Adenocarcinoma classification: patterns and prognosis
Lung cancer is the most frequent human malignancy and the principal cause of cancer-related death worldwide. Adenocarcinoma is now the main histologic type, accounting for almost half of all the cases. The 2015 World Health Organization has adopted the classification recently developed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification has incorporated up-to-date advances in radiological, molecular and oncological knowledge, providing univocal diagnostic criteria and terminology. For resection specimens, new entities have been defined such as adenocarcinoma in situ and minimally invasive adenocarcinoma to designate adenocarcinomas, mostly nonmucinous and ≤ 3 cm in size, with either pure lepidic growth or predominant lepidic growth with ≤ 5 mm invasion, respectively. For invasive adenocarcinoma, the new classification has introduced histological subtyping according to the predominant pattern of growth of the neoplastic cells: lepidic (formerly non mucinous brochioloalveolar adenocarcinoma), acinar, papillary, micropapillary, and solid. Of note, micropapillary pattern is a brand new histologic subtype. In addition, four variants of invasive adenocarcinoma are recognized, namely invasive mucinous (formerly mucinous brochioloalveolar adenocarcinoma), colloid, fetal, and enteric. Importantly, three variants that were considered in the previous classification have been eliminated, specifically mucinous cystadenocarcinoma, signet ring cell, and clear cell adenocarcinoma. This review presents the changes introduced by the current histological classification of lung adenocarcinoma and its prognostic implications.
The relative frequency of adenocarcinoma of the lung has been increasing steadily over the past few decades, as opposed to squamous cell carcinoma, most likely as a result of spreading of low nicotine-tar cigarettes 1. Therefore, nowadays adenocarcinoma represents by far the most frequent histologic type of lung cancer, accounting for more than 40% of the total. It slightly predominates in male patients, but not infrequently occurs in women, also relatively young, and in individuals who have never smoked.
Over the last decade, the unprecedented advances in the understanding of lung adenocarcinoma, with regard to radiology, molecular biology, and medical oncology, made necessary a reconsideration of its classification in view of the new knowledge, which involved not only pathologists, but also radiologists, molecular biologists, clinicians, and surgeons. As a matter of fact, the latest WHO classification is the result of an integrated multidisciplinary approach.
Precursor lesions of invasive adenocarcinoma by current classification comprise two entities: atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) (Fig. 1). Both lesions show a lepidic type of growth, which was previously named as “bronchioloalveolar”, a term discontinued because of its ambiguity. This growth pattern is characterized by a proliferation of cuboidal to columnar cells with variably atypical nuclei and occasional intranuclear inclusions, growing alongside preexistent alveolar walls. Immunohistochemically, these lesions are always positive for CK7, napsin A, and TTF1, and show an extremely low proliferation index (below 5%). Notably, the diagnosis requires a surgical specimen with complete sampling of the lesion to exclude the presence of an overtly invasive component, hence they cannot be diagnosed on cytological or bioptic samples.
1. Atypical adenomatous hyperplasia
AAH is a centroacinar lesion of small dimensions (≤ 0.5 cm), constituted by a clonal proliferation of atypical polygonal cells, lining the alveolar walls and associated with mild septal thickening. The cells are cuboidal or low columnar, sometimes hobnailing, and show mild to moderate atypia. In general, the background lung does not show significant fibrosis or inflammation. Apart from AIS, the differential diagnosis includes entrapped alveoli, peribronchiolar metaplasia, and pneumocytic hyperplasia with reactive atypia 2.
AAH usually cannot be detected by radiological imaging, or correspond to small ground-glass opacities at high-resolution CT scan, therefore in most instances, they represent incidental findings in lung surgical samples resected for other diseases.
2. Adenocarcinoma in situ
AIS is a neoplastic lesion, > 0.5 cm and ≤ 3 cm in size, composed mostly of nonmucinous cells with an exclusively lepidic pattern of growth and without features of invasion (either stromal, vascular, pleural or STAS-see below). AIS often shows relatively abrupt outer margins, and its cells are columnar with overlapping nuclei and a more pronounced cytologic atypia if compared to AAH.
AIS corresponds to the tumor previously designed as nonmucinous bronchioloalveolar carcinoma and is staged as pTis. A mucinous variant of AIS can also occur, but it is extremely rare. The latter shows subtle atypia, still basally located nuclei, intracytoplasmic mucin, and occasionally goblet cells.
