Lung cancer staging DR KOMALDEEP JUNIOR RESIDENT PULMONARY

Lung cancer staging DR. KOMALDEEP JUNIOR RESIDENT PULMONARY MED TBHP

Causes and Risk factors of Lung Cancer

diagnosis

Definition of Clinical Stage The extent of disease that can be determined from history and physical examination, biopsy procedure, imaging studies, endoscopy, and exploration prior to initial treatment.

Importance : Why do we need Clinical Staging? To aid the clinician in the planning of treatment. To give some indication of prognosis. To assist in evaluation of the results of treatment. To facilitate the exchange of information between treatment centres. To contribute to the continuing investigation of human cancer.

CLINICAL STAGING Pre-treatment PATHOLOGICAL • based on findings gathered by the doctor by non-invasive or minimally invasive techniques like physical exam, radiological exam, endoscopic ultrasound, bronchoscopy, mediastinoscopy and thoracoscopy. • Based on the examination of the tissue samples obtained from the primary tumor, nodes or metastasis • used to plan the initial therapy • may be modified by additional information found during pathological examination Post-treatment • Helpful in planning additional treatment and follow-up

CLASSIFICATION DATA SOURCE Clinical (pretreatment) (c. TNM) symptoms, physical examination, imaging, endoscopy; biopsy; surgical exploration without resection etc Pathologic (p. TNM) surgical resection and pathology Post therapy (yc. TNM or yp. TNM) after systemic or radiation before surgery or as primary therapy denoted with a yc (clinical) or yp (pathologic) Retreatment (r. TNM) at time of retreatment for recurrence or progression Autopsy (a. TNM) as determined at autopsy

Staging and grading stage grade Cancer stage refers to the size and/or extent (reach) of the original (primary) tumor and whether or not cancer cells have spread in the body. Tumor grade is the description of a tumor based on how abnormal the tumor cells and the tumor tissue look under a microscope. It is an indicator of how quickly a tumor is likely to grow and spread.

Dr. Pierre Denoix, a surgical oncologist (Institut Gustave-Roussy in Paris) analyzed a series of papers published between 1943 and 1952. Published by the International Union Against Cancer (UICC) in 1968 The second “international” recommendation came in 1974 with the support of the American Joint Committee on Cancer (AJCC). 6 th edition in 1997; 5, 319 cases; USA, published in 2002. 7 the edition; 100, 869 patients; 46 sources in 19 countries-, 81, 015 were eligible for inclusion. 7 th edition took effect on january 1 st , 2010. 1 1977 1978– 1983 2 1983 1984– 1988 3 1988 1989– 1992 4 1992 1993– 1997 5 1997 1998– 2002 6 2002 2003– 2009 7 20 o 9 2010 -

History of staging of sclc According to veterans administration lung study group: 2 stages of SCLC. Limited stage disease LD SCLC: Confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes. Extensive stage disease ED-SCLC: Any disease not meeting limited stage criteria and with Distant metastasis The international association for the study of lung cancer (IASLC) revised the VALG classification in accordance with the TNM system. LD definition is consistent with stages I to IIIb ED is limited to patients with distant metastasis.

TNM Staging system for Lung Cancer T= Tumor : size or contiguous extension of the primary tumor N= Node : the absence, or presence and extent of cancer in the regional draining lymph nodes. M= Metastasis : the absence or presence of distant spread or metastases involvement in organs and tissues “We’re all in the same game; just different levels, Dealing with the same hell; just different devils. ”

Descriptor Definition subgroups T 0 No evidence of primary tumour T 1 Tumour <3 cm, in the greatest dimension surrounded by lung or visceral pleura, not proximal than the lobar bronchus Tumour </= 2 cm in greatest dimension Tumour >2 cm but </=3 cm in the greatest dimension T 1 a T 1 b T 2 Tumor >3 cm but <7 cm or Tumor with any of the following features: Involves main bronchus >2 cm distal to carina Invades visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung. T 2 a : >3 but <5 cm T 2 b: >5 but <7 cm T 2 a T 2 b T 3 Tumour >7 cm or directly invading chest wall, diaphragm, phrenic nerve, mediastinal pleura or patietal pericardium Tumour in the main bronchus <2 cm distal to carina Atelectasis/obstructive pneumonitis of the entire lung Separate tumour nodules in the same lobe

T 1 tumor Tumor <3 cm diameter Surrounded by lung or visceral pleura Without invasion of more proximal than lobar bronchus. T 1 a: <2 cm T 1 b: >2 cm but <3 cm

