

order to op ti mal ly characterize a detected nodule, it is im por tant to retrospectively obtain images through the nodule with the narrowest collimation possible (0.5 mm to 1.25 mm, depending upon the CT man u fac tur er).

The ability to obtain high quality multiplanar and

3-D reconstruction images from routine MDCT stud-

ies has the potential to further improve nodule detec-

tion and characterization. For example, it has been

demonstrated that multiplanar coronal and sag it tal

reformatted images increase the rate of lung nodule

detection compared to axial images (Fig. 14.1) (Eibel

et al. 2000). Moreover, multiplanar reformatted images

can also be used to improve ac cu rate localization

of nodules. For example, mul ti pla nar reformatted

images can be used to aid pre op er a tive localization

of small nodules prior to video-assisted thoraco-

scopic surgery and to en hance accurate staging of

primary tumors with re spect to fi ssural involvement

(Fig. 14.2). In order to optimize the quality of multi-

Staging of Lung Cancer with MDCT 207

Fig. 14.1. Value of 2-D multiplanar reconstruction images in lung nodule detection. a. Coronal reconstruction maximal intensity projection image shows two small lung nodules in left lower lobe (arrows). b. Axial image from original CT dataset shows the larger of the two left lower lobe lung nod ules located centrally (curved open arrow). This nodule was initially overlooked on the axial image but was readily de tect ed on the reformation images. Centrally located nodules are more easily detected on multiplanar reformation images than on axial images (Reprinted with permission from Choi and Boiselle 2002)

a

b

Fig. 14.2. Improved assessment of relationship of neoplasm to fi ssure with multiplanar reformation image. a. Frontal chest radiograph shows a nodule in right upper lobe (arrow). b. Axial CT image confi rms the lung nodule and shows spic u lat ed mar- gins, consistent with neoplasm. Relationship to fi s sure is not well demonstrated. c. Sagittal reformation max i mal intensity projection image demonstrates extension of the nodule across the major fi ssure into the adjacent superior segment of the right lower lobe. Also note fi ssural thickening (arrow) a

c

b

surgical planning because such lesions require en bloc resection of the lung neoplasm and adjacent chest wall (McLoud 2002).

CT has a limited ability to detect chest wall in va sion:

The only reliable indicators of chest wall in va sion on CT are the identifi cation of rib destruction and the extension of a mass beyond the ribs into the adjacent chest wall (Quint et al. 1995). It is im por tant to be aware that the identifi cation of pleural thick en ing adjacent to a mass is not necessarily rep re sen ta tive of invasion of the parietal pleura by tu mor, be cause a similar appearance may be produced by local fi brous adhesions (McLoud 2002).

Due to its ability to routinely provide thin col li - ma tion axial images and high quality multiplanar reformation images, it is likely that MDCT will lead to an improved accuracy for detecting chest wall

study of choice for assessing for in volve ment of these structures, particularly with re gard to spinal and brachial plexus involvement (McLoud 2002). How- ever, for patients with con train di ca tions to MR imag- ing (such as the presence of a pacemaker), the high quality of coronal and sag it tal reformatted images provided by MDCT (Fig. 14.4) provide a reasonable imaging alternative. Future stud ies are necessary to compare the ac cu ra cy of multiplanar reformation CT images with direct mul ti pla nar MR images in the staging evaluation of these lesions.

As defi ned in Table 14.1, a T-4 lesion is defi ned by invasion of “vital” structures, such as the me di asti num, heart, great vessels, trachea, carina, esophagus, or ver- tebral body. T-4 lesions are generally con sid ered unre- sectable, although exceptions are made for certain cases at some highly specialized centers. Al though direct

