Lung cancer: developments, concepts, and specific aspects of the new WHO classification

Abstract

Introduction

Diagnostic methods and algorithms for the diagnosis of pulmonary neoplasms have considerably changed over the recent years. Based on large-scale molecular characterization studies and the development of targeted therapies, precise morphological, immunohistochemical, and molecular pathological tumor subtyping is now of utmost importance for evidence-based treatment decisions. Changes of diagnostic concepts initially referred to biopsies and cytology specimens but are now also transferred to resection specimens.

Methods

This review is focused on recent developments in morphological and immunohistochemical subtyping of pulmonary neoplasms and concepts of tumor progression. It also provides perspectives on relevant changes of diagnostic concepts within the context of the new WHO classification.

Conclusion

It becomes apparent that a three-step diagnostic concept based on morphology, immunohistochemistry, and molecular pathology is important to meet the requirements of an increasingly more complex, interdisciplinary care of lung cancer patients and to allow for reliable, clinically meaningful tumor diagnoses.

Introduction

Historically, lung cancer was categorized into small cell (SCLC) and non-small cell carcinoma (NSCLC). While SCLC patients are usually treated with chemotherapy, NSCLC patients in early tumor stages benefit from surgical resection. According to the 2004 WHO classification (Travis et al. 2004), the group of NSCLC was further subdivided into adenocarcinomas (ADC), squamous cell carcinomas (SQCC), large cell carcinomas (LC), and sarcomatoid carcinomas as well as tumors with respective mixed components (e.g., adenosquamous carcinomas; ADC–SQCC). This has not essentially changed in the new WHO classification (Travis et al. 2015). With approximately 60 % ADC form the largest group among all NSCLC and are thereby the most frequent cause of a tumor-related death (Siegel et al. 2013).

Recent data demonstrated that a precise histomorphological, immunohistochemical, and a molecular characterization of NSCLC are important parameters in the prognostic assessment and thus treatment decisions. This review will focus on recent developments in this field including selected aspects of the new WHO classification as well as specific differential diagnoses of NSCLC (Travis et al. 2015).

Adenocarcinoma

In recent years, ADC emerged as a prime example of an individualized treatment of cancer patients. Propelled by comprehensive molecular characterization studies, numerous potential molecular targets were discovered which are currently tested in hundreds of tumor-specific treatment concepts worldwide. Respective studies could already demonstrate a significant improvement of the patients’ prognoses, but also revealed that molecular-driven treatment concepts alone are not sufficient to comprehensively characterize these tumors with respect to important clinical and especially prognostic parameters (Petersen 2013; Warth et al. 2013b).

For years there is increasing evidence from histomorphological studies worldwide, that specific growth patterns of ADC are of high prognostic relevance. Respective concepts were specifically developed in Asian countries, for example by Masayuki Noguchi. Based on these findings and the developments in the field of the predictive molecular pathology, a novel international, multidisciplinary ADC classification was developed and published in 2011 (Travis et al. 2011), which now forms the backbone of the new 2015 WHO classification (Travis et al. 2015). Important changes of this classification refer to a new definition of ADC precursor lesions, the subtyping of ADC based on a semiquantitative assessment of specific growth patterns, as well as changes of the terminology of ADC subtypes. ADC growth patterns are now assessed in 5 % increments and categorized as either lepidic, acinar, papillary, micropapillary, or solid predominant ADC. The majority of all ADC cases are composed by different patterns, and only <10 % show a pure pattern which has blurred the importance of morphology in subtyping. The novel concept of typing lung adenocarcinoma by the predominant pattern has a significant, in some studies even a stage-independent prognostic impact, correlates with the probability of metastatic spread, and is likely also associated with a different response to adjuvant radio-chemotherapies (Warth et al. 2012a).

In principal, lepidic predominant ADC have the best prognosis followed by acinar, papillary, solid, and micropapillary ADC, which has meanwhile been confirmed by numerous validation studies around the globe (Petersen 2013; Travis et al. 2013; Weichert and Warth 2014). Furthermore, it has been demonstrated that this new concept can be reproducibly applied in the routine diagnostic setting (Thunnissen et al. 2012; Warth et al. 2012b, c). For a more detailed overview, we refer to recently published reviews on this topic (Petersen 2013; Travis et al. 2013; Warth et al. 2013b). Most recent studies further refined the histomorphological classification by adding the cribriform pattern, which is currently considered as a spectrum of the acinar pattern. However, first data indicate that cribriform predominant ADC have a worse outcome and might rather be placed in the high-grade than the intermediate-grade prognostic group (Kadota et al. 2014; Moreira et al. 2014; Warth et al. 2015a).

