Classification of lung adenocarcinoma and surgical perspective of lung cancer

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1. Individualized scope of lung parenchymal resection
Since the 1960s, regardless of tumor size, anatomical lobectomy has become the standard for surgical treatment of non-small cell lung cancer . However, the lung function of middle-aged and elderly people with frequent lung cancer is often limited. How to reduce trauma, narrow the scope of resection, and retain more lung function has always been the main theme of thoracic surgery. Thoracic surgery scholars gradually consider narrowing the scope of surgery after exploring the early surgical treatment of lung cancer in order to maximize both tumor resection and lung function preservation.
From the 1970s to the 1980s, with the development of imaging technology, several authors reported that more limited lung resection can achieve a similar effect to lobectomy in early non-small cell lung cancer (T1N0). This type of surgery is called limited resection. Limited resection is defined as a resection of less than one lobe, such as wedge resection of peripheral lung cancer or anatomical segmental resection ( segment resection).
Localized resection can theoretically retain more lung function, reduce the perioperative mortality and the incidence of complications, and the disadvantage is that it may increase the recurrence rate due to insufficient resection range and inability to completely clean N1 lymph nodes. The theoretical advantages and disadvantages of localized resection are obvious. Obviously, to answer this important question requires a randomized controlled clinical trial. As a result, a multi-center prospective randomized controlled clinical trial with far-reaching influence in the field of pulmonary surgery has begun.
The North American Lung Cancer Study Group (LCSG) LCSG821 study has 43 centers participating in a prospective randomized controlled clinical trial of surgery to identify localized resection for early treatment. Can NSCLC (peripheral type, T1 N0) replace lobectomy. The experiment took 6 years to enter the group since 1982, and the preliminary results were published from more than ten years ago to 1995.
Let ’s review the enrollment and operation criteria of the study: the enrolled patients had peripheral lung cancer with a clinical stage of T1N0 (on the posterior anterior chest radiograph, the longest diameter of the tumor was ≤3cm), but they were not seen through fiberoptic bronchoscopy To the tumor. A pneumonectomy requires the removal of more than two adjacent lung segments. Wedge resection of the lung requires the removal of normal lung tissue at least 2 cm from the tumor. The surgeon determines the size of the tumor after opening the chest.
Intraoperative frozen section examination includes lung segment, lung lobe, hilar, and mediastinal lymph nodes to determine whether it is N0 (if a pathological diagnosis is not obtained before surgery, an intraoperative frozen section diagnosis is required). A lymph node biopsy takes at least one lymph node from each group and sends it for frozen section. The surgeon also evaluated whether local resection was possible during the operation. After the resection of the lung lobe or lung segment and the sampling of all lymph node groups, the surgeon should confirm that the tumor has been completely removed by frozen section. If the staging is found to exceed T1 or N0, lobectomy should be performed immediately and judged to be unsuitable for enrollment.
Only after the above steps are determined to meet the enrollment requirements, the patients will enter the randomized group. The random group was confirmed by telephone during the operation by the research center. We can find that the design of the LCSG821 study is very strict even if it is placed today, so the design method of the study was followed by the design of subsequent randomized controlled clinical trials of related surgery.
The results of the study are disappointing: Compared with lobectomy, patients undergoing localized resection have a three-fold increase in local recurrence rate (wedge resection, three-fold increase, and segmental resection, 2.4-fold increase), and tumor-related deaths The rate has increased by 50%! In LCSG821, 25% (122/427) of patients with clinical stage I (T1N0) found a higher N stage during intraoperative lymph node biopsy, and the volume of local recurrence rate and tumor-related mortality in the three groups at the time of tumor diagnosis were similar. Moreover, unexpectedly, localized resection did not reduce the perioperative mortality, and besides FEV1, there was no advantage in long-term lung function!
The results of the LCSG821 study strongly support that lobectomy remains the gold standard for early resectable NSCLC. The higher local recurrence rate of localized resection suggests that the reason may be the residual micrometastasis of the lung lobes or the presence of N1 lymph node micrometastasis in the lung that cannot be completely removed by this procedure. In addition, chest radiographs may not be enough to find the multiple small nodules often found on CT. However, the LCSG was disbanded in 1989 because it was not funded by NCI, so the LCSG821 study was not able to publish the final detailed results. This is a regret left by the study.
