February 2011 Three major international academic organizations: IASLC, ATS, and ERS jointly published a new international multidisciplinary classification of lung adenocarcinoma. Oncologists, respiratory pathologists, pathologists, radiologists, molecular biologists, and thoracic surgeons from the three aforementioned organizations systematically reviewed 11,368 references and held a series of meetings to discuss the progress of the new classification, make recommendations, and write up updated classification criteria [1].
Historical evolution of the classification of lung adenocarcinoma.
In 1967, 1981 and 1999, the WHO classification of lung cancer was developed, but at that time, the classification was entirely developed by pathologists in a single discipline. It was not until 2004 that relevant genetic and clinical information was introduced. With the development of oncology, molecular biology, pathology, radiology and surgical techniques, especially after the discovery that EGFR gene mutations can predict the efficacy of TKI drugs in the treatment of lung adenocarcinoma and determine the prognosis of lung cancer [2], that pemetrexed and bevacizumab are not suitable for the treatment of squamous carcinoma [3], and the role of different imaging manifestations for clinical treatment and determination of patient prognosis, the integrated multidisciplinary classification The need for a multidisciplinary and comprehensive classification gradually emerged, resulting in a new classification for 2011. The first pathological recommendation was to discontinue the term “BAC” [1].
Alveolar carcinoma of the fine bronchioles BAC
As early as 1876, Prof. Louis Malassez discovered and reported a pathological type that differs from other malignant tumors of the lung in that, in addition to maintaining an intact alveolar structure, it is characterized by well-differentiated tumor cells, growth along the alveolar wall, and only a mild reaction of the basement membrane. With the accumulation of clinical data and intensive experimental studies, the nomenclature of fine bronchoalveolar carcinoma was formally proposed by Professor Averill Liebow in 1960, and the definition was subsequently widely accepted and listed as one of the two subtypes of lung adenocarcinoma in the first WHO histological typing of lung cancer in 1967.In 1999, the definition of fine bronchoalveolar carcinoma was further refined to require that all tumor cells to grow in a squamous pattern, the alveolar structure to remain intact, and the tumor cells to not invade the basement membrane, blood vessels, or pleura. However, there are numerous types of lung adenocarcinoma with BAC features, resulting in its overly broad application. It includes small isolated peripheral adenocarcinoma, microinvasive adenocarcinoma, mixed invasive adenocarcinoma, widely disseminated highly staged adenocarcinoma, and mucinous BAC which is almost always invasive; while the five-year survival rate for the first two can be at or near 100%, widely disseminated highly staged adenocarcinoma has poor prognosis. It is the application of BAC that has been questioned because of the different prognoses that occur with the same diagnosis. As a result, new classification recommendations eliminated the application of BAC and replaced it with other terms, thus further classifying lung adenocarcinomas originally classified as BAC as adenocarcinoma in situ (AIS); microinvasive adenocarcinoma (MIA); volvulus-like growth predominant adenocarcinoma (non-mucinous); adenocarcinoma, invasive predominant with some non-mucinous volvulus-like component; and invasive mucinous adenocarcinoma [1]. These recommendations were also adopted by the 2012 edition of the NCCN guidelines. In contrast, AIS and MIA are new terms used for imaging shadows in lung adenocarcinoma that are purely GGN or partially solid nodules with predominantly volvulus-like components, which also have 5-year survival rates at or near 100% after surgical resection [4].
Relationship between imaging presentation and pathological features of lung adenocarcinoma
The previous method of classifying lung adenocarcinoma did not require reference to imaging data, but in the new classification, the terminology for describing small nodular tumors, including pure GGN (non-solid nodules), solid nodules and partially solid nodules (semi-solid nodules), is recommended according to the size of the solid component in the nodules. Moreover, it was clearly proposed that a maximum diameter of less than 3 cm is the upper limit for pathological diagnosis of AIS and MIA [1]. Hairy glass-like lesions smaller than 3 cm and hairy glass-like shadows around solid lesions may be histologically atypical adenomatous hyperplasia or adenocarcinoma of the lung in situ growing along the alveolar wall. In contrast, the solid component suggests the presence of an invasive tumor in the lesion. However, the question arises whether the upper limit of 3 cm is appropriate and whether hairy glass-like lesions larger than 3 cm have the same good prognosis as AIS and MIA?
