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  In this article
 »  Abstract
 » Introduction
 »  Contrast Enhance...
 »  Magnetic Resonan...
 »  Positron Emissio...
 »  Endoscopic Metho...
 » Mediastinoscopy
 » Surgical Staging
 »  Preoperative Sta...
 »  Is Accurate Stag...
 »  Concerns About N...
 »  Our Policy of Me...
 » Conclusion
 »  References
 »  Article Figures

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REVIEW ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 68-72
 

Mediastinal staging for non-small cell lung cancer revisited. It is being done under aegis of ICON and Lung cancer consortium asia


1 Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. D Pandey
Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.219579

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 » Abstract 

Mediastinal staging is a crucial factor in the decision making in patients with non-metastatic non-small cell lung cancer (NSCLC). Mediastinoscopy has historically been the gold standard for this purpose. With the advent of PET-CT, the role of an invasive staging modality like mediastinoscopy has been diminishing. Newer developments in endoscopic staging like EBUS and EUS-FNA have also provided means to get a cytological diagnosis of enlarged lymph nodes. With the meta-analyses showing encouraging results of neoadjuvant chemotherapy in operable lung cancers including the early stage disease, the sanctity of invasive mediastinal staging for the sole purpose for selecting patients for upfront surgery is debatable. This article discusses the various modalities for mediastinal staging in NSCLC. We also present our perspective regarding the need for a balanced approach between the accuracy of mediastinal staging, invasiveness of the staging modalities, and alternate staging methods. With the liberal use of neoadjuvant chemotherapy in operable NSCLC, the role of invasive mediastinal staging procedures is likely to get limited further, giving way to non-invasive staging modalities like PET-CT.


Keywords: Mediastinal staging, PET CT scan, Mediastinoscopy, non-small cell lung cancer


How to cite this article:
Pandey D, Ramanathan P, Pandey R, Prabhash K. Mediastinal staging for non-small cell lung cancer revisited. It is being done under aegis of ICON and Lung cancer consortium asia. Indian J Cancer 2017;54:68-72

How to cite this URL:
Pandey D, Ramanathan P, Pandey R, Prabhash K. Mediastinal staging for non-small cell lung cancer revisited. It is being done under aegis of ICON and Lung cancer consortium asia. Indian J Cancer [serial online] 2017 [cited 2020 Mar 29];54:68-72. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/68/219579



 » Introduction Top


Lung cancer is the most common cause of death from cancer worldwide, estimated to be responsible for nearly one in five (1.59 million deaths annually, 19.4% of the total).[1] Approximately 80% of newly diagnosed lung cancers are non-small cell lung cancer (NSCLC). At the time of diagnosis approximately 43% of patients who are suffering from NSCLC are locally advanced.[2]

In a nonmetastatic NSCLC, mediastinal staging is the most crucial factor for decision making. A patient with an otherwise resectable primary (T1-3) and nonmetastatic mediastinal nodes (N0-1) would be generally subjected to surgery. Patients with supraclavicular or contralateral mediastinal lymph node metastases (N3 disease) would not be candidates for surgery and would be offered definitive chemoradiation or palliative chemotherapy. In patients with metastasis to ipsilateral mediastinal lymph nodes (N2 disease), surgery would not be considered upfront and such patients would be subjected either to neoadjuvant chemotherapy or definitive chemoradiation.

Because of the impact of mediastinal nodes on the decision making process for NSCLC, various methods have been used to arrive at an accurate staging of the mediastinum. In this article, we shall review the various methods used for mediastinal staging with special reference to positron emission tomography-computed tomography (PET-CT) and mediastinoscopy. We shall also present our algorithm for mediastinal staging in the light of growing evidence of neoadjuvant chemotherapy for the treatment of NSCLC.