Fig. 14.3. Chest wall invasion from peripheral lung cancer on CT and MR imaging. a. Sagittal multiplanar reformation CT image demonstrates peripheral mass in right upper lobe, with extension into chest wall (arrow) between upper pos te ri or ribs. Chest wall invasion was not well demonstrated on the original axial images. b. Sagittal T-1 weighted MR image of same patient. The higher con- trast resolution of MR results in slightly better demonstration of the tumor infi ltrating the fat between the posterior ribs (arrow)

a b

Staging of Lung Cancer with MDCT 209

Fig. 14.4. Apical lung tumor. Coronal (a) and sagittal (b) multiplanar reformation CT images demonstrate a right api cal lung mass. The reformation images showed the extent of tumor to greater detail than axial images (not shown). Al though MR is the study of choice for superior sulcus tumors, MDCT with multiplanar reformation images is a reasonable alternative for patients with contraindications to MR

a b

Fig. 14.5. Advanced-stage, inoperable non-small cell lung can cer. Contrast-enhanced axial CT image of patient with ex ten sive non-small cell lung cancer demonstrates extensive me di as ti nal involvement, including invasion of the airway at level of carina. Note extension of neoplasm into proximal mainstem bronchi (arrows). Also note centrally obstructing tumor, with associated left upper lobe collapse

invasion of vital structures is some times clearly delin- eated with axial CT images (Fig. 14.5), it is not always possible to distinguish con ti gu i ty of tumor with the mediastinum from ac tu al invasion of vital mediastinal structures (McLoud 2002). Several technical factors can en hance the assessment for invasion of vital struc- tures using MDCT, including the use of intravenous con trast enhancement, selection of narrow collimation (less than or equal to 3 mm), and the creation of mul- ti pla nar reformation and 3-D reconstruction images (Figs. 14.6–14.8). Despite the important tech no log i cal advances afforded by MDCT, however, some cases will still remain indeterminate by CT imaging.

Approximately one decade ago, the Radiologic Di ag nos tic Oncology Group (RDOG) study pro- spec tive ly compared CT and MR imaging in the

pre op er a tive staging evaluation of patients with non

small cell lung cancer (Webb et al. 1991). This study

showed that MR was slightly more accurate than

CT for de ter min ing invasion of vital mediastinal

vas cu lar struc tures, although this difference was not

sta tis ti cal ly signifi cant. MR should be considered as

a sec ond-line, problem-solving tool for cases that

are in de ter mi nate for mediastinal invasion by CT,

es pe cial ly in patients who have a contraindication to

io di nat ed contrast agents. Indeed, it can be diffi cult

to assess for invasion of vascular structures on un en -

hanced CT studies. Considering the development of

signifi cant advances in both CT and MR in the past

decade, a new prospective trial is needed to assess

the relative merits and respective roles of these tech-

niques in the staging evaluation of NSCLC.

a poor prognosis (less than 10% 5-year survival rate) and is considered inoperable (Moun tain 1997).

14.3.1 N-2 and N-3

With regard to the assessment of mediastinal lymph nodes, CT relies upon anatomic features, most no ta bly lymph node size, in order to distin- guish between benign and malignant lymph nodes.

Although very early investigations with CT sug- gested sensitivities and specifi cities comparable to

Fig. 14.6. Improved assessment of central airway invasion with 3-D reconstruction image. a. Axial, contrast-enhanced CT at level of aorticopulmonary window shows large nodal mass compressing the carina. Origin of right mainstem bron chus (arrow) is severely narrowed but is diffi cult to fully as sess because of its oblique orientation with respect to the axial plane. b. 3-D external volume rendering of airway re veals irregular deformity of distal trachea and carina, as well as severe narrowing of proximal right mainstem bronchus (arrow) with distal patency. Compared with axial images, the 3-D images provided a more accurate assessment of the over all extent of airway involvement (Reprinted with permission from Boiselle et al. 2002)

a b

Fig. 14.7. Invasion of superior cava. Coronal reformation im age shows central neoplasm (N) invading the superior vena cava, consistent with a T-4 lesion. Also note extensive neo plas tic involvement of the mediastinum, encasing the aorta and other vascular structures

14.3 N-Status

The nodal status (N) provides important in for ma tion

for determining prognosis and planning ap pro pri ate

therapy. For example, a patient with a T-1 or T-2 lesion

and no evidence of regional metastatic nodal disease

(N0) or distant metastases (M0) has a rel a tive ly favor-

able prognosis (approximately 65% 5-year survival)

following surgical resection (Moun tain 1997). On

the other hand, a patient with a T-1 or T-2 lesion

with metastatic disease to contralateral mediastinal

lymph nodes (N3) but no distant me tastas es (M0) has

Staging of Lung Cancer with MDCT 211

mediastinoscopy, subsequent, more thorough studies have shown that the accuracy of CT is signifi cantly lower (Boiselle 2002). For example, a study that employed extensive nodal sampling and correlative CT imaging of nodal stations showed a relatively low sensitivity (62%) and specifi city (64%) for predict- ing neoplastic in volve ment using 1 cm as the upper limits of normal size for short axis of lymph nodes (McLoud et al. 1992). These results emphasize the limitations of using nodal size to determine nodal status: Enlarged nodes may be hyperplastic rather than neoplastic, and small nodes may harbor foci of metastatic dis ease (Boiselle et al. 1998).