A completely novel morphological concept is the definition of invasion. Current histomorphological criteria for invasive tumor growth such as stromal, vascular, or pleural invasion are now supplemented by a novel histomorphological criterion designated as spread through air spaces (STAS). STAS is defined as micropapillary clusters, solid cell nests, or single cells within the lung parenchyma, surrounding the outer edge of the tumor without direct connection of the cells to the main tumor mass. For an optimal assessment of STAS, it can be helpful to draw an idealized, usually slightly curved line along the most peripheral coherent tumor cell formations. Since it represents a manifestation of tumor spread, STAS is not included in the percentage measurement of subtype patterns. First data demonstrate that STAS is significantly associated with a worse outcome and early tumor recurrence (Kadota et al. 2015; Warth et al. 2015b).

Salivary gland tumors of the lung

The local glands of the bronchial mucosa can be the origin of the salivary gland tumors of the lungs. Although rare, one should always consider this group of tumors in the differential diagnosis to other lung tumors, especially if there is a low-grade cytomorphological aspect of the cells (sparse cellular and nuclear polymorphy, low proliferation) while histomorphological and/or immunohistochemical characteristics (solid growth, mixed differentiation, negative for TTF-1) might (erroneously) argue for a high-grade neoplasm (Fig. 1). In particular, solid predominant ADC are a typical pitfall in this differential diagnostic context.

Fig. 1.

a, b Lung adenocarcinoma with bronchial mucosa association, intraluminal growth, high degree of differentiation and little proliferation (a, HE). There is microfocal mucous formation (b, Alcian Blue) and signs of mucoepidermoid differentiation pointing to a tumor with characteristics of a mucoepidermoid salivary gland carcinoma. c Pulmonary adenocarcinoma with high degree of differentiation (see right upper part) and simultaneous hyperplasia of neuroendocrine cell at the border of a small bronchus (left lower part). d Basaloid squamous cell carcinoma of the lung with basaloid growth and focal retraction artefacts similar to a basal cell carcinoma of the skin. e, f Subtypes of sarcomatoid carcinomas of the lung. The pleomorphic carcinoma (e) is characterized by a combination of a non-small cell carcinoma, in this case of a squamous cell carcinoma (upper part) with a malignant sarcomatoid component similar to a spindle cell sarcoma (lower part). The distinction between a spindle cell carcinoma (f) and a sarcoma is only possible by the detection of a cytokeratin expression and/or an epithelial precursor lesion like a severe squamous dysplasia of a squamous cell carcinoma in situ within or at the border of the malignant spindle cell tumor

The most frequent entities in the group of the salivary gland tumors are mucoepidermoid carcinomas, adenoid cystic carcinomas, and epithelial–myoepithelial carcinomas; however, it can be challenging to assign tumors of the bronchial glands to a specific entity (Fig. 1). In such cases, adjacent bronchial structures and/or intrabronchial tumor growth but also the exclusion of other entities such as carcinoids can be important clues for the right diagnosis. One must also be aware that extrapulmonary salivary gland tumors can metastasize into the lungs. Thus, the patients’ history especially with regard to operations in the head and neck region even many years ago might harbor important clues for the correct diagnosis.

Squamous cell carcinomas

Traditionally, squamous cell carcinomas of the lung (SqCC) are histologically characterized by keratinization or intercellular bridges and were further subdivided according to the 2004 WHO classification based on their histomorphological differentiation. This resulted into papillary, clear cell, small cell, basaloid, and alveolar-filling variants of SQCC, which, however, has never been shown to be of any clinical relevance. Since tumor classifications should always be as easy and reproducible as possible to allow for evidence-based treatment decisions, the number of SQCC variants was reduced in the new 2015 WHO classification (Travis et al. 2004). However, as already known from other organs, the new entity of a non-keratinizing SqCC was established, which is characterized by the expression of squamous immunomarkers, specifically p40, p63, and/or cytokeratins (CK5, CK5/6). It is a paradigm shift that expression of immunomarkers and no longer histomorphology alone defines the diagnosis in NSCLC resection specimens. This represents an important step toward tumor-specific, individualized therapies and will reduce the number of NSCLC cases which were classified as LC up to now (see below).