 » Contrast Enhanced Computed Tomography of the Thorax Top


Contrast enhanced computed tomography of the thorax is the initial baseline investigation for the staging of lung cancer. Most common criteria accepted throughout for mediastinal lymphadenopathy is the enlargement of mediastinal lymph nodes >1 cm in short-axis diameter. Other criteria which have been practiced but not popular are (a) long-axis diameter ≥1 cm, (b) short-axis diameter ≥1.5 cm; (c) short-axis diameter ≥1 cm plus evidence of central necrosis or disruption of the capsule; and (d) short-axis diameter ≥2 cm regardless of nodal morphology. Out of 7368 patients from combined studies the median prevalence of mediastinal metastasis was only 30%, median sensitivity and specificity of CT scan in detecting the mediastinal nodal metastasis were 55% and 81% respectively.[3]

Volterrani et al.[4] described multi criteria approach in detection of N2 disease by CT scan and showed better results. The sensitivity, specificity, positive and negative predictive values, and accuracy of this multi criteria were 100%, 98.5%, 100%, 94.4% and 98.8% respectively, whereas using the size criterion alone 64%, 61%, 87%, 40%, and 62% respectively. Multi criteria included location, size (modified for stations 4R/L, 5 and 7 from 10 to 9 mm, from 9 to 8 mm, and from 11 to 12 mm respectively), structure (includes central hypodensity and calcification), and enhancement pattern.


 » Magnetic Resonance Imaging of the Thorax Top


Magnetic resonance imaging (MRI) is more helpful than CT in detecting mediastinal invasion, superior sulcus tumors, chest wall, diaphragm, brachial plexus or vertebral involvement. Although diffusion-weighted MRI has shown promise for mediastinal nodal staging,[5] it is not a routine imaging performed for lung cancer.


 » Positron Emission Tomography-Computed Tomography Top


Positron emission tomography is a functional imaging with poor spatial resolution. This helps not only in diagnosing the tumor but also in detecting metastases, predicts biological aggressiveness of tumor and gives information regarding response to treatment. Dual time PET-CT or “integrated PET-CT” is superior to PET scan alone.[6],[7] Its ability to detect metastases at distant sites as well as mediastinal nodes makes it a preferred staging investigation. In a meta-analysis comparing PET and CT for mediastinal staging in lung cancer, the median sensitivity and specificity of PET scan were 85% and 90% respectively.[8] In the same meta-analysis, it was shown that PET was more sensitive but less specific when CT showed enlarged lymph nodes (median sensitivity 100%, median specificity 78%) than when CT showed no lymph node enlargement (median sensitivity 82%, median specificity 93%). False negative rates seen in PET without integrated CT, excess delay between the scan and surgery, low uptake tumors (like adenocarcinoma in situ, well differentiated adenocarcinoma, typical carcinoid), central tumor location, hot spot effect (inability to differentiate between mediastinal lymph node from central tumors), young females and current smokers.[9] An maximum standardized uptake value (SUVmax) of 2.5 or more in mediastinal lymph nodes is considered to be an indicator of metastatic node,[10] although there have been suggestions to increase the SUVmax cut-off in regions that are endemic for granulomatous and nonspecific inflammations.[11] There may be 15–20% variation in rate of the SUVmax between different PET centres for primary lung cancers. To compare different PET centres either PET predictive ratio (PPR) or ratio SUVmax are used. PPR is defined as the ratio of the SUV of the lymph node max to that of the primary tumor (cut-off value to predict malignancy >0.49) and ratio SUVmax as ratio of the optimum SUVmax cut-off of the lymph nodes to the median SUVmax of the primary tumor.[12],[13]


 » Endoscopic Methods (Endoscopic Ultrasound and Endobronchial Ultrasound) Top


Endoscopy is performed using echoendoscope providing better evaluation of mediastinal nodes either through esophageal route (endoscopic ultrasound [EUS]) or through bronchial route (endobronchial ultrasound [EBUS]). Depth of 3 mm to 8 cm from transducer can be analyzed. EUS can evaluate inferior pulmonary ligament and the esophageal, subcarinal, and aorto-pulmonary window nodes (stations 9, 8, 7, 4L, 5) with a median sensitivity of 89% and median specificity of 100%. Other advantages of EUS are in evaluation of mediastinal invasion, metastases to liver, coeliac axis and adrenals. EUS needle aspiration is considered negative when three aspirations shows no evidence of malignancy.[3],[14] EBUS is helpful in the evaluation of paratracheal (station 2, 4), subcarinal (station 7) and distant nodes (station 10, 11) with a median sensitivity of 89%. Other advantages of EBUS are ability to measure the distance of the tumor from the carina, and to distinguish tumor infiltration of airway wall from external compression.[3],[14],[15] A new EBUS scoring system including shape, distinct margin, heterogeneous ultrasound pattern, absence of the central hilar structure, short-axis >1 cm and high blood flow in a LN (measured by colour power Doppler index) has better identification of mediastinal nodes and less invasive. Malignancy is suspected if the score is >2.[16] Combined EUS/EBUS helps near complete assessment of mediastinal nodes with a median sensitivity of 91% and specificity of 100%. Both procedures are possible at single sitting. Both can be combined with fine-needle aspiration (FNA) of the suspicious nodes to document metastases.


