A Spotlight on Lung Neuroendocrine Neoplasms

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WHO Classification of Tumours, 5th Edition, Volume 5: Thoracic Tumours

The aim of this spotlight is to provide a summary of the latest information on Lung Neuroendocrine Neoplasms (NEN) including the latest terminology, epidemiology data, and guidelines.   This follows the publication of the Thoracic WHO classification 5th edition (2021): terminology and criteria for neuroendocrine neoplasms (Blue Book).  This book has been anticipated to see if the panel compiling this follows the lead of the Gastroenteropancreatic Neuroendocrine Neoplasms (GEPNEN) editions issued in 2017 (Endocrine) and 2019 (Digestive systems) by removing the antiquated misnomer term ”Carcinoid” in line with the recommendations made by senior NEN doctors in 2020 to have commonality across all blue books. Neuroendocrine neoplasm update: toward universal nomenclature © 2020 Society for Endocrinology 2020, Guido Rindi and Frediano Inzani.

I can tell you the Thoracic committee failed to take the leap but left the door ajar.  For example, the heading for all lung types is ‘Neuroendocrine Neoplasms’ an indication they accept the overarching terms of Neuroendocrine Tumours (NET) and Neuroendocrine Carcinoma.  They also listed the section containing NET as “Carcinoid/Neuroendocrine Tumour”.  Apparently, the refusal to remove the term carcinoid completely is related to worry about the clarity of communication with the thoracic treating physicians. Despite a lack of confidence in the ability of thoracic treating physicians, it does provide a naming choice and I hope all those in the NEN community will now take the right one and update their use of this terminology.  The graphic below is a direct extract from the Index of the Thoracic Blue Book as evidence of the choice of language:

There are other differences including the lack of Grade 3 well-differentiated and the use of Mitotic Count rather than Ki67 used in GEPNENs and these points are covered below.

WHO Classification of Tumours up to and including 2021 edition

Despite knowledge of a more aggressive atypical Lung NET which features a mitotic count exceeding 10 mitoses/2mm², they have not decided to introduce a Grade 3 NET into Lung NETs.  Instead, those cases will be considered a Large Cell Neuroendocrine Carcinoma. It is anticipated that a revised classification will be issued once they have more data, i.e. it’s a temporary fix. 

with apologies for the use of the ancient misnomer term 'Carcinoid'

Ki67 vs Mitotic Count in Lung NENs

You will have noticed that the Lung committee has opted for a grading measurement system known as mitotic count measured in mitoses/2mm².  Currently, Ki67 is a standard and routine marker in the reporting of all GEPNETs. The role of Ki67 in those tumours is both prognostic and to some extent drives therapy choices. For lung NETs, the utility and the role of Ki67 continues to be a matter of debate.

Evidence is still emerging along with a practical rationale for the routine inclusion of Ki67 in the reporting of lung NETs.  Although Ki-67 proliferation index is not an essential criterion in the 2021 WHO Classification, for Lung NETs, it is introduced as a desirable criterion, and it may be useful to incorporate this into the pathology reports. This is of importance especially when evaluating a metastatic Lung NET specimen, to support clinical decisions, because medical oncologists are accustomed to the use of Ki-67 index to stratify therapeutic options for progressing digestive and pancreatic NENs. Metastatic pulmonary (and thymic) Lung NETs are treated with similar regimens and Ki-67 index may be requested in some circumstances.  In metastatic Lung NETs, the Ki-67 index may in rare cases exceed standard criteria, causing differential diagnosis problems with high-grade LCNEC and representing a challenge for therapeutic decisions.  Routine reporting of Ki67 is also recommended in the guidelines by regional NEN scientific organisations such as the European and North American NET societies (ENETS and NANETS). It is likely that Ki67 will remain a routine marker in the assessment of lung NET, similar to the digestive system NETs. There are specific Ki67 technical and interpretive assessment (i.e. MIB1 clone, scoring 500+ cells in hot-spots) standards, and such standardisation will require further studies in lung NETs.  For those interested in the technical detail of this subject, read more in Reference 2 below. 


You may hear well-differentiated Lung NETs described in various ways including Pulmonary NETs, Bronchial NETs, and Broncho-Pulmonary NETs (BPNETs). Of course, they still get referred by the ancient and antiquated misnomer name of Carcinoid, e.g. Typical Carcinoid (TC)or Atypical Carcinoid (AC).  Going forward, I will only refer to their names as per the official 2021 edition selecting Neuroendocrine nomenclature rather than the misnomer names. 

As a reminder, the term Neuroendocrine Neoplasms (NENs) is an umbrella term for both well-differentiated Neuroendocrine Tumours (NETs) and poorly differentiated Neuroendocrine Carcinomas (NECs). These terms will be used throughout to help with context and accuracy. 

