11th European Perspectives in Lung CancerAmsterdam, March 5-6, 2010

Stefano GaspariniPulmonary Diseases Unit

Azienda Ospedaliero-Universitaria “Ospedali Riuniti”Ancona - Italy

MEDIASTINAL STAGING:SURGICAL CON

LYMPHNODE STAGING FOR LUNG CANCER

INTERNATIONAL SYSTEM FOR STAGING

N0 No lymphnodes metastasisN1 Metastasis to lymphnodes in the

peribronchial or ipsilateral hilarregion

N2 Metastasis to ipsilateral mediastinaland/or subcarinal lymphnodes

N3 Metastasis to controlateral mediastinallymphnodes

5 YEARS SURVIVAL

N0 60%N1 40%N2 22%N3 3%

Surgery

Chemotherapy / SurgeryChemotherapy / No surgery

Mediastinal lymph node involvement is present in 26%-38% ofNSCLCs at the time of diagnosis and in pts without extrathoracic

involvement it is the most significant factor in determining surgicalresectability

TRADITIONAL METHODS FOR STAGING LUNG CANCER

IMAGING

-CT scan

-PET

SURGICAL TECHNIQUES

-MEDIASTINOSCOPY

-ANTERIOR MEDIASTINOTOMY

-VATS

CT SCAN ?

Non invasive Staging of NSCLCA review of the current evidence

Toloza EM et al. CHEST 2003; 123: 137S-146S

0,56 0,83

Approximately 40% of all nodes deemed malignant by CT criteria are actually benign

Mc Loud TC. Radiology, 1992

If the pulmonologist were to trust the CT, nearly 20% of patients with lung cancer and mediastinal

lymphadenopathy could be precluded from curative surgery, when in fact the lymphadenopaty was not

metastatic diseaseSilvestri GA. CHEST, 2003

PET ?

Percutanous needle aspiration ?

Non invasive Staging of NSCLCA review of the current evidence

Toloza EM et al. CHEST 2003; 123: 137S-146S

0,79 0,93

The non invasive Staging of NSCLCThe Guidelines

Silvestri GA. CHEST, 2003; 123: 147S-156S

A negative result of mediastinal PET scan may obviate the need for mediastinoscopy prior to thoracotomy;

A positive result of mediastinal PET scan should not negate further evaluation or the possibility of resection

Surgical procedures ?

Invasive Staging of NSCLCA review of the current evidence

Toloza EM et al. CHEST 2003; 123:157S-166S

Accessible LNs: 2R, 2L, 4R, 4L, anterior 7

Morbidity and mortality rates: 2% and 0,8%. Extimated cost: 7.500 Euro

1.00 0,91

Adenocarcinoma of the right upper lobewith limphonodemetastasis of the

left paratracheal lymph nodes(N3) (stage IIIB)

Bronchoscopy with TBNA:- diagnosis and “N” staging at the same time;

- outpatient

- time employed: 20 min

SCHIEPPATI E.La punction mediastinaltraves del espolon traquelRev As Med Argent 1949, 663: 497-499

- Transbronchial needle aspiration in the diagnosis and staging of bronchogenic carcinoma.

Am Rev Respir Dis 1983; 127: 344-347

- Flexible transbronchial needle aspiration for staging of bronchogenic carcinoma.

Chest 1983; 84: 571-576

- Flexible transbronchial needle aspiration: technical consideration.

Ann Otol Rhinol Laryngol 1984; 93: 233-236

- Flexible transbronchial needle aspiration biopsyfor histology specimens.

Chest 1985; 88: 860-863

- Transbronchial needle aspiration: how I do it.J Bronchol 1994; 1: 63-68

- Staging of bronchogenic carcinoma by bronchoscopyChest 1995; 106: 588-593

Transbronchial needle aspiration...

...TBNA for friends...

What’s yourname?

DIAGNOSTIC BRONCHOSCOPY

DIAGNOSTIC AND STAGINGBRONCHOSCOPY

TBNA OF MEDIASTINAL LESIONS

NECESSARY REQUIREMENTS:- contact of the lesions with the airways- availability of a skilled cytopathologist- specific training of the bronchoscopist

- contact of the lesions with the airways

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Wang, 1984Shure, Fedullo, 1984Harrow, 1984Schenk, 1986Wang, 1985Metha, 1989Schenk, 1993Bilaceroglu, 1996Rodriguez de Castro, 1997Harrow, 2000Patelli, 2002

6438464380618574787972

TBNA: sensitivity (%)

Meta-analysis (17 studies):Sensitivity: 78%Specificity: 100%

Chest 2007; 132: 208s

FACTORS INFLUENCING TBNA SENSITIVITY

•Presence of lymph node enlargement on CT scan•Lymph node location•Lymph node size•Number of aspirates performed•Rapid on-site cytopathologic examination•Nature of the lesion (malignancy, type of tumor)•Kind of needle employed•Operator’s ability and experience•Technique of guidance

LYMPH NODE LOCATION

Patelli M et al. Ann Thorac Surg 2002; 73: 407-411194 procedures: overall TBNA sensitivity was 71%Right paratracheal station: sensitivity 84%Subcarinal station: sensitivity 79%Left paratracheal station: sensitivity 52%

Harrow EM et al. Am J Respir Crit Care Med 2000; 161: 601-607TBNA at 607 lymphnode locations in 360 patients.Better results in the right sided tumors (positive 64% vs 34%).Right paratracheal and subcarinal lymph nodes aspirateswere more likely to provide a positive cytology than leftparatracheal TBNA.

