Introduction
Introduction
Lung cancer is the leading cancer related cause of death in the western world [1]. The prognosis is directly related to the stage of the disease. Treatment strategies
are largely based on the cell type of the tumor, i. e. either small cell lung cancer
(SCLC) or non-small cell lung cancer (NSCLC), and the presence of mediastinal involvement
or distant spread of the tumor [1]
[2]. The treatment of SCLC is mainly chemotherapy whereas NSCLC treatment is fully stage
dependent ranging from surgery only to down-staging chemotherapy with subsequent surgery
or entirely experimental chemotherapy/radiotherapy.
Non-small cell lung cancer (NSCLC) usually metastasizes first to hilar and mediastinal
lymph nodes. Subsequently, hematogenous metastasis to distant sites may occur. Because
survival is inversely correlated with stage, a meticulous staging procedure is required
to determine the treatment and prognosis [3]
[4]. For staging of NSCLC, the TNM classification has been developed, in which T stands
for local tumor extension, N for lymph node metastasis, and M for distant metastasis.
The lymph node map by Mountain et al, and its revisions are often used for the description
of the N factor of the TNM classification [5] (Table [1] and [2]).
Table 1 TNM classification of lung Cancer
| Primary tumor |
|
· Tis - Carcinoma in situ |
|
· TX - Positive malignant cytologic findings, no lesion observed |
|
· T1 - diameter of 3 cm or smaller and surrounded by lung or visceral pleura (see
Image 1) or endobronchial tumor distal to the lobar bronchus |
|
· T2 - Diameter greater than 3 cm (see Images 2 - 3); extension to the visceral
pleura, atelectasis, or obstructive pneumopathy involving less than 1
lung; lobar endobronchial tumor; or tumor of a main bronchus more than 2 cm from the
carina |
|
· T3 - Tumor at the apex (see Image 5); total atelectasis of 1 lung; endobronchial
tumor of main bronchus within 2 cm of the carina but not invading
it; or tumor of any size with direct extension to the adjacent structures such as
the chest wall mediastinal pleura (see Image 8), diaphragm,
pericardium parietal layer, or mediastinal fat of the phrenic nerve |
|
· T4 - Invasion of the mediastinal organs, including the esophagus trachea, carina
(see Image 11), great vessels (see Image 13), and/or heart;
obstruction of the superior vena cava; involvement of a vertebral body; recurrent
nerve involvement; malignant pleural or pericardial effusion; or
satellite pulmonary nodules within the same lobe as the primary tumor |
| • |
Regional lymph node involvement |
|
· N0 - No lymph nodes involved |
|
· N1 - Ipslateral bronchopulmonary or hilar nodes involved |
|
· N2 - Ipsilateral mediastinal nodes or ligament involved |
|
- Upper paratracheal lower paratracheal nodes |
|
- Pretracheal (see Image 4, Image 7, Image 10) and retrotracheal nodes |
|
- Aortic and aortic window nodes |
|
- Para-aortic nodes |
|
- Para-esophageal nodes |
|
- Pulmonary ligament |
|
- Subcarinal nodes (see Images 12 - 17) |
|
· N3 - contralateral mediastinal or hilar nodes involved (see image 19) or any scalene
or supraclavicular nodes involved |
| • |
Metastatic involvement |
|
· M0 - No metastases |
|
· M1 - Metastases present (see Images 20 - 27) |
Table 2 Stage groupings
| • |
IA - T1N0M0 |
| • |
IB - T2N0M0 |
| • |
IIA - T1N1M0 |
| • |
IIB - T2N1M0 or T3N0M0 |
| • |
IIIA - T1-3N2M0 or T3N1M0 |
| • |
IIIB - Any T4 or any N3M0 |
| • |
IV - Any M1 |
TNM Classification
TNM Classification
The TNM classification is subdivided in cTNM and a pTNM where the cTNM is based on
the clinical evaluation while the pTNM is based on the pathological results after
operation.
The difference in the 5 years survival based on the cTNM classification compared to
the pTNM stresses the importance of an exact classification (Fig. [1] and [2]).
Exact mediastinal staging of patients with non-small-cell lung cancer (NSCLC) is therefore
important to improve selection of the treatment of patients with lung cancer. Up to
10 % of lung cancer operations result in explorative thoracotomies without tumor resection,
and an additional 25 - 35 % of the operations are unsuccessful because of postoperative
recurrent disease [6]
[7], apparently because the stage of the disease is more advanced than expected preoperatively.