 » Mediastinoscopy Top


Mediastinoscopy is considered the gold standard for the mediastinal staging for lung cancer. A standard cervical mediastinoscopy is done through suprasternal incision under general anaesthesia. The highest mediastinal (station 1), upper paratracheal (station 2), prevascular and retrotracheal (station 3), lower paratracheal (station 4) and subcarinal (station 7) lymph nodes are accessible for direct palpation and biopsy using this technique. Ideally five nodal stations should be assessed (2R, 2L, 4R, 4L and 7) with at least one node from each station.[3] Extended cervical mediastinoscopy combines cervical mediastinoscopy with mediastinoscopic evaluation of the sub aortic space as a single procedure [17] and is thus useful in assessing station 5 and 6 nodes too. Station 5 and 6 lymph nodes can be better evaluated by anterior mediastinotomy (Chamberlain procedure) in which the surgeon can directly palpate and biopsy the nodes in extrapleural sub aortic space.[18] Despite all these endeavours, the paraesophageal (station 8) and pulmonary ligament (level 9) lymph nodes are inaccessible to mediastinoscopic evaluation.

In a review of >5500 mediastinoscopies, the overall sensitivity of standard cervical mediastinoscopy was 81% with a negative predictive value of 91%.[19] Extended cervical mediastinoscopy and Chamberlain procedure or anterior mediastinotomy can enhance the sensitivity of the standard cervical mediastinoscopy. Because this technique is coupled with biopsy of suspicious nodes, the specificity approaches 100%. However, it remains an invasive procedure with a potential of serious complications like bleeding, recurrent nerve injury, pneumothorax and arrhythmias. Nevertheless, the procedure is safe in expert hands with a mortality of 0–0.3% and morbidities of 1–3%.[20]


 » Surgical Staging Top


Surgical staging comprises video assisted thoracoscopic surgery (VATS), and thoracotomy. VATS has better assessment of all nodal stations but cannot assess the opposite mediastinum. Median sensitivity is 99% and specificity is 100%. Other advantages of VATS is determination of T4 and unexpected pleural metastases.[3],[21],[22],[23] Finally, a systematic mediastinal nodal sampling or dissection can be performed while performing a definitive surgery through thoracotomy or VATS. American College of Surgery Oncology Group (ACOSOG Z0030) showed no difference in morbidity and mortality between lymphadenectomy and lymph node sampling.[24] The Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) also recommend systemic lymph node dissection as the proper technique in assessing mediastinal nodes intra operatively.[25]


 » Preoperative Staging of the Mediastinum: Positron Emission Tomography-Computed Tomography Versus Mediastinoscopy Top


Two investigations that have the greatest promise in the evaluation of mediastinal nodes preoperatively are PET-CT and mediastinoscopy. PET-CT is now recommended as a routine staging work-up for NSCLC. Its ability to detect distant metastases in addition to stage the loco regional disease makes it a single most important staging investigation for this disease. Integration of PET with CT scan (PET-CT) has improved the ability to detect metastasis in normal sized lymph nodes but the problem of false-positive results remains. This problem is more pertinent in India where the granulomatous inflammations like active and healed tuberculosis are endemic and enlarged nodes with nonspecific inflammation are also common. Hence it has been recommended that suspicious mediastinal nodes on PET-CT be subjected to cytological or histological confirmation.

The endoscopic evaluation by EUS and EBUS in combination has a potential to map and stage nearly the entire mediastinum. These can be combined with FNA of suspicious nodes to document and confirm the nodal stations involved. These techniques are still under evolution and more experience and data are required before they can come into routine clinical practice as staging investigations for NSCLC.

