I was reminded of the important topic of occult N2 NSCLC by a comprehensive review that just came out in the Journal of Thoracic Oncology (abstract here) by a friend, thoracic surgeon Frank Detterbeck, who leads the thoracic oncology program at Yale. To review the basics of lymph nodes for lung cancer, N0 means no lymph nodes are involved; N1 means that lymph nodes are involved on the same side as the primary cancer and inside the confines of the lung; N2 nodes are in the middle of the chest, in the mediastinum, which is between the lungs, and on the same side as the main cancer; N3 nodes are involved and on the other side of the mediastinum or above the clavicles. Lymph nodes beyond those points are M1, or metastatic sites, and would be treated as advanced lung cancer. Occult N2 disease is also sometimes called unsuspected or surprise N2 disease as well, and it refers to a surprise upstaging of patients who were thought to have stage I or II NSCLC before surgery, but after the operation, there's evidence that one or more mediastinal nodes are involved.

For NSCLC, one of the important aspects of staging in patients who don't have obvious stage IV disease is staging, which is done largely based on scans, but getting tissue from mediastinal lymph nodes is a controversial central feature. However, I think the controversial nature is whether it's definitely needed or recommended for patients who have what appears to be a stage I lung cancer (in whom the likelihood is so low it's not definitely needed), or who have imaging that is very, very consistent with cancer in the mediastinum (in whom the likelihood is so high it's not definitely needed). In between are many potential surgical candidates with larger stage I, or stage II, or not entirely clear but likely stage III NSCLC. In such patients, most well trained thoracic surgeons will try to get tissue with a mediastinoscopy (or other approach, like a transbronchial ultrasound or transesophageal ultrasound, both of which can sample mediastinal nodes) before surgery, because we know that outcomes are not good with surgery alone for such patients, and our standard is to give chemo or chemo/radiation before possibly proceeding with surgery. However, some surgeons don't do mediastinoscopies, even in cases with enlarged mediastinal nodes or other features that should suggest a high index of concern (you can't find a fever if you don't take a temperature). You'll never lose surgery business if you are willing to do surgery indiscriminately, on people who shouldn't as well as should have surgery. They may feel that surgery is the most important factor, so it's worth just pressing forward and dealing with the outcomes later. That's below the standard of care, but that's exactly what happens all too often, particularly when surgeons who aren't specially trained in thoracic surgery do lung cancer resections. What is worse, sometimes during the surgery, they don't bother going into the mediastinum to look for nodes (this can be done as a mediastinal dissection during the larger operation, if not as a separate mediastinoscopy procedure from the lower neck, going below the sternum (breastbone).

I'll just emphasize that selection of a well trained and careful thoracic surgeon is extremely important in managing stage I - IIIA NSCLC. A poorly trained or just not motivated surgeon can do a remarkable disservice to a patient and sabotage their best opportunities for good results, and a well trained and thoughtful thoracic surgeon can maximize that. I say that as a non-surgeon. There should be a book on "When Bad Surgery Happens to Good People". However, even if patients are treated exactly by the book by a great surgeon or oncology team, sometimes you find unsuspected mediastinal disease at the time of the full surgery, even in patients whomay have had a negative mediastinoscopy (which is a sampling, not an exhaustive search for nodes) before surgery.

Dr. Detterbeck's review is very heavy on tables and data, but there are a few take home points. First, there's a difference between a surprise N2 patient who had small mediastinal nodes and a negative mediastinoscopy and a patient who had enlarged mediastinal nodes that the surgeon just didn't bother to check before surgery. Dr. Detterbeck makes the point that the patients who should be considered high suspicion but have surgeons who don't look aren't really "surprise N2" as much as "ignored N2". Patients with ignored N2 disease are more likely to leave cancer behind, which is associated with very poor outcomes. They're also more likely to be the patients with several levels of nodal involvement, who many experts argue should receive chemo and radiation without planned surgery, or at least a plan of chemo or chemoradiation and then assessment of the mediastinum before deciding on whether surgery is appropriate after that.

On the other hand, patients who have had good pre-operative staging and are found to have a true surprise node involved have a far better prognosis than that. Long-term survival (i.e., cures) are typically in the 20-30% range, perhaps even higher. This may not sound great, but it's much better than results when surgeons just press on, leave cancer behind, and/or do surgery in patients with multiple mediastinal areas involved with cancer.

So what do you do for a patient who didn't have pre-operative chemo and has one or more N2 lymph nodes found at surgery? There isn't a clear standard, but recommending chemo is certainly appropriate. Some of the patients in the European trials of post-operative chemo had N2 nodal involvement, and there's a significant benefit from chemo in those high-risk patients. The benefits of post-operative chemo are proportional to the risk of recurrence (how much room for gain is there?), so you'd want to recommend chemo in any patient for who that's remotely feasible. I and many other experts prefer cisplatin-based combination chemo, but may in plenty of patients who have just undergone a big lung surgery, that may not be possible. You do what you can.

For post-operative radiation, most experts feel that if there's ever a patient who should get adjuvant radiation, it's someone with mediastinal nodes involved (see prior post for detailed discussion). If you're inclined to do that, the issue of timing chemo and radiation comes up. I've described that murky mess in a prior post as well, and it remains unresolved. My thinking is that most patients who aren't in remarkable shape after major lung surgery are going to have a very hard time doing chemo and radiation concurrently, which is plenty hard even for people who aren't recovering from a lobectomy or pneumonectomy. Because of that, I'd recommend adjuvant concurren chemoradiation only for the fittest of the fit, and otherwise I'd recommend sequential chemo and radiation for the clear majority of mere mortals who aren't in serious training for a marathon. Which first? I'd prioritize the chemo before radiation, because the chemo is the modality with the clearly established survival benefit, so I'd rather get that in and then consider radiation the icing on the cake. The alternative of leading with radiation leaves a greater chance of some intervening problem that will keep a patient from getting the chemo that is a clear standard for high risk post-operative NSCLC patients. Plus, the issue of N2 nodal involvement is largely that it suggests a higher chance of progressing distantly, which is combated by chemo and not another local treatment like radiation after surgery.

Overall, surprise N2 disease is something we should be seeing less and less of, now that PET scans can detect so much of what would have been a surprise 10 years ago, and newer techniques like endobronchial ultrasound (EBUS) and esophageal ultrasound (EUS) provide new ways to get to mediastinal nodes. While this can happen rarely in the best managed cases, patients will continue be understaged as long as medical teams ignore the opportunity to get good pre-operative staging. It's very important for the patient community to know how variable surgical practice is in the real world, and to ensure that they're seeing someone prioritizing optimal patient care over optimal surgical revenue. The best surgeons know when surgery shouldn't be performed and work to clarify which patients are best served by an operation.