Therefore the correct staging is critical because treatment is directly related to
the stage of the. Thus, incorrect staging would lead to improper treatment, and material
demunition of patient survivability (Fig. [3]).
Mediastinal lymph node staging can be divided into imaging and sampling. Computed
tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography
(PET) may be used to image mediastinal lymph nodes [8]. Pathologic sampling of suspicious lesions can be performed by mediastinoscopy,
thoracoscopy, transthoracic fine-needle aspiration, transbronchial fine-needle aspiration,
and endoscopic ultrasonography with fine-needle aspiration [8]
[9]
[10]
[11].
Fig. 1 5 year survival cN versus pN.
Fig. 2 Survival cTNM versus pTMN.
Fig. 3 Operability by stage.
CT
CT
The background of the differences in 5 years survival in cTNM and pTNM is based on
the sensitivity and diagnostic values of the different modalities used in the cTNM
classification compared to the operative findings.
Neither CT scan nor MRI are able to distinguish malignant from hyper plastic, anthracotic,
granulomatous or fibrotic lesions, more so after induction treatment. With reported
sensitivities and specificities of 69 %, respective 71 % for CT scan and 45 %, respective
65 % for MRI, both techniques prove too inaccurate for reliable loco regional staging.
Looking at the different objects in the TNM staging system, the accuracy in T staging
is 60 % and N staging 65 %.
This result is depended of the N stage because the accuracy here is 65 % for N0, 42
% for N1, 32 % for N2 and 43 % for N3. Therefore N under staging is found in 23 %
and an over staging in 30 %.
By CT scan which is one of the main methods in evaluating lung cancer the N-classification
is only correct in 50 %, over staged in 25 % and under staged in 25 % [13]
[14].
FDG PET
FDG PET
Many retrospective [15]
[16] and prospective studies [17]
[18]
[19] have shown FDG PET to be an accurate imaging modality in the nodal staging of NSCLC.
Meta-analytic comparisons of PET and CT [20]
[21]
[22]
[23] showed that PET was significantly more accurate than CT in demonstrating nodal metastases.
However, a metaanalysis (eller er det et review) has shown that PET/CT has a sensitivity
of 0.84, a specificity of 0.89 and a PPV of 0.79 and a NPV of 0.93 [24].
The diagnostic capability of FDG PET is limited not only by cellular activity but
also by tumor volume. FDG uptake by small tumor cell foci is often poorly depicted
due to partial volume effect. Current PET scanner achieves transaxial resolution of
4-5 mm full-width-half-maximum. A tumor focus smaller than 5 mm may not be detected
by the current scanners. The maximum dimensions of tumor focus in false-negative lymph
nodes ranges from 1 to 7.5 mm (mean 3.4 mm) [25].
Yoshida et al. [25] showed that the spatial resolution limitations of FDG PET were responsible for 13
of 14 (93 %) false-negative PET results demonstrating that FDG PET is not reliable
in diagnosing small tumor foci in Lymph nodes.
Another disadvantage of FDG PET is its limited anatomical resolution due to the paucity
of anatomic information in metabolic images [19]. Although PET-positive Lymph nodes were localized referring to contrast-enhanced
CT findings, it is hard to distinguish hillar Lymph nodes from adjacent mediastinal
Lymph nodes.
False-positive PET scans is mostly attributable to inflammatory conditions, including
tumor necrosis, obstructive pneumonia, previous pulmonary tuberculosis, pulmonary
fibrosis, and rheumatoid arthritis. FDG is not a specific marker of malignancy and
FDG uptake can be seen at sites of active, acute inflammation, which is due to increased
glucose uptake by activated macrophages and inflammatory cells [26]. Inflammatory conditions are well-known factors associated with false-positive PET
scans in indeterminate pulmonary nodule evaluation [27]. Roberts et al. [28] reported that concurrent inflammatory lung disease and centrally located tumors
were causative factors of false-positive PET scans in mediastinal nodal staging in
NSCLC.
Fritscher-Ravens et al. showed that in using EUS FNA, PET and CT they found false
positive inoperable diagnoses: PET = 9/36, CT = 3/20.