In the 20 years since the publication of the research results, the conclusions of the LCSG821 study have not been vigorously challenged. But just in the past 20 years, the imaging diagnosis technology and histopathological classification research of lung cancer have developed rapidly. Combined with a retrospective case series report of a small sample, it is suggested that some special types of small lung cancer are only enough for limited lung resection.
For example, studies have shown that the probability of lymph node metastasis in patients with a tumor size of 3 to 10 mm is almost 0, while N2 lymph node metastasis of solid lung nodules > 2 cm can reach 12%. As a result, at the end of the first decade of the 21st century, a prospective multi-center phase III randomized controlled study of comparative localized pneumonectomy and lobectomy in North America and Asia was initiated. This time, they will challenge the conclusion of the LCSG821 study at a higher starting point.
In 2007, a multi-center prospective randomized controlled clinical trial CALGB 140503 in North America was launched. The study randomly divided patients with peripheral non-small cell lung cancer stage IA of ≤2 cm in diameter into lobectomy group and lung segment or wedge shape Resection group. 1258 patients are planned to be enrolled. The main observation indicators were tumor-free survival, and the secondary indicators were overall survival, local and systemic recurrence rate, lung function, and perioperative complications.
In 2009, Japan ’s multi-center prospective randomized controlled clinical trial JCOG0802 was initiated. The enrollment criteria was peripheral type IA non-small cell lung cancer with a tumor length of ≤2 cm. Patients were randomly divided into lobectomy group and segmentectomy group. , Plans to enroll 1100 patients. The primary endpoint was overall survival, and the secondary endpoints were progression-free survival, recurrence, and postoperative lung function.
The two new studies basically followed the design of the LCSG821 study, with similar inclusion criteria and surgical procedures. But these two new studies did not simply repeat the LCSG821 study, and they have new designs and higher standards for the shortcomings of LCSG821. First of all, in order to achieve sufficient statistical power, the group size is large More than 1000 cases, this is the sample size that can only be achieved by multi-center surgical clinical trials.
Second, both new studies require high-resolution enhanced CT, which can detect smaller multiple nodules compared to the LCSG821 chest radiograph. In addition, both new studies only included peripheral lung tumors ≤2 cm, excluding pure ground-glass opacity (GGO).
In the end, the patients included in the group all belong to T1a according to the 2009 stage of lung cancer, and the biological consistency of lung tumors is very high. Both studies plan to end enrollment by 2012, and all patients will be followed up for 5 years. With reference to the LCSG821 study, we may have to wait another five years, or even ten years, from the end of clinical trial enrollment to obtain preliminary results.
Limited to backward imaging techniques and insufficient understanding of the biological characteristics of early lung cancer , the LCSG821 study ultimately concluded that localized lung resection is inferior to lobectomy. Lobectomy is still the standard procedure for early non-small cell lung cancer curative surgery. Localized pneumonectomy is limited to compromised surgery and applies to elderly patients with insufficient lung function. Two new studies give us new expectations. The example of early breast cancer narrowing the scope of surgery makes us also look forward to the change of surgical methods in the near future of early lung cancer .
In order to make localized resection adequate tumor treatment, clear preoperative and intraoperative diagnosis is the key. The accuracy of frozen section analysis to determine whether small lung cancer has infiltrating components during surgery needs to be further improved. The predicted value of frozen section ranges from 93-100%, but not all articles explicitly report the accuracy of frozen section analysis.
There may be a problem with the evaluation of tumor margins from frozen sections, especially when automatic staples have been used on both sides. Attempts have been made to scrape or rinse the gutter, and subsequent cytological analysis. When performing sublobar resection, frozen section analysis of the interlobular, hilar, or other suspicious lymph nodes is helpful to assess the staging. When positive lymph nodes are found, as long as the patient has no cardiopulmonary function restrictions, lobectomy is recommended.