Basaloid carcinomas

Basaloid carcinomas are poorly differentiated epithelial tumors with basaloid cytomorphology (Brambilla et al. 1992). Morphologically, they are related to basal cell carcinomas of the skin (Fig. 1), but, in contrast to these tumors, they have a poor prognosis (Moro-Sibilot et al. 2008). In the 2004 WHO classification, basaloid carcinomas were considered as both a specific subtype of SqCC and of LC, which frequently resulted in confusion. From the differential diagnostic point of view, they further have to be separated from poorly differentiated large cell neuroendocrine carcinomas (LCNEC); others even considered basaloid carcinomas as a subtype of ADC (Marci et al. 2007). However, global expression data demonstrated that basaloid carcinomas are predominantly associated with SqCC characteristics. Therefore, in the new 2015 WHO classification basaloid carcinomas are now exclusively defined as a specific subtype of SqCC and no longer considered a subtype of LC (Travis et al. 2015). Basaloid carcinomas must thus express squamous immunomarkers, especially p40.

NUT midline carcinomas

A completely new entity in the 2015 WHO classification is the so-called NUT midline carcinoma (Travis et al. 2015). This tumor was initially described in 1991 and is considered as an exceedingly rare, highly malignant, intrathoracic, undifferentiated carcinoma, which can show abrupt changes into areas with squamous differentiation. NUT midline carcinomas are characterized by translocations between nuclear protein of testis (NUT) on chromosome 15q14 and the BRD4 gene on chromosome 19p13.1 or more rarely the BRD3 gene on chromosome 9q34.2 (Stelow 2011). Respective tumors are more often localized in the mediastinum/thymus than in the lungs. NUT midline carcinomas are of interest with respect to targeted therapies, since BRD genes are a specific class of epigenetic regulators with available selective inhibitors (Dawson and Kouzarides 2012; Dawson et al. 2012).

Adenosquamous carcinomas

Adenosquamous carcinomas (ADC–SqCC) are characterized by a synchronous morphological squamous and adenomatous differentiation of at least 10 % each from the whole tumor. The clear morphological separation of both lineages is of utmost importance for the diagnosis. With respect to the immunophenotype, only two different cell populations with clear-cut morphological squamous and non-squamous differentiation qualify for the diagnosis. In particular, the co-expression of TTF-1 and p40 in morphologically indistinct tumor cell populations does not allow for this diagnosis but instead should be diagnosed as solid predominant ADC according to the new WHO classification (Travis et al. 2015). This is specifically important since immunohistochemistry besides morphology is now another option for resection specimens to ultimately attribute undifferentiated large cell or sarcomatoid carcinomas to a specific lineage. ADC–SQCC is usually associated with a worse survival compared to pure ADC or SQCC (Janssen-Heijnen and Coebergh 2001). Thus, one must assume a stronger tendency of this entity to progress toward a poorly differentiated carcinoma. In case of low-grade malignancies with mixed differentiation, mucoepidermoid carcinoma represents a relevant differential diagnosis.

Sarcomatoid carcinomas

According to the 2004 and 2015 WHO classification, sarcomatoid carcinomas of the lungs are classified as pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma (Travis et al. 2004, 2015). In general, all entities among the group of sarcomatoid carcinomas show a tendency to differentiate toward a mesenchymal phenotype (Fig. 1). However, the mesenchymal components can show a high variability. With respect to the phenotype, spindle cell carcinomas are morphologically rather isomorphic spindle cell neoplasms showing their epithelial nature only by the expression of cytokeratins. In contrast, pleomorphic carcinomas show the combination of a morphologically distinct NSCLC component (usually SQCC, but possibly also ADC or large cell carcinoma) with malignant spindle cells. Carcinosarcomas, in turn, usually show a higher degree of differentiation and diversity of the mesenchymal component, for example malignant chondrogenic, osteogenic, or rhabdomyogenic tissue. In the breast, these tumors are classified as metaplastic carcinomas, which might be the more appropriate terminology with respect to the above-mentioned aspects as well as considering that in other organs the diagnosis of carcinosarcoma does not necessarily require a differentiated mesenchymal component.

Pulmonary blastomas are biphasic tumors, characterized by a primitive epithelial component similar to fetal ADC and a primitive mesenchymal component, where foci of osteosarcoma, chondrosarcoma, or rhabdomyosarcoma can be found.