T 2 Tumor >3 cm but <7 cm or Tumor with any of the following features: Involves main bronchus >2 cm distal to carina Invades visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung. T 2 a : >3 but <5 cm T 2 b: >5 but <7 cm

T 3 tumor Tumour >7 cm with : directly invading chest wall, diaphragm, phrenic nerve, mediastinal pleura or patietal pericardium Tumour in the main bronchus <2 cm distal to carina without involvement of carina. Atelectasis/obstructive pneumonitis of the entire lung Separate tumour nodules in the same lobe

T 4 tumor Tumour of any size with invasion of : Heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body Or carina Or separate tumour nodules in a different ipsilateral lobe

Regional lymph nodes (N) descriptor definition N 0 No regional lymph node metastasis N 1 Metastasis in ipsilateral peribronchial and/or perihilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N 2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes N 3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph nodes

N 0 & n 1 Metastasis in ipsilateral peribronchial and/or perihilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N 1 means at least stage IIa

n 2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes N 2 means at least stage IIIa

n 3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph nodes N 3 means at least stage IIIb N 3 -nodes are clearly unresectable.

Distant metastasis descriptor definition M 0 No distant metastasis M 1 a Separate tumour nodules in a contralateral lobe or tumour with pleural nodules or malignant pleural effusion M 1 a contr nod Distant metastasis in extrathoracic organs M 1 b subgroups M 1 a pl dissem

m 1 M 1 a : Separate tumour nodules in a contralateral lobe Or Tumour with pleural nodules or malignant pleural effusion. M 1 b: Distant metastasis in extrathoracic organs

Special situations descriptor definition subgroups Tx, Nx, Mx T, N or M status cannot be assessed Tis Focus of in situ cancer Tis T 1 Superficial spreading of tumour of any size but confined to the wall of the trachea or main stem bronchus T 1 ss

GENERAL RULES: All cases should be confirmed microscopically. Two classifications are described for each site: Clinical classification AND Pathological classification After assigning T, N and M and/or p. T, p. N and p. M categories, these may be grouped into stages. The TNM classification and stage grouping, once established, must remain unchanged in the medical records. If there is doubt concerning the correct T, N or M category to which a particular case should be allotted, then the lower (i. e. , less advanced) category should be chosen. In the case of multiple simultaneous tumours in one organ, the tumour with the highest T category should be classified and the multiplicity or the number of tumours should be indicated in parentheses.

TNM Groupings A tumour with four degrees of T, three degrees of N, and two degrees of M will have 24 TNM categories T, N, and M are grouped into so-called anatomic stage/prognostic groups , commonly referred to as stage groups. Groups are classified by Roman numerals from I to IV with increasing severity of disease. Stage I generally denotes cancers that are smaller or less deeply invasive with negative nodes Stage II and III define cases with increasing tumor or nodal extent Stage IV identifies those who present with distant metastases (M 1) at diagnosis. In addition, the term Stage 0 is used to denote carcinoma in situ with no metastatic potential. Stage 0 is almost always determined by pathologic examination.

stage grouping : "shorthand notation"

Stage I Non-Small Cell Lung Cancer is found only in the lung Surgical removal recommended Radiation therapy and/or chemotherapy may also be used “If you don’t look at the lymph nodes, everyone has stage 1 disease”

Stage II Non-Small Cell Lung Cancer The cancer has spread to lymph nodes in the lung Treatment is surgery to remove the tumor and nearby lymph nodes Chemotherapy recommended; radiation therapy sometimes given after chemotherapy

Stage III Non-Small Cell Lung Cancer The cancer has spread to the lymph nodes located in the center of the chest, outside the lung Stage IIIA cancer has spread to lymph nodes in the chest, on the same side where the cancer originated Stage IIIB cancer has spread to lymph nodes on the opposite side of the chest, under the collarbone, or the pleura (lining of the chest cavity) Surgery or radiation therapy with chemotherapy recommended for stage IIIA Chemotherapy and sometimes radiation therapy recommended for stage IIIB

Stage IV Non-Small Cell Lung Cancer The cancer has spread to different lobes of the lung or to other organs, such as the brain, bones, and liver Stage IV non-small cell lung cancer is treated with chemotherapy

Limitations of new classification No data at all being included from Africa, South America or the Indian subcontinent. Russia, China, and Indonesia are not represented or only poorly represented. The database used for the 7 th edition predates the widespread and routine use of PET which has had an enormous impact on clinical staging algorithms. Lympahngitis carcinomatosis is believed to be associated with worse prognosis in lung cancer patients. However, there is no evidence to support this. The new TNM classification does not specifically take account of lymphangitis.

