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L' exeresi dei linfonodi in caso di asportazione di
forme neoplastiche polmonari rappresenta un fondamentale momento di diagnosi,
terapia e previsione prospettica oltre di studio evolutivo delle forme
neoplastiche.
Riporto lo studio a cui io mi adeguo:
Eur J Cardiothorac Surg 2006;30:787-792
© 2006 Elsevier
Science NL
Invited paper
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ESTS guidelines for intraoperative lymph node staging in non-small cell lung
cancer
Didier Lardinois a , Paul De Leyn
b , Paul Van Schil c , Ramon Rami
Porta d , David Waller e ,
Bernward Passlick f , Marcin Zielinski g
, Klaus Junker h , Erino Angelo Rendina
i , Hans-Beat Ris j , Joachim Hasse
k , Frank Detterbeck l , Toni Lerut
b , Walter Weder a , *
a Department of Thoracic Surgery, University
Hospital, Zurich, Switzerland
b Department of Thoracic Surgery, University Hospital, Leuven,
Belgium
c Department of Thoracic and Vascular Surgery, University Hospital,
Antwerp, Belgium
d Division of Thoracic Surgery Hospital, Mutua de Terrassa, Spain
e Department of Thoracic Surgery, University Hospitals Leicester NHS
Trust, Glenfield Hospital, Leicester, United Kingdom
f Department of Thoracic Surgery, University Hospital, Freiburg,
Germany
g Department of Thoracic Surgery, Pulmonary Hospital, Zakopane,
Poland
h Department of Pathology, University Hospital, Bochum, Germany
i Division of Thoracic Surgery, University Hospital La Sapienza,
Roma, Italy
j Division of Thoracic and Vascular Surgery, University Hospital,
Lausanne, Switzerland
k Department of Thoracic Surgery, University Hospital, Freiburg,
Germany
l Division of Cardiothoracic Surgery, University of North Carolina,
Chapel Hill, USA
Received 15 September 2005; received in revised form 5 July
2006; accepted 14 August 2006.
* Corresponding author. Tel.: +41 1
2558802; fax: +41 1 2558805. (Email:
walter.weder@usz.ch
).
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Abstract
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The European Society of Thoracic Surgeons (ESTS) organized a workshop
dealing with lymph node staging in non-small cell lung cancer. The
objective of this workshop was to develop guidelines for definitions
and the surgical procedures of intraoperative lymph node staging, and
the pathologic evaluation of resected lymph nodes in patients with
non-small cell lung cancer (NSCLC). Relevant peer-reviewed
publications on the subjects, the experience of the participants, and
the opinion of the ESTS members contributing on line, were used to
reach a consensus. Systematic nodal dissection is recommended in all
cases to ensure complete resection. Lobe-specific systematic nodal
dissection is acceptable for peripheral squamous T1 tumors, if hilar
and interlobar nodes are negative on frozen section studies; it
implies removal of, at least, three hilar and interlobar nodes and
three mediastinal nodes from three stations in which the subcarinal
is always included. Selected lymph node biopsies and sampling are
justified to prove nodal involvement when resection is not possible.
Pathologic evaluation includes all lymph nodes resected separately
and those remaining in the lung specimen. Sections are done at the
site of gross abnormalities. If macroscopic inspection does not
detect any abnormal site, 2-mm slices of the nodes in the
longitudinal plane are recommended. Routine search for
micrometastases or isolated tumor cells in hematoxylin-eosin negative
nodes would be desirable. Randomized controlled trials to evaluate
adjuvant therapies for patients with these conditions are recommended.
The adherence to these guidelines will standardize the intraoperative
lymph node staging and pathologic evaluation, and improve pathologic
staging, which will help decide on the best adjuvant therapy.
Key Words: Lung cancer • Intraoperative lymph node staging •
Pathologic evaluation of lymph nodes
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1.
Introduction |
Defining the stage of a malignant disease is key for planning therapy,
estimating prognosis and for comparison of studies
[1]. The extent of lymph node involvement in patients with non-small
cell lung cancer (NSCLC) is the most important prognostic factor
and influences therapeutic strategies [2]. There are
internationally accepted definitions for lymph node staging in NSCLC,
however, there are some unanswered questions regarding extent,
nomenclature definition, and surgical procedure of intraoperative
lymph node evaluation. Furthermore, the quality of pathologic
assessment is ill-defined and may vary between observers
[3].
The council of the European Society of Thoracic Surgeons (ESTS)
initiated a workshop which took place in Zurich on 25th March and 6th
July 2004 in order to standardize definitions, surgical procedures,
and pathologic evaluation. Based on peer-reviewed publications with a
level of evidence from II to IV [4], these
guidelines were open for discussion on the society's website for its
members and the relevant replies were integrated in the final
document.