One might question why giant cell carcinomas are placed in the group of sarcomatoid carcinomas and not in the large cell carcinoma category, as the term “giant cell” implies the presence of large tumor cells. However, these often multinucleated giant cells show usually both an epithelial and a mesenchymal phenotype as demonstrated by the co-expression of vimentin (Addis et al. 1988; Chejfec et al. 1991; Kuroda et al. 1994) and a discohesive growth. Another characteristic of this tumor type is a prominent inflammatory infiltrate which usually contains large amounts of neutrophilic granulocytes. Thus, this entity is characterized by (a) giant cells, (b) epithelial–mesenchymal transition, and (c) an inflammatory component.

To all of these rare entities in the group of sarcomatoid carcinomas, only very few studies were published in recent years and none of them provides significant arguments for changes in their classification. However, immunohistochemical and molecular analyses will also help to better classify these rare tumors with respect to a specific lineage of differentiation and thus to allow for a more tumor-specific therapy (Travis et al. 2015).

Large cell carcinomas

Large cell carcinomas (LC) are characterized by a non-small cell morphology and the absence of specific histomorphological characteristics of ADC, SQCC, or a tumor with neuroendocrine differentiation. Thus, it is the lack of differentiation that defines large cell (undifferentiated) carcinomas. However, LC have the tendency to show an epithelial–mesenchymal transition. This is particularly true for LC with a rhabdoid phenotype in which the expression of vimentin was frequently reported (Cavazza et al. 1996; Chetty et al. 1997; Falconieri et al. 2005; Kaneko et al. 2002; Shimazaki et al. 2001; Tamboli et al. 2004; Yilmazbayhan et al. 2005). The recognition that undifferentiated lung carcinomas can show a complete loss of cytokeratin expression and their epithelial phenotype during tumor progression resulted in the development of a tumor progression model in which different tumor types are placed according to their mesenchymal phenotype and their malignant potential (Fig. 2). However, one has to mention that single tumors do not necessary follow this way of progression but may show different forms of dedifferentiation and progression (see below).

Fig. 2.

Epithelial–mesenchymal transition (EMT) of non-small cell lung carcinoma (Nitsche et al. 2012). The direct conversion of an adenocarcinoma or a squamous cell carcinoma into a sarcomatoid carcinoma is a relatively rare but nevertheless possible event. In addition, the model recapitulates the fact that NSCLC often show a mixed differentiation and represent the degree of tumor progression and malignancy of individual NSCLC entities in relation to epithelial–mesenchymal transition. Furthermore, it indicates that lung carcinomas can entirely loose their epithelial phenotype during dedifferentiation and thus formally needs to be classified as sarcomas. Within the pathological reports, however, it should be mentioned that in case of malignant primary lung tumors these neoplasms might have evolved from a lung carcinoma. Otherwise, there might be discrepancies to the clinical aspect of the neoplasm

In daily routine diagnostics, there are further challenges with the diagnosis of LC as well. Since targeted therapies based on tissue-derived biomarkers are becoming the standard in NSCLC treatment, it is more and more important to analyze whether LC are associated with a specific squamous or a non-squamous phenotype and, respectively, associated molecular alterations. For years most pathologists begun to immunohistochemically analyze LC to shed more light on this open question and to allow for the testing of lineage-specific predictive biomarkers, although this was formally not in accordance with the recommendations of the 2004 WHO classification (Travis et al. 2004). Thereby, it has been revealed that the majority of LC have a specific lineage of differentiation (Warth et al. 2012d); most of them can be classified as undifferentiated ADC or SQCC according to their immunophenotype. This is exemplarily also shown by recent data from the SEER data base, demonstrating a significant decrease in LC diagnoses over time (Lewis et al. 2014).

This development is further supported by molecular data, since the genetic alterations of most LC can reliably be assigned to either ADC or to a lesser amount to SqCC and also the prognosis of the patients is then in line with the respective entity (Travis et al. 2015). Since specific predictive biomarker testing is based on the initial tumor subtyping, LC patients benefit from an immunohistochemical or molecular re-classification of their tumors since they might become eligible for targeted therapies with improved outcome compared to the standard LC regimens. Thus, according to the new WHO classification LC are now further characterized by immunohistochemistry and/or molecular analyses and classified as solid predominant ADC or non-keratinizing SqCC if the phenotype is consistent with these lineages (Travis et al. 2015).