OTHER CLASSIFICATION Ann Arbour lymphomas Duke’s classification colon cancer Breslow scale and Clark’s level melanoma

MEDIASTINAL STAGING Determining the involvement of the mediastinal lymph nodes. Mediastinal lymph nodes status and the presence or absence of direct tumor mediastinal invasion will determine the eligibility of the patient to treatment with intention to cure (surgical treatment) or a palliative care intending to prolong life and better quality of life.

A Brief History Naruke et al proposed the 1 st lymph node map in the 1960 s The Next 30 years: Mountain system proposed in 1973(2, 155 patients) : The Mountain Era Revised in 1997(5, 319 patients) The IASLC Staging System: Performed by the International Association for the Study of Lung Cancer

IASLC lymph node map 2009 Supraclavicular nodes 1 Superior Mediastinal Nodes 2 -4 2 r 2 l right and left upper paratracheal 3 a 3 p : prevascular and prevertebral 4 r 4 l: right and left lower paratracheal Aortic Nodes 5 -6 5: subaortic 6: paraaortic Inferior Mediastinal Nodes 7 -9 7: subcarinal 8: paraesophageal 9: pulmonary ligament Hilar, Lobar and (sub)segmental Nodes 10 -14 10: hilar 11: interlobar 12: lobar 13: segmental 14: subsegmental

American Thoracic Society mapping scheme. Supraclavicular zone (1) Superior Mediastinal Nodes (2 -4) 2. Upper Paratracheal 3 A. Pre-vascular 3 P. Pre-vertebral 4. Lower Paratracheal Aortic Nodes (5 -6) 5. Subaortic 6. Para-aortic Inferior Mediastinal Nodes (7 -9) 7. Subcarinal. 8. Paraesophageal (below carina). 9. Pulmonary Ligament Hilar, Interlobar, Lobar, Segmental and Subsegmental Nodes (10 -14)

Non- invasive Chest radiography Mediastinoscopy : GOLD STANDARD Computed tomography Video Assisted Thoracic Surgery PET scan Anterior Mediastinotomy (Chamberlain procedure; MRI Endobronchial Ultrasound with Fine Needle Aspiration (EBUS-FNA) Endoscopic Ultrasound with Fine Needle Aspiration(EUS-FNA) Transbronchial Fine Needle Aspiration (TBNA-FNA)

CHEST RADIOGRAPHY In certain situations, the plain film may be sufficient to detect spread to the mediastinum. For example, the presence of bulky lymphadenopathy in the superior or contralateral mediastinal areas may be considered adequate evidence of metastatic disease. Can detect pleural effusions that obliterate costophrenic recesses and lung nodules larger than 7 mm. Every patient suspected of having lung neoplasm must have a posterior-anterior and lateral chest radiograph Still, most patients should undergo CT scan of the chest unless they are so debilitated that no further evaluation or treatment is planned.

COMPUTED TOMOGRAPHY OF THE CHEST The lung lesion itself is more specifically evaluated by CT scan, characteristics of the primary mass (i. e. , smooth bordered, spiculated, calcified, etc. ), the limits of the lesion are better assessed and the rest of lung parenchyma may be screened for additional lesions. Routine chest CT may also evaluate the presence of distant metastasis to the liver, adrenals or bones, which are some of the commonest sites of metastatic disease. The bony structures of the thoracic cavity can also be evaluated by chest CT.

POSITRON EMISSION TOMOGRAPHY This imaging modality is based on the biologic activity of neoplastic cells. PET is better used in conjunction to CT (PET-CT) in which single machine incorporates CT and PET during the same scan. LIMITATIONS : Brain metastasis Inflammation: TB, fungal etc. Slow growing neoplasms: BAC, carcinoid tumour Size smaller than 7 mm

MRI There are very few circumstances in which magnetic resonance imaging (MRI) is a useful tool in staging lung cancer. Helps in evaluating limits and possible invasion in soft tissue, bone and vascular structures but, with new generations of multislice CT scans that are capable to perform three-dimensional angiotomography, MRI has diminished one of its main indications, which is to evaluate vascular and neural invasion in superior sulcus tumor. Its main use is to image the brain when suspecting of metastasis at this organ.