Sensitivity, specificity, accuracy in nodal staging for CT was 29, 83, and 65 % and
for PET 39, 79, and 66 %, respectively. There were 10 (14 %) false-positive PET scans
and 14 (20 %) false-negative PET scans.
Mediastinoscopy
Mediastinoscopy
Preoperative evaluation of the mediastinal lymph nodes is important in patients with
lung cancer in order to determine operability and/or need for neoadjuvant treatment.
46 years after its introduction by Carlen’s in 1959 [31], mediastinoscopy is still the golden standard in the evaluation of the mediastinal
lymph node and in the preoperative staging of patients with lung cancer [32]
[33]. Mediastinal exploration is described as cervical mediastinoscopy, parasternal mediastinotomy,
extended cervical mediastinoscopy and thoracoscopy depending on the surgical technique.
Cervical mediastinoscopy (CM) is generally accepted as a safe and highly accurate
procedure in the staging of lung cancer. Nodes accessible to CM are those of the superior
(level 2R and 2L) and inferior (level 4R and 4L) Para tracheal and subcarinal (level
7) nodal stations. Additionally, extended CM and left parasternal mediastinotomy allow
exploration of the aortopulmonary window (level 5) and anterior mediastinal nodes
(level 6) (Fig. [4]).
A special problem is remediastinoscopy (RM) because of fibrosis due to the first procedure
and the associated risk of injury to vital structures [34]
[35]
[36]. Neoadjuvant clinical trials with induction chemotherapy or chemo radiation should
all involve a restaging procedure to confirm the differences in the results of different
treatment modalities. In downstaged patients restaging is also important to select
therapy-responsive patients with high probability of complete resectability, thereby
reducing the number of futile thoracotomies in patients with locally advanced lung
cancer [37]
[38]
[39].
Fig. 4 Mediastinal and hillar lymph nodes stations.
EUS-FNA and EBUS-TBNA
EUS-FNA and EBUS-TBNA
To establish an easier and more accurate staging procedure EBUS TBNA and EUS FNA has
been developed. They target lesions and lymph nodes adjacent to trachea, main bronchi
and esophagus and the hillar regions. Both techniques are used to assess the entire
mediastinum or to stage predominantly only one nodal station, and can be used for
the systematical standardized exploration of individual nodes as performed by mediastinoscopy
[41]
[42]
[43]
[44]
[45].
Comments
Comments
With the current status and the development of the multidisciplinary treatment modalities
it is outmost important that we solve the basic problems with the imaging systems
which do not enable us to establish an exact diagnosis and a precise stage because
we need cells for an exact diagnose.
Mediastinoscopy is still the golden standard but has its limitations, i. e. incomplete
mediastinoscopy, most frequently seen at station 7 and the posterior and inferior
mediastinum, assessment of loco regional extent of recurrent cancer, a second primary
cancer, re-staging after neoadjuvant chemotherapy and metastases from cancers in other
organs to the mediastinum and hillar regions.
Remediastinoscopies is although possible often difficult to perform but it is very
important to establish a correct stage also after downstaging so only patients who
benefits from operation will be offered this treatment (Fig. [5]).
The often undiagnosed hillar lymph nodes metastases in N1 nodes, is a special problem.
Traditionally hey can only be reached by thoracotomy (scopy). Because of the possibilities
of neoadjuvant therapy in primary lung cancer it is nessecary also to diagnose the
N1 lymphnodes. In the evaluation of patients after downstaging a correct restaging
is important in evaluating the results from different treatment modalities, Metastasis
from other organs is also often found in the N1 nodes.
In the staging process of cN1 disease, it is possible to perform mediastinoscopy and
thoracoscopy to avoid unnecessary thoracotomy especially in adenocarcinoma, even though
mediastinal nodes and pleural dissemination were negative on computed tomography investigation.
These methods requires general anesthesia and open surgery.
Therefore we need a method which is easy and minimal invasive, based on an outpatient
procedure and enables us to collect tissue on which basis a diagnose can be established
and the stage of cancers can be determined so a proper and effective treatment can
be established.
Fig. 5 Overall survival dependent on pN2 clearance in the univariate analysis (patients with
tumor resection after downstaging treatment), n = 71; P = log-rank test P value Sugerbaker:
ASCO Educational book, 1994.