The differential diagnosis includes AAH and minimally invasive adenocarcinoma (MIA), which are two ends of the same disease spectrum. It is likely that this distinction has a minimal clinical impact since these three entities have an excellent prognosis. In addition, the differential diagnosis includes also reactive cellular atypia due to inflammatory diseases. On CT scans these lesions appear as ground-glass opacities, sometimes difficult to distinguish from lung inflammatory changes.
MINIMALLY INVASIVE ADENOCARCINOMA
MIA is a new tumor entity first included in the new WHO classification, defined as a solitary lesion ≤ 3 cm in size, with a predominant lepidic pattern and with foci of invasion ≤ 0.5 cm. When multiple foci stromal of invasion are present, only the size of the largest invasive area should be considered for classification.
The invasive component may have acinar, papillary, micropapillary, or solid architecture or consists of single cells dispersed in desmoplastic stroma. Vascular/pleural invasion and tumor necrosis rule out this diagnosis. Cytologically, MIA is almost invariably nonmucinous, with a cell morphology overlapping with AIS. Microinvasive areas can be found close to central scars. MIA according to the WHO classification is considered as pT1a(mi). The main differential diagnosis is with AIS. On CT scan, the lepidic component appears as a ground-glass opacity, whereas the microinvasive areas sometimes correspond to small solid areas.
The latest classification has addressed the utmost heterogeneity of growth patterns of invasive adenocarcinoma of the lung with the introduction of the subtyping according to the predominant pattern. These patterns are often found in combination within the same tumor, therefore, lung adenocarcinoma is now classified based on the pattern most represented in cross-sectional area of histological sections (so-called predominant pattern), with reporting of the percentage of all the other identifiable patterns in 5% increments. It is our impression that a 5% increment may lead to a low agreement among pathologists, and a 10% increment evaluation may be more realistic. Nevertheless, this accurate histologic stratification is useful when dealing with multiple lung adenocarcinomas, because their morphologic comparison may help to differentiate multiple synchronous or metachronous primaries from intrapulmonary metastases 3, but more importantly it carries prognostic information, which will be discussed further on. Moreover, it is known that some morphologic features tend to be associated with specific molecular alterations, which make cancer susceptible and eligible to specific targeted therapeutics. The degree of cytological atypia does not have impact on the classification. The five subtypes of lung adenocarcinoma based on the WHO classification are the following (Fig. 2):
The latest WHO classification has also revised substantially the special forms of lung adenocarcinoma (Tab. I). Three entities have been eliminated, namely mucinous cystadenocarcinoma, signet ring cell, and clear cell adenocarcinoma. Currently, mucinous cystadenocarcinoma is included in colloid adenocarcinoma, the presence of signet ring cells should be indicated in an addendum, while clear cell adenocarcinomas are now classified according to their growth pattern without mentioning clear cell morphology. Moreover, two new entities have been introduced, the invasive mucinous and the enteric adenocarcinoma, therefore, besides the different growth patterns, the following four variants of adenocarcinoma are recognized (Fig. 3), and can be associated with other subtypes of lung adenocarcinoma.
Distinguishing among adenocarcinoma different patterns and subtypes usually is not particularly difficult, with an interpersonal agreement varying from good to moderate, depending on the studies 12 13. The main problems arise in the differentiation of lepidic from acinar and papillary pattern 14, and of papillary from micropapillary pattern, especially in cases with a less than optimal tissue fixation.
Many clinical and pathological factors have been found to be associated with patient outcome. The clinical prognostic factors for lung adenocarcinoma patients include gender, age, smoking history and stage 15 16.
Several studies have revealed and confirmed the prognostic value of the recent classification 17-20. As mentioned above, the precursor lesions AAH, AIS, and MIA have all an excellent prognosis, with about 100% survival rate. In fact, in lepidic lesions the main prognostic factor is the size of invasive component 21 22. Coherently, adenocarcinomas with predominant lepidic pattern have a better prognosis than the other subtypes of invasive adenocarcinoma, with survival inversely correlated with the size of the invasive component 23 24. Moreover, the smaller the solid component identified by CT scan, the better the prognosis 21.