The design of clinical research controls is often aimed at the places where the positive and negative views collide most. From the design of the above clinical trials, we can see the main controversial focus and critical points of sublobar resection.
For the adenocarcinoma with diameter less than 2cm, the main component of GGO is JCOG 0804, and the solid component is less than 25%, which is equivalent to MIA with the largest infiltrating component of less than 0.5cm. The solid component is 25-100%, which is equivalent to LPA in invasive adenocarcinoma with an infiltrating component greater than 0.5 cm; CALGB 140503 does not specify the ratio of solid and GGO, and the enrolled population is mainly invasive adenocarcinoma.
Therefore, for the AAH and AIS lung cancer with better biological behavior in the JCOG 0804 group, the current mainstream views can be accepted for observation or sublobar resection, and there is no new evidence for the choice of MIA-LPA-ID surgery methods less than 2cm. At this time, it is not urgent to expand the clinical indications for localized resection, but it is possible to perform compromised surgery in elderly patients with poor lung function. At present, Wang Jun and others in China are also conducting clinical research on sublobar resection versus lobectomy in the elderly lung cancer population.

Figure : Sub-lobar resection clinical study enrolled population and new classification of lung adenocarcinoma
2. Personalization of the extent of lymphadenectomy: A multi-center randomized controlled study of the extent of lymphadenectomy by the American College of Oncology and Surgery for ten years.
ACOSOG-Z0030 announced the results. Due to the particularity of the study design, as we expected, this is a negative result study: there is no difference in overall survival between the systematic sampling group and the systematic dissection group, and the mediastinum is 4% The lymph node stage was sampled as N0 during the operation and N2 after the dissection (meaning that 4% of patients who received non-lymph node sampling were incompletely removed, and this part of the patients may lose the benefits of subsequent adjuvant chemotherapy.
Before applying the conclusions of this study to clinical practice, it is necessary to pay attention to the two factors of “high selectivity of early cases ” and “change in the concept of traditional lymphadenectomy scope ” in the study design : 1. Enrolled cases : Non-small cell lung cancer with pathological N0 and non-hilar N1, T1 or T2; 2. Precise pathological staging method: intrathoracic lymph nodes through mediastinoscopy, thoracoscopy or thoracotomy; 3. Concept of sampling and dissection: intraoperative freezing After biopsy, the pathology was randomly divided into groups.
The right side lung cancer samples 2R, 4R, 7 and 10R group lymph nodes, and the left side samples 5, 6, 7, 10L group lymph nodes, and removes any suspicious lymph nodes; patients assigned to the sampling group do not receive further lymph node resection, randomized to Patients in the dissection group further systematically removed the lymph nodes and surrounding fatty tissue within the scope of anatomical landmarks, right side: right upper lobe bronchus, innominate artery, singular vein, superior vena cava and trachea (2R and 4R), near the anterior blood vessel (3A) and retrotracheal (3P) lymph nodes; left side: all lymph node tissues (5 and 6) extending between the phrenic nerve and the vagus nerve to the left main bronchus, requiring no lymph node tissue between the main pulmonary artery window and protecting the laryngeal regurgitation nerve.
Regardless of whether it is left or right, all sub-proximal lymph node tissues between the left and right main bronchus (7), and all lymph node tissues on the lower lung ligament and adjacent to the esophagus (8, 9) should be cleaned. After the pericardium and on the surface of the esophagus, there should be no lymph node tissue at all, and all lung lobes and interlobular lymph nodes (11 and 12) should be removed during lung resection.
Before applying this conclusion to clinical practice, we must pay attention to the two aspects of “selection of early patients” and “changes in the concept of LN resection scope” in the study design: ① The patients included were N0 with pathological stage and N1 with no hilum, T1 Or T2 stage non-small cell lung cancer (NSCLC); ② precise pathological staging by means of mediastinoscopy, thoracoscopy or thoracotomy biopsy intrathoracic LN; ③ intraoperative patients were randomly divided into sampling group and systemic after pathological staging of frozen biopsy Cleaning group.