Mediastinoscopy remains the gold standard for accurate mediastinal staging because of its 100% specificity. However, certain lymph nodal stations are inaccessible to conventional cervical mediastinoscopy. Lymph nodes in sub aortic and para-aortic regions (station 5 and 6), paraesophageal (station 8) and pulmonary ligament nodes (station 9) are inaccessible by a standard cervical mediastinoscopy. Extended cervical mediastinoscopy and anterior mediastinotomy (Chamberlain approach) would allow sub aortic and para-aortic nodes to be assessed.[17],[18] Addition of VATS can aid in the assessment of all the mediastinal nodes. However, VATS is more commonly performed just before the definitive surgery under the same anaesthesia. Thus it does not usually add any value to the preoperative staging of the mediastinum.


 » Is Accurate Staging of Mediastinal Nodes Absolutely Critical? Top


The question as to which investigation stages the mediastinum most accurately is not controversial. The addition of mediastinoscopy will obviously enhance the accuracy of mediastinal staging. The value of PET-CT remains undiminished because of its ability to detect distant metastases in addition to mediastinal staging. The real question is not which investigation stages the mediastinum best, but whether such an accurate staging of the mediastinum actually improves the outcome of the patients with NSCLC. If it doesn't, is it worth subjecting all the patients with nonmetastatic NSCLC to an invasive procedure under anaesthesia purely for the purpose of staging?

This line of thinking stems from the results of neoadjuvant chemotherapy in NSCLC. So far, the standard practice for T1-3 N0-1 disease is upfront surgery followed by adjuvant chemotherapy. Adjuvant chemotherapy can be avoided only in patients with T1-2a N0 disease after complete resection.[26] On the other hand, for any patient with N3 nodal metastases and in most with T4 lesions, the disease is considered unresectable and the patient is offered definitive chemoradiation. In the majority of patients with N2 nodal disease, the treatment protocol is either neoadjuvant chemotherapy followed by reassessment for surgery, or definitive chemoradiation. Our policy in these patients with N2 disease is neoadjuvant chemotherapy followed by surgery if the disease responds or remains stable on chemotherapy.

In a meta-analysis of 12 randomized controlled trials comparing preoperative chemotherapy followed by surgery and surgery-alone for operable patients with NSCLC, preoperative chemotherapy improved survival with a hazard ratio (HR) of 0.82 (95% confidence interval 0.69–0.97, P = 0.02). This was shown to be equivalent to an absolute benefit of 6%, improving 5-year overall survival across all stages from 14% to 20%.[27] In another more recent meta-analysis of 13 randomized controlled trials, neoadjuvant chemotherapy resulted in a significant improvement in overall survival of patients with NSCLC as compared to surgery-alone arm (combined HR = 0.84, 95% confidence interval 0.75–0.95, P = 0.0001) in operable NSCLC patients.[28]

While the value of neoadjuvant chemotherapy in stage III NSCLC can be accepted without much debate, the moot point is whether the patients with early operable NSCLC also benefit from such an approach. Both the meta-analyses cited above included operable patients across all stages and demonstrated a significant survival benefit. It may be debated that there has been no head-to-head comparison between neoadjuvant and adjuvant chemotherapy for NSCLC. Nevertheless, the magnitude of benefit of neoadjuvant chemotherapy is compares favourably to that of adjuvant chemotherapy for this disease. The International Adjuvant Lung Cancer Trial that studied 1867 patients with stages I to III NSCLC showed a survival benefit in patients assigned to adjuvant chemotherapy as compared to surgery-alone arm (5-year overall survival 44.5% vs. 40.4%, HR for death 0.86, 95% confidence interval 0.76–0.98, P < 0.03).[29] When we are faced with a situation in which the magnitudes of benefit of neoadjuvant and adjuvant chemotherapy are similar, there seems to be no scientific basis for preferring one over the other. The only patients who can certainly be spared of chemotherapy in lung cancer are those with T1N0 and low-risk T2a N0 disease. These patients can be identified based on noninvasive PET-CT quite accurately.