This paradigm shift in the classification of LC has not only the described advantages for the patients with respect to therapy but is also a consequent step in regard to the whole field of tumor typing. In general, for other entities such as mesenchymal neoplasias it is already common practice that immunohistochemical marker constellations and specific molecular alterations are diagnostic for specific entities, which is also in line with the general development in pathology that new, reliable diagnostic methods are subsequently integrated into the routine diagnostic setting. Furthermore, immunohistochemistry for NSCLC subtyping is already an established and internationally accepted method for cytology and biopsy material (Warth et al. 2013a).

Carcinoma-like soft tissue tumors of the lungs

Primary sarcomas of the lung are rare; exclusion of a carcinoma should always be considered first in the differential diagnostic setting. However, there are also soft tissue tumors of the lungs, which might mimic carcinomas. For example, epithelioid hemangioendotheliomas can occasionally show histomorphological similarities to a solid carcinoma and can only be separated by the detection of endothelial immunomarkers (Fig. 3). One must also be aware that these tumors can rarely express cytokeratins. The molecular genetics of epithelioid hemangioendotelioma is meanwhile well understood; they are frequently affected by translocations affecting the hippo signaling pathway (Antonescu et al. 2013).

Fig. 3.

a, b Undifferentiated large cell carcinoma (a, HE) with the expression of vimentin (b). c, d Epithelioid hemangioendothelioma with epithelioid-solid tumor growth and little proliferation. In conventional histology, there was only a discrete indications for vascular differentiation, i.e., the formation of vascular lumina (c, HE). The diagnosis is possible by the detection of the expression of endothelial markers (d, CD31) and specific translocations or gene fusions. e, f Poorly differentiated pulmonary adenocarcinoma with transition into a small cell neuroendocrine carcinoma. The tumor has solid growth (e) with necrosis and only focal cribriform differentiation (f). In the immunohistochemical analysis, TTF1 (g) and CK7 were positive, i.e., markers that are expressed by pulmonary adenocarcinoma. At the same time, neuroendocrine markers (CD56, Synaptophysin) and a high proliferation (Ki67, h) were detectable. Thus, it has to be assumed that the neoplasm will show the biological behavior of a small cell carcinoma, which is the appropriate diagnosis in this case

In case of a malignant round cell tumor in a young, non-smoking patient, one should consider the differential diagnosis of a small cell soft tissue tumor. The most frequent organ localization of synovial sarcoma is the lung (Knösel et al. 2010). Similar to Ewing sarcomas, it can be diagnosed by the detection of a specific gene fusion or the corresponding chromosomal translocation. With regard to further soft tissue tumor entities in the lung and their relative frequency, we refer to an article of the Jena reference center for soft tissue tumors (Nitsche et al. 2012).

NSCLC, not otherwise specified (NOS)

If NSCLCs cannot be reliably classified in cytology or biopsy material based on morphological criteria alone, the application of diagnostic immunomarkers is recommended (Travis et al. 2015). In these constellations, the tumor will be designated as NSCLC independent from the results of the immunohistochemical analyses, but with a specific comment to allow for the testing of lineage-specific molecular alterations (“NSCLC, the immunophenotype favors A/B/C”). This defensive classification algorithm is a consequence of the fact that yet available diagnostic immunomarkers for NSCLC show a limited specificity and sensitivity (Warth et al. 2012d). This is also true for NSCLC metastases, which are also assigned to a lineage of differentiation based on the immunophenotype if the morphology alone does not allow for a reliable subtyping. However, resection specimens should always be assigned to a specific entity, still the lack of specificity and sensitivity of immunomarkers can pose a problem. Specifically, one must avoid diagnosing a ADC–SQCC just based on the co-expression of respective immunomarkers if there is no clear morphological evidence for different tumor cell populations.

NSCLC with neuroendocrine differentiation

NSCLC can show morphological and immunohistochemical characteristics of a neuroendocrine differentiation. However, the prognostic relevance of this phenomenon is still unclear. For some cases, there is the clear association of a NSCLC with a neuroendocrine carcinoma in form of a so-called combined small cell lung carcinoma or a combined large cell neuroendocrine carcinoma, which both are considered as highly aggressive tumors (Travis et al. 2015). For these tumors, at least 10 % of each tumor component were essential for the diagnosis in the old 2004 WHO classification (Travis et al. 2004), which is comparable to ADC–SQCC or pleomorphic carcinomas. However, in the 2015 WHO classification there is now no longer a lower threshold for combined carcinomas with ADC, SQCC, or sarcomatoid carcinoma components (Travis et al. 2015).