Types of Lung Neuroendocrine Neoplasms

Lung Neuroendocrine Neoplasms are split into two main groupings in the index above: well and poorly differentiated.  Like GEPNENs, the well-differentiated types are known as NET and poorly differentiated ones are known as NEC (although there are some nomenclature exceptions with both Lung NETs and NECs).  They are defined by their morphologic and immunohistochemistry (IHC) features.  One key difference is the use of mitotic count rather than Ki67 used by GEPNENs including a different unit of measurement for GEPNENs using mitotic count, i.e. 2mm² rather than 10HPF.

One of the other key differences to the GEPNEN classification is the lack of Grade 3 well differentiated Lung NETs.  I think downstream that category will be added but in preparing for this post, I have read informed comments as to why they did not take that leap now.  I will explain that further below.

Lung NEN Epidemiology Primer

Well-differentiated lung NETs comprise approximately 27% of all NETs (90% Typical and 10% Atypical) only making up 1% to 2% of all primary cancers found in the lungs.  The prevalence of well-differentiated lung NET has increased by approximately 6% per year over the last 30 years in both men and women.

In contrast, a decreasing trend in Lung NEC (particularly Small Cell Lung Cancer (SCLC)) incidence has been observed, this is thought to be in line with a decrease in tobacco smoking, the key risk factor for most cancers of the lung.  Nonetheless, I looked at US figures from ASCO for 2021 where I found the following statement:  ” ….. that an estimated 235,760 adults (119,100 men and 116,660 women) in the United States will be diagnosed with lung cancer. This includes people diagnosed with both SCLC and Non Small Cell Lung Cancer (NSCLC). However, since the mid-2000s, lung cancer incidence rates have dropped by around 2% each year. About 13% of people diagnosed with lung cancer have SCLC”.  It follows that the incidence rate of small cell Lung NEC (SCLC) is currently around 30,648 making it the most common type of Neuroendocrine Neoplasm.  Large Cell Lung NEC accounts for around 3% of all lung primary tumours. Based on the ASCO figures above, that is approximately another 7000 NEC to add to annual incidence figures which now total approximately 38,000 Lung NEC in USA each year. I can tell you this figure is much higher than the figures frequently banded around for all NETs in SEER updates for Neuroendocrine Neoplasms (based on 7 per 100,000 in USA makes it approximately only 22,400).   It means that the Neuroendocrine Neoplasm data used and referred to in many studies by all our scientific and advocate organisations almost certainly do not include Small or Large Cell Lung NEC.  Neuroendocrine Neoplasms – not as rare as you think. It also means unlike GEPNENs, where the incidence rate of NET is higher than NEC, in lung NENs, the opposite applies. 

You will see from the index in the opening section that they included a section on Diffuse idiopathic pulmonary neuroendocrine hyperplasia (DIPNECH) which is explained below.

Diffuse idiopathic pulmonary neuroendocrine hyperplasia (DIPNECH)

By definition, this is considered a pre-invasive lesion that may progress into ‘tumorlets’ or Lung NETs, usually Typical Lung NET.  It tends to present as multiple bilateral tumorlets (<0.5 cm size) and neuroendocrine cell hyperplasia. Case studies suggest it can also be found alongside Lung adenocarcinomas.  The largest study I could find was from Mayo Clinic which said “DIPNECH remains a rare disease more commonly diagnosed in women in their early 60’s. DIPNECH appears to have an indolent course with obstructive symptoms being the most common finding. A minority of patients experienced symptom relief with therapy. Overall, DIPNECH appears to have a low risk of progressing to Lung NET based on the observation of this study.”

Well Differentiated Lung NETs

The epidemiologic data for Lung NENs is very different to GEPNENs in that the incidence rate for Lung NEC far outweighs the Lung NET variants, the opposite is true for GEPNENs.   It also points to Lung NENs being the most common type of NEN in an anatomical grouping context.  The main reason for that is the large amount of Lung NEC (see why below). There does not appear to be a relationship between well-differentiated lung NETs and smoking (unlike Lung NEC). However, there is evidence suggesting that Lung NETs are morphologically distinct from Lung NECs and that might partly explain some of the differences.

Typical Lung NETs (Grade 1) account for approximately 90% of well-differentiated lung NETs and approximately 25% of all NETs.  Tumours normally measure at least 0.5 cm, with fewer than two mitoses per 2mm2 of viable area of tumuor. They lack necrosis.

Atypical Lung NETs (Grade 2), Less common and make up most of the remaining 10%.  Atypical versions have two to 10 mitoses per 2mm2 of viable area of tumour, normally with the presence of necroses that are often focal (i.e. a localised area of disease).