The prognostic relevance of histologic subtypes is demonstrated in early stage disease, where lepidic subtype is associated with good prognosis, acinar and papillary subtypes show intermediate prognosis, whereas micropapillary and solid subtypes correlate with the worst prognosis 17-20. Sica et al. proposed a grading system for lung adenocarcinomas based exclusively on histologic pattern, with grade 1 corresponding to lepidic growth, grade 2 to acinar and papillary, and grade 3 to solid and micropapillary 17. The two prevalent grades were combined into a score, which proved to predict prognosis in a large series of lung adenocarcinomas. Kadota et al. 25 and von der Thusen et al. 26 proposed two different grading systems, both combining histologic pattern and mitotic count. The best grading system for lung adenocarcinoma has still to be determined.
It is worth noting that the adverse prognostic impact of micropapillary component seems to be independent to its extent 27. On the other hand, when solid growth pattern is predominant, metastases to regional lymph nodes occur in > 75% of cases at the time of surgical resection. Furthermore, growing evidences suggest that cribriform arrangement, currently part of acinar subtype, correlates with a poorer prognosis 28 29. However, the prognostic impact of histologic subtyping in advanced stage patients has to be clarified. Since some recent studies found that histologic subtyping correlates with recurrence risk after sublobar resection, it is plausible that in a near future adenocarcinoma subtype will impact treatment strategy.
Beyond histological patterns, other morphological parameters have been found to possibly affect the clinical outcome. In particular, two recent studies have investigated the prognostic impact of the presence of spread through air spaces (also known as STAS) in patients with adenocarcinoma. STAS consists of tumor minute micropapillae, solid nests or single cells, spreading via airways outside the main tumor rim. STAS has been found to correlate significantly with micropapillary and solid patterns, high-stage, increased recurrence, worse disease-free and overall survival, suggesting that STAS is an adverse prognostic factor 30 31. However, further studies are warranted in order to validate these findings.
Diagnosis of adenocarcinoma in small biopsies and cytology
The diagnosis of adenocarcinoma, particularly in small biopsies, requires either the classical histologic features of adenocarcinoma (lepidic, acinar, papillary or micropapillary patterns) or immunohistochemical confirmation by TTF1 (Fig. 4). As an alternative, also the demonstration of mucin production is contemplated, which is however rarely applied in routine practice. Obviously, diagnostic features of squamous cell carcinoma (unequivocal intercellular bridges and keratinization) are banned.
The current recommendation for the diagnosis of lung cancer on small biopsies or cytology samples is to precisely classify the histotype, while the subclassification of adenocarcinoma types is not standard practice and is not recommended. However, considering that only a minority of lung adenocarcinomas can be resected, and as such can be subtyped more precisely on surgical specimens, recent studies have explored the possibility of applying the new WHO classification on cytology samples. Despite some peculiar cytomorphological features have been shown to be more frequently associated with specific adenocarcinoma subtypes (papillary clusters with fibrovascular cores in papillary adenocarcinoma, acinar structures in acinar adenocarcinoma), most studies have concluded that cytology cannot reliably subclassify adenocarcinoma 32-34. The main problem has been the heterogeneity of morphological patterns observed in most adenocarcinomas 33. However, in order to guide patient treatment decisions, defining reproducible cytomorphological parameters, in particular associated either with the most aggressive histotypes or, possibly, with predictive genetic alterations, remains a relevant unachieved goal.
The current histological classification takes into account all the recent progress made in understanding the radiological, molecular and biological features of lung adenocarcinoma and is corroborated by relevant prognostic value.
Figures and tables
|2015 WHO classification||2004 WHO classification|
|Atypical adenomatous hyperplasia||Atypical adenomatous hyperplasia|
|Adenocarcinom in situ||Non mucinous bronchioloalveolar carcinoma|
|Invasive lung adenocarcinoma subtypes|
|Minimally invasive adenocarcinoma|
|Acinar predominant||Mostly mixed, some acinar|
|Papillary predominant||Mostly mixed, some papillary|
|Micropapillary predominant||Mostly mixed, some papillary|
|Solid predominant||Mostly mixed, some solid|
|Lung adenocarcinoma variants|
|Invasive mucinous||Mucinous bronchioloalveolar carcinoma|
|Colloid||Mucinous (“colloid”) Mucinous cystadenocarcinoma|
|Signet ring *|
|Clear cell *|