A second manuscript dealing with the preoperative evaluation of
intrathoracic lymph node status in patients with NSCLC will be
published in the near future as the result of a second ESTS workshop.
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2. Anatomy
and lymph drainage of the lungs |
Three planes of lymphatic drainage from the lungs are of clinical
importance: anterior, mediastinal, and posterior (intercostal) routes.
Several studies have demonstrated a great anatomical variability of
the lymphatic system of the lungs which might serve as possible
explanation for the somewhat unpredictable pattern of lymphatic
metastases of lung tumors [5].
From the surgical point of view it is important to note that
segmental and subpleural lymphatics may drain directly to paratracheal
or supraclavicular stations which is a possible explanation for
skip metastases to these lymph node stations without involvement of
intrapulmonary or hilar nodes [6]. In a study of 179
patients undergoing bronchial lymphoscintingraphy during
investigation for NSCLC [7], mediastinal skip
metastases identified in 25% of cases. In addition, crossover
lymphatic drainage across the midline was frequently found. This
provides an explanation for tumor spread to contralateral mediastinal
lymph nodes, and for routine investigation of the contralateral
mediastinum by mediastinoscopy or PET. Of particular importance was
the propensity for left lower lobe tumors to drain to the right
paratracheal lymph node groups.
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3. Mapping
of lymph nodes to the appropriate station |
The need for precise evaluation of lymph node status was identified
in order to guide therapy, to estimate prognosis, to compare results
from different institutions, and to conduct multi-institutional
trials.
The evolution of lymph node mapping began with the 1978 report by
Naruke et al. [8], when anatomical definitions were first
used. In 1983, the American Thoracic Society produced a system
in which the vague terms ‘hilar’ and ‘mediastinal’ were replaced with
definitions of nodal levels based on constant anatomical landmarks
which could be identified in the operating theatre
[9]. In 1986, a Revised International Staging System was produced
by the AJCC and UICC [1] in which the lymph node
levels remained unchanged but the components of the N2 group changed
and in which a N3 category was created. In 1997, the latest revised
International Staging System was released [2] and
a new pulmonary and mediastinal lymph node map proposed
[10] (Fig. 1 ). In this latest revision
the clinical staging system was based on CT landmarks making
identification of stations 2 and 4 more difficult during surgery. Of
importance was the inclusion of nodes along the anterior surface of
the main stem bronchus within the pleural reflection line in station
4 (N2). Furthermore, the nodes in the midline should be classified as
N2 rather than N3.
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4. What are
the persisting obstacles to lymph node mapping? |
4.1 Anatomical allocation
The group identified five areas where difficulty exists in the
interpretation of the definitions. These were: (1) the watershed
between stations 2 and 4 in the paratracheal region; (2) the
transition zone between station 4 and 10 at the tracheo-bronchial
angle; (3) the border between station 7 in the subcarinal area and
station nodes 10 on the medial side of the main stem bronchi; (4) the
lower border of subcarinal station 7 and the beginning of
paraesophageal station 8; and (5) the lymphatic watershed in the
superior mediastinum which was proposed to be along the left margin
of the trachea. Apart from the landmark of the take-off of the upper
lobe bronchus from the main bronchus as a boundary between station 4
and 10, it was felt that the demarcation between these other stations
was either arbitrary or not identifiable at mediastinoscopy or
intraoperative staging. Most of these controversies are relevant
because they either change clinical and pathological stage (according
to the current TNM staging) in points 2, 3, and 5 above or may have
prognostic implications as in 1 and 4.
The limitations of present nodal charts will be addressed in a new
International Nodal Chart that will be included in the next revision
of the UICC Staging System to be enacted in 2009.
4.2 Number of nodes (ratio) and number of stations
The importance of the number of investigated versus involved nodes
and lymph node stations has not been addressed in the current staging
systems. It is thought that the number of lymph node stations
involved by tumor and their anatomical location are important
prognostic factors [11].
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5.
Intraoperative lymph node assessment |
5.1 General remarks
Although it is admitted that nodal staging of non-small cell lung
cancer should be as accurate as possible, the extent of mediastinal
lymph node assessment during surgery is controversial and there is no
consensus.
Different techniques are used, ranging from simple visual inspection
of the unopened mediastinum to an extended bilateral lymph node
dissection. Furthermore, different terms are used to define these
techniques.
There are data which clearly show that systematic sampling or
nodal dissection improves intraoperative staging in contrast to
selected lymph node sampling, especially in the detection of
multi-level N2 disease [12,13].