Because of the low specifi city of CT, enlarged nodes must be biopsied for staging purposes. It is important to be aware that benign nodes as large as 4 cm in diameter have been described in associa- tion with bronchogenic carcinoma (Jett et al. 1997).

False-positive nodes most often occur in the setting of postobstructive pneumonitis from a centrally ob struct ing neoplasm (Fig. 14.9).

Similar to CT, MR relies predominantly upon nod al size for predicting neoplastic involvement.

Thus, MR has similar limitations to CT in the as sess ment of mediastinal lymph nodes. Historically, the direct multiplanar imaging capability of MR has of fered a relative advantage over axial CT images in the assessment of certain nodal stations, such as the aor ti cop ul mo nary window and subcarinal nodal

sta tions (Boiselle et al. 1998). However, with the abil i ty of MDCT to routinely perform high-quality mul ti pla nar reformation images, this is no longer a sig nifi cant distinction. MR has also historically of fered a relative advantage over CT in the assess- ment of hilar nodes, particularly when intravenous con trast en hance ment is suboptimal or absent on CT (Boiselle et al. 1998). With the improved vascular en hance ment of hilar vessels afforded by MDCT,

Fig. 14.8. Invasion of left atrium. a. Axial CT image shows cen tral lung cancer resulting in obstruction of right upper lobe bron- chus (arrow). b. Coronal reformation image dem on strates invasion of superior aspect of left atrium (arrow) [Case courtesy of Dr. Kyung S. Lee, Samsung Medical Center, Seoul, Korea]

a b

Fig. 14.9. False-positive lymph node. Axial CT image shows a central neoplasm obstructing the right upper lobe bronchus, with associated post-obstructive atelectasis and pneu moni tis.

Enlarged precarinal lymph node (arrow) proved to be hyper-

plastic at biopsy, with no evidence of neoplasm

i nos co py and thus require another method of biopsy such as anterior or parasternal mediastinotomy (Fig. 14.10).

Second, CT can be used to guide nodal biopsies.

Although preliminary studies (Protopapas and West cott 1997; Zwischenberger et al. 2002) have shown promising results using CT-guided per cu - ta ne ous bi op sy for mediastinal nodal staging, this tech nique currently plays a limited role compared to other bi op sy procedures. In a recent study of 89 pa tients who underwent CT-guided biopsy of me di - as ti nal lymph nodes greater than 1.5 cm in diameter, a diagnosis was made in 78% of cases (Zwis chen - berg er et al. 2002). Although virtually all nodal sta- tions were ac ces si ble with this technique, these in ves - ti ga tors em pha size that aorticopulmonary nodes can be dif fi cult to access with this method. Based upon their fi nd ings, Zwischenberger et al. con clud ed that CT-guid ed biopsy should play a larger role in staging lung cancer.

CT can also be used to guide transbronchial bi op sy procedures, either indirectly with virtual

and FDG PET visually correlated with CT in the detection of N2 metastatic mediastinal lymph nodes in patients with NSCLC, the highest diag- nostic accuracy was observed when a combined CT-PET approach was employed (Vansteenkiste et al. 1997). Thus, CT and FDG PET should be considered as com ple men ta ry rather than com- petitive imaging techniques. Recently, integrated PET-CT has become available and has been shown to be more accurate than CT alone, PET alone, or conventional visual correlation of PET and CT (Lardinois 2003). At present, integrated PET-CT is the most accurate method of nodal staging for non-small lung cancer.

14.3.2 N-1

CT has also been shown to have a low sensitiv- ity and specifi city for assessing hilar lymph node me tastas es. The evaluation of hilar lymph nodes has become an important factor in the selection of patients with early lung cancer and poor pulmonary reserve for minimal resection procedures such as seg men t ec to my and wedge resection (Boiselle 2002). It has re cent ly been suggested that hilar nodal contour may be a more accurate predictor of meta- static in volve ment than nodal size (Shimoyama et al. 1997). In a study that assessed the ability of CT to detect hilar nodal metastases, Shimoyama et al.

