A revised tumor classification based on 70,967 evaluable patients with non–small cell lung cancer (NSCLC) and 6,189 patients with small cell lung cancer is now available to lung cancer specialists around the world in the form of the 8th edition of the tumor, node, and metastasis (TNM) classification system.
All these changes require discipline from us. If we follow these rules, we will better classify lung cancers with multiple lesions.— Ramon Rami-Porta, MD
According to Ramon Rami-Porta, MD, a thoracic surgeon at Hospital Universitari Mutua Terrrassa in Terrassa, Spain, the innovations in the new version of the cancer staging system will help to refine prognosis and improve tumor stratification in future trials.
“These recommendations will certainly prompt research, especially in smaller tumors, for which we now have a variety of therapeutic possibilities,” he said at the 2016 World Conference on Lung Cancer,1 organized by the International Association for the Study of Lung Cancer (IASLC). “And hopefully these recommendations will facilitate homogeneous tumor classification and collection of prospective data, particularly for lung cancers with multiple lesions.”
In 1998, IASLC established its Lung Cancer Staging Project, which led to the development of an international lung cancer database that is periodically updated with the registration of new data. The new edition is published by the Union for International Cancer Control (UICC),2 the American Joint Committee on Cancer (AJCC),3 and IASLC4 in their respective staging manuals.
IASLC collected data not only for lung cancer, but also for mesothelioma and thymic tumors, so that the new TNM classifications for thoracic malignancies are based on large amounts of data. “This gives robustness to the 8th edition of the TNM classification for thoracic malignancies,” he noted.
The ‘T’ Component
Practice-changing modifications have been made to the “T” component of the classification, he said. More changes have been made regarding tumor size, and names have been given to tumors that were not previously defined.
Tumor size is now a much more relevant prognostic factor than in previous editions and is now a descriptor in all T categories. Therefore, tumor size measurement should be carefully performed, because small changes in size mean important changes in prognosis, he said.
Now, adenocarcinoma in situ—Tis(AIS)—and minimally invasive adenocarcinoma –T1mi—have their own coding in the TNM classification, and the smallest solid tumor has been redefined as T1a (≤1 cm in largest dimension).
“I think this is an important innovation in the 8th edition because it increases our awareness of the existence of these small tumors, and this may prompt changes in therapy and research,” he said. “New therapeutic options, such as stereotactic radiotherapy and radiofrequency ablation, can be studied in small tumors, but also importantly, we can study how tumor biology behaves in these small lesions.” According to Dr. Rami-Porta, not all small lesions are treated at the time of diagnosis, so growth, density, molecular profile, and genetic signatures of these tumors can be observed over time.
In part-solid tumors, only the solid/invasive part is taken into consideration when measuring tumor size. “More publications consistently show that the size of the solid component leads prognosis,” he said. Now, at computed tomography (CT) scan, the solid part of the tumor should be measured, and a pathologist should identify the invasive component under a microscope. “So this is an innovation that changes our practice, since we’re used to measuring the whole tumor size.”
Another important recommendation concerns the measurement of tumor size in clinical practice. It has been shown that measuring tumor size on the mediastinal window may underestimate the real tumor size, so the new staging manual recommends measuring tumor size based on the lung window on CT.
Visceral pleural invasion and its two categories (PL1: invasion beyond its elastic layer; and PL2: invasion of the pleural surface) have also been confirmed as important prognostic factors. “This is the minute anatomic location of the tumor,” said Dr. Rami-Porta. “The visceral pleura is hardly seen, and we surgeons who touch it don’t see it.”
The guidelines advise pathologists to intensively investigate visceral pleural invasion, and, if it is not evident by standard hematoxylin-and-eosin stains, elastic stains should be used. He referenced a study in which 100 tumors were thought to be stage I, but when elastic stains were used, the stage increased in nearly 20% because of visceral pleural involvement. “It’s important that pathologists know this,” he warned. “If there are no clear signs of visceral pleural involvement, use elastic stains to double-check.”
The ‘N’ Component
Although the revised staging system brings no changes to the “N” categories, analyses for the new edition have shown that quantification of nodal disease has prognostic implications. “The ‘N’ component is very easy,” he said. “We tried to quantify nodal disease; in the 7th edition we did it with nodal zones, and in the 8th we used nodal stations.”
There are five possibilities for quantifying nodal disease based on stations. The more nodal stations involved, the worse the prognosis, and the prognosis of tumors with involvement of multiple N1 stations has been found to be similar to that of tumors with single-station N2 disease without concomitant N1 disease (skip metastases).
The following factors weigh heavily in quantifying nodal disease: the number of involved lymph nodes, the number of involved nodal zones and stations, and the ratio between the number of involved nodes and the number of removed nodes. All these factors can be assessed at pathologic staging. Dr. Rami-Porta said findings for the 7th edition already raised the issue of indicating upfront resection in patients who had tumors with single–N2 zone involvement, because their prognosis was the same as that of tumors with multiple N1 zones, and the same question will be raised in light of research for the 8th edition.
In both cases, however, the quantification of nodal disease derived from pathologic staging of tumors that had been resected, and the resection had been accompanied by a properly performed systematic nodal dissection. This is difficult to replicate with clinical staging—the moment at which therapeutic decisions are made—unless a transcervical mediastinoscopic lymphadenectomy is performed.
Lymphadenectomy is the only preresection test that can define single-station or single-zone N2 disease reliably. “Nowadays, the means we have to determine nodal disease and to quantify clinical staging are imperfect unless we perform a transcervical lymphadenectomy. It’s the only way to try to quantify nodal disease at clinical staging,” he said. “This information is really useful in our clinical work because we can refine postoperative prognosis of those patients who undergo resection and are found to have nodal disease.”
The ‘M’ Component
With the updated staging system, there is no change to intrathoracic metastases (M1a), but single extrathoracic metastases have a better prognosis than multiple extrathoracic metastasis in one or several organs, and different categories have been defined for them: M1b for single and M1c for multiple extrathoracic metastases.
“Single extrathoracic metastases have been found to have the same prognosis as intrathoracic metastases, but we decided to keep them separate because TNM is pure anatomy, and there is a difference between intrathoracic and extrathoracic metastases,” he noted. “Treatments and diagnostic approaches differ.”
Dr. Rami-Porta said the subclassification of extrathoracic metastases will facilitate a more homogeneous definition of metastatic disease as well as oligometastatic and oligoprogressive disease, “which is quite loosely defined nowadays,” he said. “This will increase our capacity to prognosticate and also allow us to better stratify future clinical trials on advanced lung cancer.”
Some TNM subsets have moved from one stage to another, and new stages and substages have been created to accommodate groups of tumors with similar prognoses. The new staging system also provides a set of rules to classify lung cancers with multiple lesions in a homogeneous way.
According to Dr. Rami-Porta, the 8th edition of the TNM staging manual will help to refine prognosis both at clinical and pathologic staging and to stratify tumors in future clinical trials. However, the new classifications will require more attention to detail with regard to the precise measurement of tumor size, use of elastic stains to identify visceral pleural invasion, quantification of nodal disease, determination of number and location of metastases, and use of clinical judgment to indicate treatment.
“All these changes require discipline from us,” he said. “If we follow these rules, we will better classify lung cancers with multiple lesions.” ■
Disclosure: Dr. Rami-Porta reported no potential conflicts of interest.