THE SEARCH FOR METASTATIC DISEASE To detect metastatic disease at common metastatic sites, such as the adrenal glands, liver, brain, and skeletal system, thereby sparing the patient fruitless surgical intervention. Computed tomography of the chest, CT or MRI with contrast of the brain, and 99 m. Tc nuclear imaging of the skeletal system, whole-body PET scans for extrathoracic staging. False-positive scans- Adrenal adenomas (present in 2% to 9% of the general population), hepatic cysts, degenerative joint disease, old fractures, and a variety of nonmetastatic space-occupying brain lesions are present in the general population. False-negative scans—that is, metastases are present but not picked up by current scanning techniques

Invasive Mediastinal Staging of Lung Cancer After distant metastasis has been ruled out, the mediastinal staging is the most important aspect to focus in these patients. The main purpose of the IMS is to differentiate: a) patients that will benefit from straight surgical resection b) patients that will benefit from neoadjuvant therapy, followed by surgical resection; c) patients who will not benefit from surgical resection, and should receive only chemo and/or radiotherapy. In general, patients with lung cancer may be divided in four categories, according to tomographic characteristics of the primary tumor and the mediastinum, regarding to size, location and extension of the disease (proposed by Dr. Frank Detterbeck and adopted by the American College of Chest Physicians Guidelines for Diagnosis and Management of Lung Cancer)

Group A: extensive mediastinal infiltration by the primary tumor. Group B: enlarged paratracheal lymph nodes. Group C: central tumor with normal-sized mediastinal lymph nodes. Group D: peripheral small tumor with normal-sized mediastinal lymph nodes.

Mediastinoscopy The procedure is done through a transverse cervical incision, with pretracheal dissection until the mediastinum and introduction of the mediastinoscope. It is possible to perform biopsies of the following lymph nodes: Pretracheal(1), Right and left high and low paratracheal (3, 2 R, 2 L, 4 R, 4 L), Subcarinal(7) The procedure may also be done with the videomediastinoscope, allowing a magnification of the operative field. Mediastinoscopy is the gold standard method to the invasive mediastinal staging, with which the other methods should be compared.

Video assisted thoracic surgery Better staging regarding the T descriptor, given we have the wide approach to the pleural cavity, making possible a better evaluation of pleural effusion, pleural metastatic disease, chest wall, diaphragm and vascular structures invasion. At the right side, paratracheal lymph nodes are relatively easily accessed, but left paratracheal lymph nodes are extremely difficult to be accessed by this method, due to the great vessel’s anatomy. VATS not a substitution but is a complementary procedure to the mediastinoscopy, especially when there is a left upper lobe tumor with enlarged lymph node station 5 and 6. Allows simultaneous resection of the tumour. Limitation: unilateral approach.

Anterior mediastinotomy (chamberlain procedure) A horizontal incision is done through second left intercostal space, and the aortic arch and left pulmonary artery are identified by palpation. Regarding to lung cancer staging, anterior mediastinotomy is used exclusively in selected patients with left upper lobe (LUL) tumor, aiming to evaluate lymph nodes at the aortopulmonary window (station 5) and preaortic (station 6). When there is cancer spread only to these stations, usually patients have a better prognosis and, if patients are fit, there are two possible treatements: 1) neoadjuvant therapy aiming to posterior pulmonary resection intending to cure; 2)surgical resection followed by adjuvant chemotherapy.

Endobronchial ultrasound with fine needle aspiration Accessible lymph nodes by this method are pretracheal (1), high and down right and left paratracheal (2 R, 2 L, 4 R. 4 L), and subcarinal(7). It may be used in substitution to mediastinoscopy, but, if the results are negative with the EBUS, the mediastinoscopy should be performed. There are many false negatives with EBUS, thus, if a high index of suspicion exists, a mediastinoscopy should be performed when EBUS was negative. Doppler feature allows for identification of vessels and landmarks for nodal stations.

Endoscopic ultrasound with fine needleaspiratio (EUSFNA) EUS is performed using an ultrasound transducer coupled with the flexible esophagoscope. This device guides the needle through the esophageal wall and allows the approach of lymph nodes in pulmonary ligament(9), paraesophageal(8), subcarinal(7) and aortopulmonary window(5). Additionally, EUS may be able to detect metastatic disease in sites as left adrenal gland, celiac lymph nodes and liver and also direct invasion to some mediastinal structures (T 4). The ideal procedure is when both (EUS & EBUS) methods are performed at the same session, with the patient under general anesthesia or sedation.

