Epidemiology
- Lung cancer is the leading cause of cancer-related deaths for both men and women.
- In 2004, an estimated 173,770 new cases of lung cancer and an estimated 160,440 deaths from lung cancer will occur in the United States.
- Most of those people will be from minority groups.
- Direct medical cost for treatment of lung cancer is approximately $5 billion annually.
- Smoking is responsible for 87 percent of lung cancer deaths. 1
Histologic Classification of Non-small Cell Lung Cancer
2
- Squamous cell (epidermoid) carcinoma
- Adenocarcinoma
- acinar
- papillary
- bronchoalveolar
- solid tumor with mucin
- Large cell carcinoma
- Adenosquamous carcinoma
- Undifferentiated carcinoma
The major distinction in terms of both staging and therapy is between
small cell lung cancer (SCLC) and
non-small cell lung cancer (NSCLC). Our discussion focuses mainly on the NSCLC types.
FDG Uptake in Lung Cancer
Lung cancer is very FDG-avid. This uptake becomes even more conspicuous as there is relatively low uptake in the surrounding aerated lung as opposed to other soft tissues. Non-aerated lung may have about three times the activity of aerated lung. As lung tissue is less "dense", an area of atelectasis would have relatively higher uptake per volume of tissue compared to surrounding normal lung. This would hold true for a lung nodule as well. Therefore nodules should not be compared to surrounding aerated lung, but rather to other solid soft tissue to assess for relatively increased uptake. Comparison typically can be made with mediastinal soft tissues or blood pool.
Possible false negatives on FDG-PET:
1. Histologic types of lung cancer with variable uptake:
- Pulmonary carcinoid
- Atypical carcinoid tumors are more likely to be FDG-avid than typical carcinoid tumors
- Bronchioloaveolar cell cancer
- Solid components of BAC on CT are more likely to be FDG-avid.
Should not be used to exclude these specific types
2. Necrosis
- An area of necrosis within a tumor will show little FDG activity
- Typically there is an FDG-avid rim however, which can be easily detected.
- Can help direct area of tumor to biopsy
- Directing a biopsy to the most FDG-avid portion of the lesion may improve the diagnostic yield and avoid a false positive biopsy result
3. Size
- Less than 8 mm
- 95% sensitivity > 8mm
- Limited resolution of PET scanner
- Unreliable evaluation due to partial voluming "dilution" effect on degree of uptake
4. Other lesions
- Granulomatous disease is a common cause of false positive single pulmonary nodule.
- Fungal granulomas due to coccidiomycosis, histoplasmosis, and aspergillosis are particularly in endemic areas.
- Granulomas due to tuberculosis.
- Sarcoidosis often has a characteristic pattern, but it can cause false positives.
- Active infections
- Post infectious nodules
SUV Criteria
Standardized Uptake Value takes into account the differences between normalizing for body weight, for lean body mass, or for surface area.
SUV calculation: SUV = [mCi/ml (decay corrected) in tissue] / [mCi of tracer injected/body weight (grams)]
- "Cut off" value between benign and malignant single pulmonary nodules is in the range 2.0-2.5.
- Value decreases for smaller lesions due to partial volume effects
- Indirect comparison can be made to the mediastinal blood pool (generally in the range of 2.5).
- A positive nodule will demonstrate uptake greater than the mediastinal blood pool.
- Using this internal control can help avoid errors in the SUV calculation
- Quantified SUV facilitates comparison with the mediastinal blood pool on the display
Sensitivity and Specificity
- FDG-PET is very sensitive though not very specific
- Sensitivity of 96.8 and specificity of 77.8 in accuracy to differentiate malignant and benign lesions3. Negative FDG-PET significantly reduces the chance that a lesion is malignant
- This decreases with smaller lesions in the 5-7 mm range, continue follow up
- May be adequate to obviate further clinical work up or continue non-invasive follow up
- FDG avidity of bronchioloaveolar cell cancer is reduced
Staging
TNM Staging in Non-Small Cell Lung Cancer
Tumor (T), node (N), metastasis (M) staging is used for non-small cell lung cancer
4.