After comparison with a single-center randomized controlled study by Wu et al. In 2002, the final conclusion was very cautious: if the frozen results of systemic hilar and mediastinal LN sampling during surgery were negative, further systemic LN dissection could not bring patients To survive and benefit. This conclusion does not apply to patients diagnosed with early-stage lung cancer and precise pathological stage N2 only through imaging. The clinical stage based on positron emission tomography (PET) -CT is not equivalent to surgical stage, if not used during surgery The surgical staging in this study must be performed in accordance with Wu And other suggestions, use systematic LN cleaning to improve the accuracy of staging and improve survival.
The conclusion of this study is based on the popularization of pre-operative accurate staging methods in European and American countries, and reflects the American concept of attaching importance to pre-operative and intra-operative N staging. In view of the fact that the current preoperative accurate staging methods in China are still insufficient, as well as the differences from traditional sampling and the systematic concept of LN resection in this study, this conclusion is currently not suitable for promotion at this stage in China.
Selective nodal dissection refers to individualized lymph node dissection based on the tumor location, imaging / pathological manifestations, and intraoperative frozen delivery of early lung cancer .
With the advancement of imaging diagnosis technology in recent years, more and more imaging findings have been found that ground-glass opacity (GGO) is the main component, and pathological morphology is mainly adherent-like growth. . Can these specific types only undergo selective lymphadenectomy without affecting survival and local recurrence? Research from Japan shows that the 10-year survival rate of patients with early-stage lung cancer found by screening exceeds 85%.
Tumors are often small, and many patients have a tumor diameter of 1-2 cm or even frosted glass. As can be seen from the above, most of this type of imaging GGO lung cancer and pathology AAH-AIS-MIA-LPA overlap, lymph nodes and The extrapulmonary metastasis rate is low, and the cancer cells are also in a relatively stable state. Moreover, there are many elderly patients, the general health is poor, and with chronic diseases, selective lymph node dissection may benefit more.
In certain patients, to narrow the dissection of intrathoracic lymph nodes in patients with non-small cell lung cancer , it is necessary to have a method that can effectively predict the presence of lymph node metastasis. We need to summarize the pathological anatomy of lung cancer lymph node metastasis, the probability of lymph node metastasis in GGO-adenocarcinoma, and also minimize the occurrence of metastatic lymph node residues when applying selective lymph node resection.
The size of the tumor alone is missing for determining whether adenocarcinoma has metastasized. Systematic lymph node dissection is based on 20% of lung adenocarcinoma less than 2cm and 5% less than 1cm have lymph node metastasis on the theoretical basis.
According to the lymph node metastasis law of the lung lobe where the primary tumor is located, lobe-specific nodal dissection can narrow the scope of surgery. Although there is still no consensus on this particular operation, it is completely “one size fits all” lymph nodes. Cleaning may have certain advantages compared to cleaning. In addition, a retrospective analysis showed that in T1 and T2 lung cancers , adenocarcinoma is more prone to mediastinal lymph node metastasis than squamous cell carcinoma.
For peripheral squamous cell carcinoma that is less than 2 cm and does not involve the visceral pleura, the chance of lymph node metastasis is small. Asamura and other studies suggest that lymph node dissection can be avoided in patients with squamous cell carcinoma with a diameter of ≤ 2 cm or patients with intraoperative hilar lymph node frozen section without metastasis.
Combining well-differentiated adenocarcinoma subtypes such as AIS, MIA and LPA can better predict metastasis. Research by Kondo et al. Showed that peripheral adenocarcinoma with a long diameter of ≤1cm and Noguchi small lung cancer pathological type A / B type (equivalent to AAH-AIS-MIA-LPA), its differentiation is good and the prognosis is good. Patients with clinical stage Ia can consider wedge resection and lobectomy-specific lymph node resection. As long as the frozen margin and lobes-specific lymph node are negative during surgery, a larger range of lymph node dissection may be avoided.
Matsuguma and other studies have shown that imaging is a tumor with GGO> 50% and pathologically adherent-like growth, and the possibility of lymph node metastasis or lymphatic vessel invasion is extremely low. Studies have shown that these patients are suitable for narrowing the scope of surgery.
