Lung NETs originate from specialized epithelial cells called pulmonary neuroendocrine cells (PNECs) which can be found interspersed among other cells lining the entire respiratory tract, from the nasal epithelium to the terminal bronchioles. PNECs exist as individual cells or as a cluster of cells, also known as neuroepithelioid bodies (NEBs). They are thought to be key in regulating fetal and neonatal airway development and play a particularly significant role as chemoreceptors for hypoxia. Throughout development, it is hypothesized that PNECs and NEBs exert a paracrine function in regulating the growth of surrounding epithelial cells, and continue their function as oxygen- sensitive chemoreceptors until adulthood.
There is still no clear understanding in the pathogenesis and stepwise malignant transformation of these PNECs and NEBs to lung NETs. One postulated theory is the concept of a putative precursor lesion called diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH). DIPNECH is a rare abnormal growth or hyperplasia in the PNECs and NEBs, resulting in the formation of multiple carcinoid ‘tumourlets’, which are usually <0.5 mm nodules, and are often associated with a surrounding fibrotic process in the lung parenchyma (Figure 1). It is predominantly a benign condition confined to the bronchial epithelium, but there is compelling evidence to suggest that it can be potentially premalignant with higher prevalence of DIPNECH often observed in the background when lung NET is diagnosed. This is currently being investigated further through longer term observational studies. Intriguingly, DIPNECH is about ten times more common in females compared to males.
Fig1. Morphological characteristics of neuroendocrine cell hyperplasia and carcinoid ‘tumourlets’. (a) Early evidence of neuroendocrine cell hyperplasia illustrated with H&E staining with finger- like intraluminal projections from underlying stroma, ×200. (b) Similar cross- sectional view as (a), but with synaptophysin staining for neuroendocrine cell hyperplasia, ×200. (c) Low power (×100) overview of carcinoid ‘tumourlets’ with surrounding fibrotic changes in the stroma. Reproduced with permission from Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010;134(11):1628– 38. Copyright © 2010 College of American Pathologists.
According to the World Health Organization (WHO) criteria, there are four known main subtypes of lung NETs, characterized based on their morphology and pathological characteristics, as summarized in Table 1 and Figure 6.4.3. Historically, well- differentiated tumours are termed lung carcinoids, and consist of typical and atypical lung carcinoids (TC and AC). There is a stronger link between DIPNECH to the formation of TC, and less is known of its association to AC. Apart from morphological appearance, the key differentiating factor between TC and AC is predominantly based on the proportion of actively dividing cells, quantified by the mitotic rate, and presence or absence of necrosis. TC has a mitotic rate of less than 2 per x10 high power field (HPF) and necrosis is not usually observed. In the commonly used three- tier tumour grading classification system, TC would be considered a low grade (grade 1) tumour. AC tends to be intermediate grade (grade 2) and has 2– 10 mitoses per ×10 HPF and is often associated with focal areas of necrotic cells. Meanwhile the more aggressive poorly differentiated lung NETs are formed of LCNEC and SCLC which are almost entirely different entities, and have no known association with DIPNECH. In contrast to lung carcinoids, both subtypes of lung neuroendocrine carcinomas (NECs) (LCNEC and SCLC) are poorly differentiated (grade 3) tumours frequently found with evidence of extensive necrosis and will have more than 10 mitoses per ×10 HPF (median mitotic rate of 70 per ×10 HPF for LCNEC and 80 per ×10 HPF for SCLC, respectively). In general, TC is 8 to 10 times more prevalent than AC, and together TC and AC constitutes 9% of all lung NETs, with the remaining 91% being high- grade NECs.
Table1. World Health Organization (WHO) classification of lung neuroendocrine tumours (NETs)
Fig2. Morphological appearance and description of the four subgroups of lung neuroendocrine tumours (NETs). (a) Typical carcinoid (TC) is characterized by bland, polygonal, and uniform tumour cells with round nuclei with no areas of necrosis. (b) Atypical carcinoid is similar to TC but has higher mitotic activity and focal areas of necrosis (circles). (c) Large cell neuroendocrine carcinoma (LCNEC) consists of large tumour cells arranged in organoid, trabecular, or palisading patterns with prominent nuclei, granular chromatin, and diffuse necrosis. (d) Small cell lung carcinoma (SCLC) consists of small round/ oval and angulated cells with dispersed ‘salt and pepper’ chromatin and extensive necrosis. Reproduced with permission from Pelosi G, Papotti M, Rindi G, Scarpa A. Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors. Endocr Pathol. 2014;25(2):151– 64. Copyright © 2014, Springer Science Business Media New York.
Most lung NETs should demonstrate immunoreactivity to chromogranin A, and synaptophysin and/ or CD56 on the immunohistochemistry panel. Cytokeratins, thyroid- transcription factor- 1 (TTF- 1) and the homeobox transcription factor CDX- 2 may also be useful in the initial test to distinguish between primary lung NETs and other potential primary NETs with metastatic lung lesions. Currently, the proliferation index Ki- 67 which is widely used as a diagnostic tool in GEP- NETs is not yet assimilated as part of the classification criteria in lung NETs. There have been several retrospective studies suggesting its utility as a prognostic tool, and there is a strong proposal for it to be incorporated into the next version update of the WHO classification to further guide clinical management.
Recently, there has also been interesting Next Generation Sequencing (NGS) data where targeted sequencing of 418 genes was performed on 53 TC, 35 AC, 27 LCNEC and 33 SCLC cases. It appeared that NETs and carcinomas shared most of the mutated genes, but had different prevalence. There is a significant enrichment of mutations in TP53, RB1, cycle regulation genes and PI3K/ Akt/ mTOR in the carcinomas compared to NETs. MEN1 alterations were exclusively a feature of well- differentiated NETs. Intriguingly, novel mutations in chromatin- remodelling genes were also found in 45% of NETs and 50% of carcinomas, and were postulated by the authors to play a major part of the pathogenesis of NETs.