For partially solid lesions, the size of the entire lesion was previously measured, but because of the good prognosis of the non-infiltrating component, the new classification recommends that both the entire tumor size and the extent of infiltration should be recorded until it is clear that the extent of infiltration (solid component) is a more effective predictor of prognosis than the actual tumor extent [1]. This suggests that in the future it may be necessary to measure only the size of the solid portion and thus base TNM staging on the measurements, which may be reduced in some patients.
In addition, for multiple small nodules in the lung, different imaging presentations may also suggest different types of pathology, further influencing the treatment strategy. If the proportion of solid components of multiple small nodules in the lung varies, and because the new classification also encourages pathologists to record all possible subtypes in 5% increments instead of 10% semi-quantitatively, thus enabling a more detailed and comprehensive diagnosis of the type of lung cancer, the different composition of each small nodule allows us to consider these nodules as multiple primary rather than due to metastasis, thus changing the staging and treatment of lung cancer strategy.
Because of the integrated multidisciplinary classification approach, pathologists can diagnose lung nodules more accurately when combined with clinical data, especially when they are similar to previously diagnosed non-small cell lung cancer that is unclassified or indistinguishable, and can be more often considered as adenocarcinoma with EGFR mutation.
Relationship between clinical presentation and biological behavior of lung adenocarcinoma
Atypical adenomatous hyperplasia (AAH) was previously considered as a pre-invasive lesion of lung adenocarcinoma, but the new classification formally identifies AIS and AAH as pre-invasive lesions in lung adenocarcinoma. In the classification of pre-invasive lesions, AAH corresponds to squamous epithelial atypical hyperplasia and AIS corresponds to squamous cell carcinoma in situ; AAH gradually evolves into AIS, then BAC, LPA and adenocarcinoma, which is the evolutionary process of general lung adenocarcinoma. The tumor also has a progressively shorter doubling time, with 988 days for AAH and 384 days for mixed BAC in invasive adenocarcinoma [5]. However, not all adenocarcinomas undergo such a progression, and some lesions remain at the AAH stage or some develop directly into adenocarcinoma. We consider whether we need to classify adenocarcinomas into non-aggressive and aggressive types, and thus adopt different therapeutic strategies.
Molecular biology of lung adenocarcinoma
It is the breakthroughs in molecular biology and the advent of TKI drugs that have revolutionized the treatment of lung adenocarcinoma. Various important molecular markers associated with lung adenocarcinoma have been identified:(1) EGFR mutation status is predictive of PFS and efficiency after first-line treatment with EGFR-TKIs in patients with advanced lung adenocarcinoma. [6] (2) EGFR mutant tumors show a relatively inert progression [6]. (3) EGFR mutations and KRAS mutations are mutually exclusive and independent [7]. (4) EML4-ALK fusion genes are more likely to be detected in those negative for EGFR/KRAS mutations [8].The prevalence of EGFR mutations is higher in Asian, never-smoking, non-mucinous adenocarcinomas at approximately 10-30%, while KRAS mutations are more common in non-Asian populations, smoking and invasive mucinous adenocarcinomas, also at 10-30% [9].EML4-ALK fusion gene has a 5% prevalence in lung adenocarcinoma. Younger, male, never or light smokers have a greater chance of developing such alterations [10] [11]. An ongoing phase II study found that crizotinib was effective in more than 80% of patients with ALK gene rearrangements [12] [13], leading to the latest NCCN guidelines for non-small cell lung cancer, which suggest that in patients with recurrent and metastatic disease, ALK testing is required on pathological examination for non-squamous carcinoma, and treatment with crizotinib is indicated if it is positive.