The rate of occult N2 disease will also depend on the methods used
for preoperative staging. Whether extending the lymph node dissection
influences survival or recurrence rate of the disease remains to be
determined [12–15].
A removal of at least six lymph nodes (UICC) from hilar and
mediastinal stations is recommended to define nodal staging
accurately and to determine pN0 status [16].
There is evidence that multi-level and multi-nodal disease or
extracapsular involvement has a poorer prognosis [17].
5.2 Recommended definitions to describe intraoperative lymph node
assessment
- - Selected lymph node biopsy
In this procedure, one or multiple suspicious lymph node(s)
are biopsied. This is only justified to prove N1 or N2
disease in patients in whom resection is not possible (exploratory
thoracotomy).
- - Sampling
Sampling is the removal of one or more lymph nodes guided by
preoperative or intraoperative findings which are thought to
be representative. Systematic sampling means a predetermined
selection of the lymph node stations specified by the surgeon.
- - Systematic nodal dissection
All the mediastinal tissue containing the lymph nodes is dissected
and removed systematically within anatomical landmarks. For
left-sided tumors, in order to get access to the high and low
paratracheal nodes, the division of the ligamentum arteriosus
can be added, resulting in the mobilization of the aortic
arch. It was recommended that at least three mediastinal
nodal stations (but always subcarinal) should be excised as
a minimum requirement. The nodes are separately labeled and
examined histologically. Beside the mediastinal nodes, the
hilar and the intrapulmonary lymph nodes are dissected
as well [16].
- - Lobe-specific systematic node dissection
In this procedure, the mediastinal tissue containing specific
lymph node stations are excised, depending on the lobar
location of the primary tumor.
- - Extended lymph node dissection
In this procedure, bilateral mediastinal and cervical lymph
node dissection is performed through median sternotomy and
cervicotomy.
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6.
Recommendation |
For complete resection of non-small cell lung cancer, a systematic
nodal dissection is recommended in all cases [18,19].
Ideally, this should be done as an en-bloc resection, when possible
of the upper mediastinal nodes on the right side (stations 2R and
4R), the limits of which are as follows: cranially, brachiocephalic
trunk; medially, the ascending aorta and origin of aortic arch;
anteriorly, the superior vena cava; posteriorly, the esophagus; and
inferiorly, the pulmonary artery. Any visible nodes in front of the
superior vena cava and/or posterior to the trachea should be removed
(stations 3a and 3p). We can recommend the en-bloc resection of the
lower mediastinum, including the fatty tissue from the diaphragm to
the subcarinal space (stations 7, 8, and 9). On the left side,
removal of the subaortic (station 5), para-aortic (station 6) and
inferior paratracheal (4 L) lymph nodes is minimally required. For a
complete nodal dissection of the left upper mediastinum, division of
the ligamentum arteriosus allowing mobilization of the aortic arch is
recommended, with special care not to injure the left recurrent
laryngeal nerve.
It is important that the nodal stations are excised and put in
different vials with separate labeling. The highest removed
mediastinal node should be identified.
After pathological examination of the lymphadenectomy specimen,
the number of involved lymph nodes and of the nodal stations, and the
status of the nodal capsule should be documented.
Modifications in specific clinical situations
- - For peripheral squamous T1, a more selective nodal dissection
depending on the lobar location of the primary tumor (lobe-specific
systematic nodal dissection) is acceptable, based on the
detailed analysis of lobe-specific lymphatic drainage
published by Naruke et al. [20] and
Ichinose et al. [21]. It has been shown that
the probability of unforeseen N2 disease is very low (<5%)
in such patients [22,23].
The Bronchogenic Carcinoma Cooperative Group of the Spanish
Society of Pneumology and Thoracic Surgery, based on Naruke's
and Ichinose's findings, recommended a minimal dissection of
at least three of the following mediastinal nodal stations
depending on the lobar location of the primary tumor
[24]. This implies dissection and
histological examination of hilar and interlobar nodes
which have to be tumor-free on frozen section analysis
and the following lobe-specific node dissection is performed:
- right upper and middle lobe: 2R, 4R and 7;
- right lower lobe: 4R, 7, 8 and 9;
- left upper lobe: 5, 6 and 7;
- left lower lobe: 7, 8 and 9.
In total, the lymphadenectomy specimen should include
at least six nodes.
- - After induction therapy, the same recommendation for lymph
node assessment should be applied. However, lymph node
dissection in the upper mediastinum after induction
therapy (especially chemotherapy, radiotherapy after
previous mediastinoscopy) may be technically difficult
[25].
- - High-risk patients.