Transbronchial needle aspiration (TBNA) TBNA utilizes a standard flexible bronchoscope and a needle, known as Wang Needle through the scope. Its main indication is to evaluate enlarged subcarinal lymph nodes (station 7). Negativity of this test should prompt the mediastinal evaluation by other method, such as mediastinoscopy. Operator dependent. TBNA is safe and performed in an outpatient basis.

Thoracocentesis Aspiration and cytological examination of pleural fluid in patients presenting with suspected malignant pleural effusion provides a diagnostic yield of approximately 60%; the addition of needle pleural biopsy may raise the possibility of detecting cancer to 75%. The presence of neoplastic cells in the fluid excludes surgical treatment. Will be of help only if there is pleural involvement by the tumor. When there is no diagnosis of pleural fluid after thoracocentesis and the effusion is recurrent, one should perform a videothoracoscopy, which have a sensibility of 95% in detecting pleural metastasis (by pleural biopsy and fluid analysis), and also has the advantage of allowing to perform the pleurodesis at the same surgical procedure.

TTNA Transthoracic needle aspiration, usually under CT or fluoroscopic guidance, is an expedient and relatively safe way to diagnose the primary tumor mass and establish a diagnosis of lung cancer. As a general rule, if a lesion is less than 3 cm in size and lateral to the mid-clavicular line, bronchoscopy would not be the diagnostic procedure of choice. Transthoracic needle aspiration should be considered under such circumstances if tissue diagnosis is necessary.

Special Situations 1. Left upper lobe tumors Patients with left upper lobe (LUL) tumors deserve a special mention, because the lymphatic system drains preferentially to lymph nodes in the aortopulmonary window (station 5) and preaortic location (station 6). These nodes are rarely involved by tumors originating from other pulmonary lobes. The approach to station 5 and 6 must be done by anterior mediastinoscopy or videothoracoscopy, and choosing between these two methods must be individualized according to each patient

2. Pancoast tumor A Pancoast tumor is a tumor of the superior pulmonary sulcus characterized by pain due to invasion of the brachial plexus, Horner's syndrome and destruction of bone due to chest wall invasion. Pancoast tumors are staged at least as T 3, because there is almost always chest wall invasion. When there is ingrowth into a vertebral body or vital mediastinal structures, the tumor is staged as T 4. Ipsilateral supraclavicular nodes (N 3) (peritumoral lymph nodes) are potentially resectable with en bloc resection, while mediastinal nodes (N 2) are not. After histological diagnosis, if noninvasive staging points to the possibility of a pulmonary resection, the mediastinum must obligatory be invasive staged.

3. Invasive re-staging after neoadjuvant treatmen If previous IMS was positive, it is obligatory to repeat it, more commonly with the mediastinoscopy; If previous IMS was negative and the new CT and PET-CT show neither enlargement nor augmentation in the SUV when compared to the CT and PET-CT performed before the neoadjuvant therapy, it is not necessary to repeat the IMS; If previous IMS was negative, but the new CT and PETCT reveal mediastinal node enlargement and/or augmentation in SUV comparing to the CT and PET-CT performed before the neoadjuvant therapy, the IMS must be performed again, usually by mediastinoscopy. Finally, after neoadjuvant therapy, if N 2 or N 3 disease is detected in this second IMS, the patient will not benefit from surgical resection; if there is no N 2 or N 3 disease, the patient should have a pulmonary resection.

Conclusion : Staging matters!!! Lung cancer staging must have a simple and logical sequence. The only possible method to cure this neoplasm is by surgical resection, therefore a correct staging should be offered to every patient facing this disease. The most important point when evaluating a patient suspected of having lung cancer, refers to the oncological status of mediastinal lymph nodes, and its evaluation, by means of radiological examinations or invasive procedures, is the critical part for every patient. Every patient should start the investigation with a chest radiograph and chest CT with intravenous contrast. The clinician must be wary of abnormal scans that may falsely suggest metastatic disease to the mediastinum and distant sites

Conclusion : Staging matters!!! After this initial evaluation, the mediastinal evaluation should be complemented based on the size of mediastinal lymph nodes, the location and size of the lung lesion. Recently, PET-CT has been added to the investigation of every patient who is a potential candidate for pulmonary surgical resection. Tissue confirmation by whatever means necessary is the rule rather than the exception prior to deciding on correct stage and the most appropriate treatment. A detailed preoperative workup is essential to choose the most appropriate therapeutic plan to each patient, with best results regarding to possible cure, improvement of quality of life, rational use of medical resources and less morbidity and mortality.