A rather common scenario in NSCLC is when PET-CT identifies mediastinal lymphadenopathy without any distant metastasis. If there are bulky nodes at multiple N2 stations or nodes at N3 stations, such nodes should be biopsied either under image-guidance or with mediastinoscopy. Such patients are not amenable to upfront surgery and would be offered either neoadjuvant chemotherapy or more commonly, definitive chemoradiation. However, in patients who are identified to have limited N2 disease on PET-CT, there is a problem in decision making. Conventional teaching suggests that these patients should have mediastinoscopy for accurate staging of the mediastinum because of the problem of false-positive mediastinal lymphadenopathy on PET-CT. The patients who are shown not to have N2 disease are operated upfront and those in whom N2 disease is proven undergo neoadjuvant chemotherapy. It is in these patients that our argument is to give neoadjuvant chemotherapy regardless of the actual status of N2 station nodes. These patients would anyway require adjuvant chemotherapy if operated upfront and thus the question is simply about the timing of chemotherapy and not its necessity. The scientific basis and practical benefits of neoadjuvant chemotherapy in operable cancers have been seen in other solid tumors like cancer of breast and rectum.


 » Concerns About Neoadjuvant Chemotherapy for Fluorodeoxyglucose-Avid but Potentially False-Positive Mediastinal Nodes Top


There may be certain theoretical issues that can be raised against advocating for neoadjuvant approach in patients who have fluorodeoxyglucose-avid N2 nodes that may not actually harbour metastasis.

  • Some of these patients may not require chemotherapy in adjuvant setting and thus these patients may be over treated. The response to this concern is that PET-CT can select quite accurately patients with very early disease (T1N0 and T2aN0) who would not need chemotherapy and they should be offered upfront surgery. All other patients will require chemotherapy in addition to surgery, and the argument is about the timing of chemotherapy, not its necessity
  • Neoadjuvant chemotherapy can lead to delay in surgery and the disease may become advanced in such time. This argument has been discussed in several other solid tumors. Majority of patients will either have a partial response or stable disease on neoadjuvant chemotherapy.[30] Progression of disease on chemotherapy indicates an aggressive biology of the disease and surgery, if performed upfront, would also be futile in these few patients [31]
  • The complications of chemotherapy may lead to delay in surgery or may even make the patient unfit for a definitive surgery. Advances in chemotherapy regimens and supportive care have made this scenario rather uncommon. The commonest chemotherapy regime used in neoadjuvant approach in NSCLC is a combination of paclitaxel and carboplatin; this is a very well-tolerated regime.



 » Our Policy of Mediastinal Staging Top


Based on the arguments explained above, our policy is to stage the mediastinum using PET-CT. The patients with T1-3, N0-1 disease on PET-CT are offered upfront surgery. All patients with N2 disease with an otherwise operable primary lesion are offered neoadjuvant chemotherapy. We are very liberal in offering neoadjuvant chemotherapy and we do not routinely try to confirm the N2 disease by histological or cytological techniques. Mediastinoscopy is not practised as a routine staging work-up for NSCLC as we believe that this can be avoided based on our arguments for a liberal use of neoadjuvant chemotherapy. Mediastinoscopy still has a place in suspected N3 disease on PET-CT when the enlarged node in N3 station is not amenable to image-guided biopsy. Another situation where mediastinoscopy would be of value is when a patient has a small primary tumor (T1/2a) with FDG-avid N2 station node on PET-CT. If the N2 station node in this situation is non-metastatic, this patient may be spared chemotherapy (neoadjuvant or adjuvant) and proceeded with definitive surgery. Our algorithm for the management of NSCLC is summarized in [Figure 1].
Figure 1: Our algorithm for management of NSCLC

Click here to view



 » Conclusion Top


Although mediastinoscopy remains the gold standard for accurate staging of mediastinal nodes, it is an invasive investigation for staging without any therapeutic benefit. Recent advances in neoadjuvant chemotherapy for NSCLC suggest that this may be a reasonable option in patients with suspected N2 disease on PET-CT without histological proof metastasis in these nodes. Avoidance of routine mediastinoscopy makes the staging work-up and management protocol of NSCLC easier without compromising the overall oncological outcome.

 
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