- T1 lesion (= 3 cm) - nodule
- T2 lesion (> 3 cm) - pulmonary mass
- The distinction between T3 and T4 helps determine resectability
Table 1: TNM Descriptors for Non-Small Cell Lung Cancer
| Primary Tumor (T) |
| 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
|
| T1 |
Tumor = 3 cm 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)
|
| T2 |
Tumor with any of the following features of size or extent:
- 3 cm in greatest dimension
- Involves main bronchus, = 2cm distal to the carina
- Invades the visceral pleura
- 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 tumors), diaphragm, mediastinal pleura, parietal pericardium; or
- tumor in the main bronchus < 2cm 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; or
- tumor with a malignant pleural or pericardial effusion, or with satellite tumor nodule(s) within the 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 ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of the primary tumor
|
| N2 |
Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
|
| N3 |
Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
|
| Distant Metastasis (M) |
| MX |
Presence of distant metastasis cannot be assessed
|
| M0 |
No distant metastasis
|
| M1 |
Distant metastasis present
|
Mountain et. al.
4
Table 2 - TNM Staging
| Stage |
TNM |
5-year Survival |
| 0 |
Carcinoma in situ |
|
| IA |
T1N0M0 |
67% |
| IB |
T2N0M0 |
57% |
| IIA |
T1N1M0 |
55% |
| IIB |
T2N1M0
T3N0M0 |
38% |
| IIIA |
T3N1M0
T1N2M0
T2-3N2M0 |
23% |
| IIIB |
T4N0-2
T1-4N3M0 |
5% |
| IV |
T1-4N0-3M1 |
1% |
- Survival is very heavily dependent upon TNM tumor stage
- Stages IA through IIIB are dependant on the T and N classification
- Stage IV disease is defined by metastatic disease
- Major distinctions:
- Stage IIA and stage IIB
- Stage IIIA and stage IIIB
Table 3 - Staging-Tumor-Node Matrix
6
The stages can also be shown as a tumor and node matrix.
|
N1 |
N2 |
N3 |
N4 |
| T1 |
IA |
IIA |
IIIA |
IIIB |
| T1 |
IB |
IIB |
IIA |
IIIB |
| T1 |
IIB |
IIIA |
IIIA |
IIIB |
| T1 |
IIIB |
IIIB |
IIIB |
IIIB |
| T1 |
IA |
IIA |
IIIA |
IIIB |
Therapy planning is determined by stage. Accurate staging is very important since it has such a major impact on both therapy and prognosis and FDG-PET plays an important role in selection of therapy.
- Stage IA and IB can often be treated with surgery alone. Adjuvant chemotherapy can be considered in stage IB.
- Stage II is treated with a combination of surgery and chemotherapy or radiotherapy.
- Stage IIIA patients typically have preoperative chemotherapy or radiotherapy. Neoadjuvant therapy can be used to shrink the tumor prior to resection.
- Stage IIIB and IV patients are generally considered incurable and are treated with palliative therapy. Some selected stage IIIB patients may be considered for an aggressive combined therapy approach.
- Stage IV patients with a single brain metastasis are a special case; a highly selected group of these patients are considered for curative resection.
Lymph Node Stations
Precise lymph node localization is useful for staging as well as for communication with the bronchoscopist or surgeon. A numbering system has been adopted to describe the various lymph node locations 5.
- Lymph node stations are designated with a single digit, 1-9, within the mediastinum.
- N2 nodes are ipsilateral to the tumor.
- N3 nodes are contralateral to the tumor in the TNM classification.
- Lymph node stations 10-14 correspond to N1 nodes
- These nodes lie distal to the mediastinal pleural reflections.
- An "R" or an "L" can be appended to right or left of midline.
Table 4 - Lymph Node Stations
| N1 Nodes |
N1 nodes are designated with two digits.
N1 nodes must lie distal to the mediastinal pleural reflection |
| 10 |
Hilar nodes |
Distal to the mediastinal pleural reflection, adjacent to the proximal lobar bronchi and the bronchus intermedius |
| 11 |
Interlobar nodes |
Lying between lobar bronchi |
| 12 |
Lobar nodes |
Adjacent to the distal lobar bronchi |
| 13 |
Segmental nodes |
Adjacent to the segmental bronchi |
| 14 |
Subsegmental nodes |
Around the subsegmental bronchi |
| N2 Nodes |
N2 nodes stations are designated with a single digit.