Changes in the new classification of lung adenocarcinoma
This new classification of lung adenocarcinoma can be said to be a revolution in the history of lung cancer. First of all, it has a clinical environmental protection concept: it proposes for the first time a classification method applicable to surgical resection specimens, small biopsies and cytology respectively; due to the emergence of three new drugs, EGFR-TKI, pemetrexed and bevacizumab, it makes the importance of clear diagnosis of pathological type and molecular type further reflected, and it suggests doing as little immunohistochemistry as possible to save specimens for molecular biology testing. maximize the benefit of targeted therapy. Second, it has the concept of integrated medicine: pathology diagnosis needs to be combined with imaging characteristics and clinical features, and also needs to be combined with molecular biology testing, which together can improve accurate and comprehensive diagnosis for clinicians and thus guide treatment. Third, advocate the concept of individualized medicine: the new classification recommends that all advanced lung adenocarcinoma should undergo genetic testing, so as to improve reference factors for treatment and prognosis, and at the same time reserve more biomarkers to improve data for future research. Treatment strategies for early stage lung cancer are also affected, based on 5-year survival rates at or near 100% after surgical resection for AIS and MIA, then surgeons will consider abandoning traditional lobectomy + systemic lymph node dissection, and the ongoing CALGB140503, JCOG0804 and JCOG0802 are comparing the results of local resection and standard resection for early stage lung cancer and believe encouraging results will emerge.
Impact of the new classification of lung adenocarcinoma on surgical treatment
Significance of the new classification: According to the new classification criteria, the new concept of adenocarcinoma in situ (AIS) replaces the original simple type BAC with predominantly squamous growth and infiltrative component <5
The microinvasive adenocarcinoma (MIA) of <5 mm replaced the original BAC with focal infiltration. These two groups of patients have a very low incidence of lymph node metastasis and can achieve near 100% disease-specific survival if they undergo surgical resection, with BAC-AIS being removed as a malignant tumor and included as a precancerous lesion along with atypical adenomatous hyperplasia (AAH). The new classification of lung adenocarcinoma gives the thoracic surgeon a sense of déjà vu, as AIS and MIA may derive from the pathological classification of breast cancer. Similarly, when reviewing the history of breast and lung cancer surgery, it is easy to see the similarities between the two. For example, breast cancer surgery has a history of more than 2000 years and has gone through a process of "from small to large and then from large to small". Lung cancer surgery, following the footsteps of breast surgery, has gone through a process of "from large to small, from small to large, and from large to small again" in just 120 years, from total lung resection with ligation of the hilar structures, wandering through sublobar resection and lobectomy, to standard anatomical lobectomy with systematic intrathoracic lymph node dissection, to selective sublobar resection and lymph node dissection. "
4 stages.
Individualized surgical treatment strategy: The current standard surgical procedure for lung cancer was established based on two major pieces of evidence-based medical evidence: for patients with clinical stage I-IIIA, lobectomy reduces the local recurrence rate compared to wedge or segmental resection; and systematic lymph node dissection improves the accuracy of postoperative pathological staging and prolongs patient survival compared to lymph node sampling. Although the term “BAC” will gradually fade from our view, the slow-growing, well-differentiated, but fickle nature of these lesions will not change, regardless of whether it is BAC or AIS. The recent strategy of individualized surgical treatment for selective resection of lung cancer is based on two important aspects: the increasing advances in imaging technology have made it possible to diagnose gross glassy changes (GGO) with increased acuity, thus enabling minimally invasive surgery for small peripheral types of lung cancer <2 cm in diameter.
cm small lung cancers, as well as a deeper understanding of the molecular biology of a range of specific types of lung cancer such as AAH-AIS-MIA.
The changing perception of the extent of lung cancer resection: at this point in 2011, the status of restrictive resection in the surgical recommendations of the new classification criteria is still not fully established, but only gives us a glimpse of a trend. Corresponding to the fast pace of the internet era, any renewal of treatment concepts has to go through a relatively long process. This requires us to gradually popularize preoperative accurate staging tools such as positron emission tomography (PET)/mediastinoscopy/endobronchial ultrasound (EBUS), to further improve intraoperative freezing to assess primary lung cancer foci, regional lymph nodes and cut margins, and to provide more evidence from prospective randomized controlled studies to better guide intraoperative individualized decision making. As can be seen, the new classification criteria for lung adenocarcinoma witness a negative-negative spiral from empirical to evidence-based to individualized concepts of lung cancer resection extent.