In combined carcinomas, all components need to have a distinct morphological and immunohistochemical phenotype. However, there is evidence for similarities of the components on the molecular level pointing toward an evolution of the components from each other. Based on this observation, a model of a neuroendocrine tumor progression was developed already a couple of years ago (Petersen and Petersen 2001) in which a pure primary neuroendocrine carcinoma is separated from a combined secondary neuroendocrine carcinoma (Fig. 4). It was established on CGH data. In this model, a neuroendocrine differentiation was considered as a sign of a more aggressive tumor biological behavior. The separation of primary and secondary SCLC is further supported by more recent genetic analyses (Fernandez-Cuesta et al. 2014b).

Fig. 4.

Small cell neuroendocrine tumor progression of lung carcinoma (Petersen and Petersen 2001). Small cell carcinoma can evolve from a NSCLC and may thus be classified as secondary SCLC and correspond to the combined subtype of SCLC. Pure small cell carcinomas are more frequent and may be termed primary SCLC. The immunohistochemical detection of a neuroendocrine differentiation should only be interpreted as a sign of tumor progression in poorly differentiated carcinomas with high proliferation because neuroendocrine markers may also be present in better differentiated NSCLC. In this setting, it does not represent an indication for tumor progression but on the contrary may be a sign of a carcinoma with high differentiation and good prognosis (see Fig. 1c). SqCC squamous cell carcinoma, ADC adenocarcinoma, LCLC large cell lung carcinoma, SCLC small cell lung carcinoma

In general, combined neuroendocrine carcinomas of the lung with morphologically distinct non-neuroendocrine and neuroendocrine components are rare. In daily routine practice, lung pathologists are more frequently faced with carcinomas showing a monomorphous cyto- and histomorphology and the expression of neuroendocrine markers that are still not easily grouped in one of the categories of neuroendocrine tumors. In this regard, cytomorphological criteria are used to differentiate between small and non-small cell carcinoma cells. Specifically, size of the nucleus, chromatin structure, and extent of the cytoplasma are important criteria. Size of the nucleus is also associated with the amount of DNA and the ploidy of the tumors (Petersen et al. 2009; Junker and Petersen 2009). Figure 3 demonstrates a difficult example of a lung cancer case with morphological evidence of an adenoid differentiation (focal acinar and cribriform growth) and respective immunophenotype (TTF-1 positive) but overall small cell size. One might be inclined to diagnose a small cell neuroendocrine ADC in this case. However, this is not a specific entity, neither of the 2004 nor of the 2015 WHO classifications (Travis et al. 2004, 2015). Since this case showed a high proliferation rate of >80 % (Ki-67) and necrosis, it is best to classify it as SCLC since it will likely show an aggressive biological behavior.

Precursor lesions of NSCLC

Several precursor lesions have been associated with lung cancer, and the following correlations are well established (Travis et al. 2004, 2015; Bubendorf 2011):

• Squamous metaplasia with dysplasia—SQCC.

• Atypical adenomatous hyperplasia—ADC.

• Neuroendocrine cell hyperplasia [tumorlet, diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH)]—Carcinoid.

In single case reports, the association of DIPNECH with low-grade ADC (Fig. 1) was described (Mireskandari et al. 2013; Warth et al. 2008). Although this is overall a rare event, it is still noteworthy given the fact that neuroendocrine differentiation is more frequently observed in the context of high-grade carcinomas (see discussion above and Fig. 4). In principle, pulmonary neuroendocrine cells represent precursor cells that may evolve into non-neuroendocrine tumors, as demonstrated for non-neoplastic cells during lung development (Linnoila 2006; Li and Linnoila 2012). Thus, neuroendocrine differentiation in non-neuroendocrine lung cancers must not necessarily be associated with tumor progression. Recent studies demonstrated that different genetic alterations and molecular mechanisms lead to carcinoids on the one hand and highly aggressive SCLC or LCNEC on the other hand (Fernandez-Cuesta et al. 2014a; Peifer et al. 2012).

Compliance with Ethical Standards

Conflict of interest

None.