LYMPH NODE SIZE

Harrow EM et al. Am J Respir Crit Care Med 2000; 161: 601-607Lymph node size can influence the results of TBNA.Positive aspirates increased with a linear relationship fromlymph nodes less than 1 cm to lymph nodes of 2-2.5 cm.None of TBNA performed on lymph node less than 5 mm waspositive, but 15% of samples from nodes between 5 and 9 mmwere diagnostic.For lymph nodes greater than 2.5 cm the sensitivity did notincrease further.

Ln size (mm) 0-4 5-9 10-14 15-20 21-25 25-30 >30

A positive TBNA may preclude the need for additional surgical staging of the mediastinum (ATS-ERS, 1997)

TBNA: COMPLICATIONSOne case of pneumothorax out of 146 TBNA performed (0.7%)Wang KP et al., 1983

Pneumomediastinum after TBNA of subcarinal lymphnodes:case reportGasparini S et al., in press

Hemomediastinum after transbronchial needle aspirationKucera RF et al., 1986Lazzari Agli L et al, Chest, 2002Gasparini S et al, Journal of Bronchology 2004

Bacteriemia following transbronchial fine needle aspirationWatts WJ, Green RA, 1984

Polymicrobial bacterial pericarditis after TBNAEpstein SK et al, 1992

Severe intratracheal bleedingNierhoff N, Knoblauch A, 1993

TBNA: ADVANTAGES

1) High specificity and great value of a positive result(no need for further invasive investigation with consequent saving of time and reduction of costs and risks)

2) TBNA can and should be performed during thefirst routine bronchoscopy (that in any case must be done on patients suspected of lung cancer)

3) Possibility to sample different lymphnode stationsduring the same procedure

5) Safe

6) Cheaper in comparison to surgical procedures

4) Possibility to sample lymphnode stations difficult toapproach by surgical procedures (low subcarinal, retrotracheal, hilar)

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Diagnosis and staging (N3 disease) during the first bronchoscopy15 min timeNo need for PET, no need for expensive technology or surgery.

HOW TO IMPROVE TBNA SENSITIVITY?

MEANS OF GUIDANCE

THE ECHOBRONCHOSCOPE

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Lung Cancer 2005; 50: 347-354

•105 patients: 163 lymph nodes sampled.•EBUS-TBNA:

Sensitivity: 94,6%Specificity: 100%Negative Predictive Value: 89,5%

•502 patients•EBUS-TBNA:

Sensitivity: 94% (regardless lymph node location or size)Specificity: 100%

REAL-TIME, ENDOBRONCHIAL ULTRASOUND GUIDED, TRANSBRONCHIAL

NEEDLE ASPIRATION: A NEW METHOD FOR SAMPLING MEDIASTINAL LYMPH NODES.

Herth FJ et alThorax 2006; 61:795-798

EFFECTIVENESS AND SAFETY OF ENDOBRONCHIAL ULTRASOUND-

TRANSBRONCHIAL NEEDLE ASPIRATION:A SYSTEMATIC REVIEW.

Varela-Lema et al ERJ 2009; 33:1156-1164

•Systematic review of 14 publications on EBUS-TBNA in lung cancer mediastinal staging

•Sensitivity: 85-100%•Specificity: 100%

•None of the studies reported serious complications

Ernst A et al. J Thorac Oncol 2008

•Current restaging modalities either have a low diagnostic accuracy (CT) or can be technically difficult (Re-mediastinoscopy)

•123 pts. with NSCLC (N2, IIIA stage), treated with induction chemotherapy, showing partial response or stable disease.

•EBUS-TBNA for restaging:Sensitivity: 76%Specificity: 100%Diagnostic accuracy: 77%

EBUS-TBNA FOR MEDIASTINAL RESTAGING AFTER INDUCTION CHEMOTHERAPY FOR NSCLC

Herth FJ et alChest 2007; 466s

•100 pts. with NSCLC showing no enlarged lymph nodes (CT) and a negative PET finding of the mediastinum

•156 lymph nodes (5-10 mm) were detected and sampled

•Malignancy was detected in 9 pts (9%)

•EBUS-TBNA can be used to accurately sample and stage pts with no sign of mediastinal involvement

ENDOBRONCHIAL ULTRASOUND-GUIDEDTRANSBRONCHIAL NEEDLE ASPIRATION OF

LYMPH NODES IN THE RADIOLOGICALLY AND PET NORMAL MEDIASTINUM IN PATIENTS

WITH LUNG CANCERHerth FJ et al

Chest 2008; 133: 887-891

SHOULD WE USE EBUS-TBNA IN EVERY CASE?