(1997) classifi ed lymph nodes with straight or con- cave margins to the lung as benign and those with convex margins as malignant. Using this criterion, these investigators reported a relatively high sensi- tivity (87%) and spec i fi c i ty (88%) for detecting hilar nodal metastases. Future studies involving larger numbers of patients are necessary to confi rm these promising results.

Fig. 14.10. Coronal reformation image shows large nodal mass

(N) in the aorticopulmonary window. This nodal sta tion is not

accessible by cervical mediastinoscopy

Staging of Lung Cancer with MDCT 213

14.4 M-Status

Extrathoracic metastases are present in a signifi - cant proportion of patients with newly diagnosed NSCLC. In most cases, clinical symptoms or labora- tory data abnormalities will signal the presence of distant metastases and guide the imaging evaluation of af fect ed patients. In recent years, the occurrence of clinically “silent” brain metastases has received in creas ing attention, particularly among patients with adenocarcinoma. At present, the role of imag- ing in the evaluation of “silent” metastases remains some what controversial.

The discussion of extrathoracic metastases in this chapter will be limited to the adrenal gland, an im por tant site of metastatic disease that is generally in clud ed on all staging thoracic CT scans. Although the adrenal gland is a relatively common site of met a stat ic disease in NSCLC, it is important to be aware that the majority of adrenal lesions detected in pa tients with NSCLC represent benign adeno- mas (McLoud 2002). For staging purposes, it is critically important to distinguish adenomas from me tastas es.

A non-invasive diagnosis of adenoma is based pri ma ri ly upon the presence of large lipid-laden cells within most adenomas. On unenhanced CT scans, adenomas are characterized by a Hounsfi eld unit (HU) measurement of less than 10. This cri te ri on is associated with a sensitivity of 71% and a spec i fi c i ty of 98% (Mayo-Smith et al. 2001). The spec i fi c i ty approaches 100% when other features such as size (<4 cm), shape (round), and margins (smooth) are also considered (Mayo-Smith et al. 2001). An ad van tage of MDCT is the ability to retrospectively ob tain images with narrow collimation, which may aid the characterization of adrenal lesions with regard to accurately assessing density and margins.

Importantly, about 30% of adenomas will dem- on strate HU >10 on CT scans (Mayo-Smith et al.

2001). MR can be helpful for further assessment of such le sions. On MR imaging, the lipid content of adenomas can be demonstrated using chemical shift imaging, which is based upon the different res- o nance fre quen cy rates of protons in fat and water molecules (Mayo-Smith et al. 2001). Tissues that con tain both lip id and water will demonstrate signal loss (dark sig nal) on out-of-phase images compared to in-phase images. This technique is highly accurate for diagnosing adenomas, with reported sensitivities rang ing from 81% to 100% and specifi cities ranging from 94% to 100% (Mayo-Smith et al. 2001).

14.5 Summary

Despite its limitations, CT remains the initial im ag ing modality of choice for the staging assess- ment of patients with NSCLC. MR plays an impor- tant com ple men ta ry role in selected elements of staging, par tic u lar ly in the evaluation of superior sulcus lesions and in the assessment of chest wall or mediastinal invasion. It may also be helpful as a sec- ondary, prob lem-solving tool for assessment of the vascular in va sion and hilar structures for patients with con train di ca tions to iodinated intravenous contrast. Im por tant ly, both CT and MR are limited by their reliance upon anatomic parameters. Com- bined an a tom ic and physiologic imaging with CT and FDG-PET is currently the most accurate non-invasive method available for staging NSCLC.

Considering the development of signifi cant ad vanc es in both CT and MR in the past decade, as well as the advent of PET imaging, a prospective trial is needed to assess the relative merits and respective roles of these three techniques in the staging eval- u a tion of NSCLC.

Acknowledgements. I grate ful ly acknowledge the contribution of Fig. 14.8 from Dr. Kyung S. Lee, Sam- sung Medical Center, Seoul, Korea and the expert photography of Michael Larson, Beth Israel Deacon- ess Medical Center, Boston, MA.

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