New lymph node dissections have been proposed for early NSCLC, including specific lung lobe dissections proposed by the European Thoracic Surgery Association (ESTS) and lymph node system sampling proposed by ACOSOG.
Because the proportion of lung cancer screening programs continues to increase, the adenocarcinoma classification developed by IASLC / ATS / ERS also brings us many new inspirations. As Van Schill et al. Reported, after sublobar resection and lymph node sampling, AIS and MIA have been free of disease for 5 years The survival period can reach 100%. Therefore, how to choose patients with sublobar or lobectomy and selective lymph node sampling becomes crucial.
In general, the need to narrow the scope of lymph node dissection in lung cancer is not as urgent as that of breast cancer and malignant melanoma, because the operations of the latter two have a direct impact on function and quality of life. Although there is no evidence to date that extensive lymph node dissection increases complications and has a significant impact on the quality of life of patients after lung cancer surgery, but
This does not mean that there is no need to try selective lymph node dissection. The surgical scope of small lung cancer still needs us to further explore, to find the best balance between “resection” and “reservation” to optimize the treatment effect and quality of life.
3. Summary
For lung cancers less than 2cm in diameter, Kodama et al.’S prospective individualized surgical classification treatment strategy for lung cancer is worthy of our reference and consideration. This study included HRCT SPNs with a diameter of less than 2cm. Imaging has no hilar mediastinal lymph node metastasis. The strategy of increasing the range of surgical resection and increasing the solid component gradually.
Observation and follow-up were performed for lesions smaller than 1 cm and pure GGO. If tumor enlargement or density increased during the observation , sublobar resection or lobectomy was performed. If the resection margin was positive or the lymph node was frozen positive, then lobectomy plus systemic lymph node dissection was performed.
For partial solid GGO of 11-15mm, lung segment resection and lymph node sampling are performed. If the resection margin is positive or the lymph node is frozen positive, then lobectomy and systemic lymph node dissection are changed;
For 11-15mm solid lesions or 16-20mm partial solid GGO, lung segment resection and lymph node dissection are performed. If the resection margin is positive or the lymph node is frozen positive, then lung resection and systemic lymph node dissection are changed;
For 16-20mm solid lesions , lobectomy plus systemic lymph node dissection are performed. In this strategy, DFS and OS of restrictive resection are still significantly superior to lobectomy, suggesting that the main prognostic factor of GGO-lung adenocarcinoma is still the biological characteristics of the tumor itself, thus recommending individualized resection strategies.
Fourth, recommended point of view
Imaging is close to 100% pure GGO lesions under 10mm, consider CT follow-up for AIS or MIA, rather than immediate surgical removal.
Lobectomy is the standard surgical procedure for early lung cancer . AIS-MIA-LPA may consider sublobar resection, but we still look forward to the postoperative recurrence rate provided by prospective clinical research.
At present, accurate intraoperative staging requires at least lymph node dissection based on lung lobe specificity. In a special subgroup of GGO [cT1-2N0 or non-hilar N1], systemic lymph node sampling is more appropriate than systemic lymph node dissection.
For AIS and MIA, lymph node sampling and dissection may not be necessary, but there is still a lack of randomized controlled studies to confirm that at present, it can be selectively applied to patients with advanced age, lung function threshold, and multiple diseases.
The accuracy of intraoperative frozen assessment of pulmonary nodular infiltrating components and the condition of the margin after sublobar resection needs to be further verified, and the intraoperative frozen examination process needs to be further standardized to better guide intraoperative decision-making.
At present, among the surgical recommendations of the new classification, for some patients with lung cancer , the status of sublobar resection and selective lymph node resection has not yet been fully established, just let us see a trend. The renewal of any kind of treatment concept will go through a relatively long process.
This requires the popularization of preoperative accurate staging methods such as PET / mediastinoscopy / EBUS, intraoperative frozen assessment of the primary focus of lung cancer , regional lymph nodes and resection margins. To better guide the individualized decision-making during the operation. The new classification of lung adenocarcinoma has witnessed the negative spiral upward process of negative resection of lung cancer from experience to evidence-based to individualization.

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