Intraoperative lymph node assessment can be minimized in high-risk
patients undergoing minimal invasive video assisted wedge
resections but if the patient can tolerate a lobectomy,
standard recommendation of lymph node assessment should
be followed [26].
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7.
Histopathological evaluation of the removed lymph nodes |
7.1 Recommendations
Recommendations about the histopathological evaluation of the lymph
nodes were published in 2001 by the ‘Association of Directors of
Anatomic and Surgical Pathology’ [3]. However, in
practice, there is no established consensus. The analysis of the
nodes depends on the center, on the pathologist and it is often
difficult to find a compromise between theoretical demands and
practical feasibility. Some recommendations can be given to define
quality criteria for this evaluation:
- - As a first step, all resected intrapulmonary, hilar, and
mediastinal nodes should be examined macroscopically. In the
presence of gross tumor, one hematoxylin-eosin (HE) stained section
should be performed at the most macroscopically suspicious site to
demonstrate the metastasis and its possible extracapsular extension.
- - If the macroscopic evaluation does not show any suspicion of
metastasis, a single section of a node should be avoided. The
probability to detect a metastasis on center section is related to
the size of the lymph node, the size of the lesion, and the
location of the tumor within the node [27]. To avoid
this problem, it is recommended to perform several sections
of the nodes, 2-mm slices in the longitudinal plane and to examine
each block separately. Thin sections of 2 mm may increase the
workload of the pathologist but increase the detection rate of
metastases. Small nodes can be sliced and embedded in one block if
possible.
- - There are different methods to detect additional metastatic
deposits in lymph nodes like serial sectioning or
immunohistochemistry (IHC). IHC using a cocktail of cytokeratins
such as the anti-epithelial antibody mAb Ber-Ep4, AE1/AE3 is
a sensitive and specific method for detecting isolated tumor
cells or clusters of cells. Three levels of section are
enough for this analysis [28,29]. However,
serial sectioning is relatively laborious and time-consuming
and is therefore not practical as a routine
[30].
- - The report from the pathologist should describe the number
of lymph nodes removed and studied, the overall number of
metastatic lymph nodes in each station, and the status
of the lymph node capsule.
7.2 Definition—micrometastasis
A micrometastasis can be detected by standard histopathology (HE
staining), by IHC or by polymerase-chain reaction (PCR) (sensitive
method).
A micrometastasis is defined as a lesion
 2 mm in diameter compared
with a metastasis which is larger than 2 mm [31]. It is
obvious that the distinction between micrometastasis and metastasis
using the size as unique criterion is arbitrary.
Another important point is the distinction between micrometastasis
and isolated tumor cells. Isolated tumor cells are defined as single
tumor cells or small cell clusters, showing no stromal reaction and
no proliferative potential. Isolated tumor cells can be detected by
IHC, PCR or by other molecular methods, and their size
0.2 mm. Thus, histopathologically,
the two terms ‘micrometastasis’ and ‘isolated tumor cells’
correspond to two different entities. However, in the literature,
there is a mixture of different terminologies and the term micrometastasis
is used for isolated cells, clusters of cells or true micrometastases
according to the definition. Indeed, nearly all the published
data are dealing with isolated cells and not with micrometastasis
[32,33].
The incidence of isolated tumor cells is about 20–30%. This
incidence was observed in several reports and also in patients with
early-stage of NSCLC [34,35].
The detection of isolated tumor cells in the lymph nodes might
have therapeutic implications, since several reports showed that
isolated tumor cells are a significant negative prognostic factor in
patients with NSCLC [36–38].
At the moment, the nodes with isolated tumor cells are not upstaged
to N1 or N2 but are labeled pN0 (i positive or negative), or
pN0 (mol positive or mol negative) if non-morphologic methods
or PCR or other molecular methods have been used [39].
Isolated tumor cells may be observed at an early NSCLC stage and
seem to predict a shortened recurrence-free interval and a shorter
overall survival, indicating a biologically more aggressive tumor. As
a consequence, it would be desirable to routinely analyze all HE
negative nodes with IHC or other molecular methods. Whether the
patients with isolated tumor cells would benefit from adjuvant
therapies has to be evaluated in prospective trials.
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Acknowledgments |
We are indebted to Mr Peter Goldstraw, from the Department of
Thoracic Surgery, Royal Brompton Hospital, London, UK, for critical
discussions and support in the realization of this manuscript.
Additionally, our thanks goes to all the ESTS members who sent their
constructive comments.
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Footnotes
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The first ESTS Workshop was organized during the first ESTS Spring
Meeting March 2004 Zurich Switzerland and was presented at the second
ESTS Spring Meeting April 2005 Athens Greece.
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Top
Abstract
1.
Introduction
Potete inviare a