CONVENTIONAL TBNA: STRONG POINTS

1) TBNA can and should be performed during thefirst routine bronchoscopy(that in any case must be done on patients suspected oflung cancer)

but routine diagnostic bronchoscopy can not be performed with an echobronchoscope…

2) Can be performed in every bronchoscopy service.No need for expensive technology

EBUS-TBNAITS USE COULD BE JUSTIFIED:

•FOR STATIONS 2R, 2L (where the trachea is a tube and has no landmarks);

•IN CASE OF SMALL LNs < 1 cm

•AT THE SECOND ATTEMPT, AFTER A NEGATIVE FIRST CONVENTIONAL BRONCHOSCOPY WITH TBNA

(more frequent in case of small LNs < 1 cm and for 4L station)

MINIMALLY INVASIVE ENDOSCOPIC STAGINGOF SUSPECTED LUNG CANCER

Wallace MB et alJAMA 2008; 299: 2510

•138 patients

•EBUS-TBNA Sensitivity: 69%

•EBUS-TBNA + EUS-FNA:Sensitivity: 93%NPV: 97%

•EBUS+EUS may allow near complete minimallyinvasive mediastinal staging

CT scan and/or PET positive for lymph nodes

LN not adjacent to airways (stations 5 and 6)

Lymph nodesadjacent to airways

Bronchoscopy TBNA

Cytologypositive

Cytologynegative

- Involvement just ofstations 2R and 2L

- Small size lymph nodes(< 1 cm)

EBUS-TBNAEUS-FNA (ln 8-9)

Surgicalprocedures

Surgicalprocedures

Cytologypositive

STAGINGCOMPLETE

Gasparini S. Clinical Lung Cancer 2006

HOW TO OPTIMIZE THE STAGING OF LUNG CANCER

What is the major complication of bronchoscopy?

Do not obtain the diagnosis!!!

Without TBNA, we miss 18-38% of diagnosis…(Harrow EM et al, Am J Respir Crit Care Med 2000; 161: 601-607

Patelli M et al, Ann Thorac Surg 2002; 73: 407-411)

TBNA is going to become the gold standard to evaluatethe mediastinal involvement in lung cancer

Without TBNA our bronchoscopy can not be optimal

Is it possible a good histotype classification with TBNA?

cytology vs. histology?

Squamo Adeno SLCL NSCLC(poor. diff)

TOTAL

Squamo 48 3 1 11 63

Adeno 4 86 6 96

SLCL 11 1 12

NSCLC(poor. diff)

2 2 18 22 (11.3%)

TOTAL 54 91 12 36 (18.6%)

193

His

tolo

gyCytology

Comparison between cytology and histology in 193 patients.S.Gasparini, M.Ferretti. Not published data.

Papanicolaou 100X

TTF-1 100X

ADENOCARCINOMA: primary vs. metastasis

Citologia, Ancona

Adenocarcinoma

Papanicolaou EGFR

Citologia, Ancona

Assessment of EGFR mutation by ultrasound-guidedtransbronchial needle aspirationNakajima T et al. Chest 2007; 132: 597-602

…but this is not enough……new knowledges in therapeutical field

make oncologists more demanding…

Analysis of cell cycle -related proteins in mediastinal lymph nodesof patients with N2-NSCLC obtained by EBUS-TBNA:

relavance to chemotherapy responseMohamed S et al. Thorax 2008; 63: 642-647

•Further analysis of tissue samples obtained by EBUS-TBNA suchas genetic analysis may help to direct patients with NSCLC todifferent molecular-based treatments.•The expression of six cell cycle-related proteins (pRb, cyclin D1, p16INK4A, p53, p21Waf1, Ki-67) in mediastinal lymph node specimens obtained by EBUS-TBNA was investigated by immunohistochemistry in 36 patients with pN2-NSCLC.•Immunostaining was feasible in all studied specimens.•P53 and p21Waf1 expressions were significantly related to the response to chemotherapy. Only p53 overexpression was associatedwith a poor response to chemotherapy.•EBUS-TBNA is a feasible tool for obtaining mediastinal nodaltissue samples amenable for immunohistochemical analysis.

Nuclear survivin in pN2 NSCLC: prognostic and clinical implicationMohamed S et al. ERJ 2008; published on line August 20, 2008

•Survivin is a member of the inhibitor of apoptosis family.

78 patients with N2-NSCLC.

•Patients’ group with combined negative survivin/single mediastinal

LN station were the most favorable prognostic group, especially in

non-squamous histopathology.

•Preoperative evaluation of survivin in EBUS-TBNA sample

in N2-NSCLC patients with single mediastinal LN station may

identify patients that are expected to have a favorale postoperative

prognosis and that may be candidates for primary resection.

Wrong problem:cytology vs. histology?

True problem:To have a good cytopathologist,

integrated in a team,that should know the needs of the clinicians and that should know the problems related

to the treatment of lung cancer

Thank you!s.gasparini@fastnet.it