N2 nodes must lie within the mediastinal pleural envelope |
| 1 |
Highest mediastinal nodes |
Above the upper rim of the bracheocephalic (left innominate) vein where it ascends to the left, crossing in front of the trachea at its midline |
| 2 |
Upper paratracheal nodes |
Below #1 and above the upper margin of the aortic arch |
| 3 |
Prevascular and retrotracheal nodes |
3A: prevascular;
3P: retrotracheal.
Midline nodes are ipsilateral for both sides |
| 4 |
Lower paratracheal nodes |
Below #2 and above the upper margin of the upper lobe bronchus and on the left, medial to the ligamentum arteriosum. |
| 5 |
Subaortic (aorto-pulmonary window) |
Lateral to the ligamentum arteriosum or the aorta or the left pulmonary artery, and proximal to the first branch of the left pulmonary artery |
| 6 |
Para-aortic (ascending aorta or phrenic) |
Anterior and lateral to the ascending aorta and the aortic arch or the innominate artery beneath a line tangential to the upper margin of the aortic arch |
| 7 |
Subcarinal nodes |
Caudal to the carina of the trachea, but not associated with the lower lobe bronchi or arteries within the lung |
| 8 |
Paraesophageal nodes (below carina) |
Adjacent to the wall of the esophagus, excluding subcarinal nodes |
| 9 |
Pulmonary ligament nodes |
Within the pulmonary ligament, including those in the posterior wall and lower part of the inferior pulmonary vein |
Advantages of FDG-PET in Lymph Node Staging
- FDG-PET has the ability to identify positive nodes that are smaller than the standard CT pathologic enlargement criteria of one centimeter as well as identify larger size nodes that are negative.
- PET imaging with anatomically fused images is advantageous in being able to identify the exact location of mediastinal nodes near the midline.
Staging - Distant metastases
- One of the most important roles for FDG-PET
- Commons sites
- adrenal glands, liver, bones
- Stage IV - palliative chemotherapy is indicated.
- Direct biopsy site to confirm the highest stage of disease expediting the work up
- FDG-PET scan can reveal a distant site of disease that can be biopsied. This often can obviate the need to biopsy the primary lesion.
- Biopsy based on an FDG-PET scan can make the diagnostic workup more effective.
Radiation Therapy
- Effects seen within the radiation port with well defined borders
- Typically low level FDG uptake
- Usually returns to normal after six months but can persist for longer
- There can be increase uptake in both the lung and the chest wall
- Focal increased or increasing uptake within the radiation port is suspicious for recurrence especially if associated with mass
- Mild to moderate uptake in a region corresponding to typical radiation changes does not suggest recurrence.
Post Therapy
Post Operative Changes
Post Radiation Changes
- Significant and often dose limiting side effect of external beam radiation therapy
- Uptake can often be quite intense
- Pattern of uptake may be more helpful in differentiating benign and malignant uptake
Radiation Pneumonitis
- A common occurrence following thoracic radiation
- Can pose a diagnostic problem on both anatomic and functional images
- Occurs in the involved portion of the lung due to associated inflammation
- Can make early detection of recurrent cancer a problem
Other Aspects
- Cost Effectiveness - FDG-PET/CT may prove to contribute to cost effectiveness by helping to invoke the appropriate therapy choices based on the most accurate staging
- Screening - This remains a controversial use of any imaging modality due to cost effectiveness issues. Perhaps in the future there will be a well established role for imaging in screening especially in higher risk patients.
Conclusions
- Diagnosis, staging, and restaging of non-small cell lung cancer is one of the most promising and powerful applications of FDG-PET.
- Use of FDG-PET in the appropriate setting can significantly affect patient outcome
- More accurate staging with FDG-PET can help guide and ensure the most appropriate therapy
- Degree of FDG uptake may provide valuable prognostic information
- Knowledge of the limitations of FDG-PET/CT will help to provide the most accurate interpretation