Location. Most well-differentiated lung NETs are located centrally in the main (10%) or lobar bronchi (75%), with the remainder located in the peripheral lung.

Grading.  Lung NETs pathology can be based on mitotic count measurement rather than Ki67 used in GEPNETs.  However, the updated 2021 WHO classification for lung NETs provides guidance on the use of the Ki-67 cell proliferation labeling index to distinguish between what appears to be high-grade lung NETs and Typical/Atypical Lung NETs, particularly in crushed biopsy specimens, in which some well-differentiated NETs may be mistaken for poorly differentiated Lung NEC (in particular Small Cell Lung Cancer (SCLC) – see NEC section below).  You will also note the lack of Grade 3 well-differentiated type as classified with GEPNETs and this will be covered below. Like other types of NET, the detection of immunohistochemical markers confirms a diagnosis of lung NET, with chromogranin A, synaptophysin, and CD56 included. However, these tumor markers are not able to distinguish between subtypes of lung NETs. Tumour expression of thyroid transcription factor-1 (TTF-1) is also checked regularly and may be utilised to confirm a diagnosis of lung NET – but it will be negative in many well-differentiated Lung NETs. 

Staging.  Both Typical and Atypical Lung NETs are capable of regional lymph node or distant metastasis, Atypical clearly being more aggressive. In a large multi-institutional study, Atypical had higher rates of lymph node involvement at diagnosis (36%) and distant metastases (26%) than Typical (9% and 4%, respectively), highlighting the importance of long-term follow-up in patients with lung NETs, including those with low-grade tumors. The full range of imaging techniques are available including nuclear as most well-differentiated Lung NET patients will express somatostatin receptors (80%).  Grade 2 Atypical NETs with higher Ki67/mitotic count numbers may also benefit from FDG PET.

Secretory Syndromes associated with Lung NETs

Although more than 90% of lung NETs are nonfunctional, functional (secretory) lung NETs may present with hormonal symptoms (i.e. Carcinoid Syndrome – wheezing, cutaneous flushing, and diarrhea) owing to tumor cell secretion of hormones and peptides, such as serotonin and histamine.  However, some of these symptoms, particularly breathing issues, usually reflect tumor location rather than an effect of a syndrome.  For example, centrally located tumors (primarily Typical Lung NETs) often present with obstructive respiratory symptoms related to tumor mass, including cough, hemoptysis, dyspnea, chest pain, wheezing, and pneumonitis. In contrast, peripherally located tumors (normally Atypical Lung NETs) usually present as asymptomatic incidental findings. Much less commonly, Cushing’s Syndrome is also reported in Lung NETs, often as a result of an ectopic adrenocorticotrophic hormone (ACTH) from a lung tumour.

Hereditary Syndromes associated with Lung NETs

Approximately 5% of cases of well-differentiated Lung NETs are associated with multiple endocrine neoplasia type 1 (MEN1).

Aggressive Well Differentiated Lung NET with morphologic features of Atypical Lung

According to the 2021 thoracic WHO classification, 10 per 2mm2 is upper limit for Atypical Lung NETs.  Anything above that would be classified as Grade 3, which in Lung NENs, is only NECs. As there is no Grade 3 well differentiated NET category in the 2021 Thoracic WHO, tumours above 10 per 2mm2 (mitotic count) having Atypical Lung NET morphology, something being increasingly recognised in the general Lung NET population, will still need to fit somewhere into the 2021 classification Provisionally, the current WHO is to classify such tumors as “LCNEC with morphologic features of carcinoid tumor”, while more data is accumulated to inform the optimum decision. 

Lung Neuroendocrine Carcinoma (NEC)

Two main types are recognised:  

Large Cell Neuroendocrine Carcinoma of the Lung (LCNEC)

Accounting for 3% of all primary lung neoplasms, LCNEC is defined as tumors with neuroendocrine morphology (organoid nesting with palisading, trabeculae, rosettes), cytologic features of non-small cell carcinoma (large cells size, prominent nucleoli, and/or abundant cytoplasm), and high proliferation rate, defined as >10 mitoses per 2mm2, but generally substantially exceeding this threshold (median 70 mitoses/2mm2). Expression of at least one of the 3 standard neuroendocrine markers (synaptophysin, chromogranin A, CD56) is required for the diagnosis. 

Small Cell Lung Cancer (SCLC), i.e. SCNEC

The defining features of the classic, oat-cell morphology of SCLC include small cell size <3 lymphocytes (pathology measurement). This cancer is also known oat cell lung carcinoma.  Normally a high proliferation rate, defined as >10 mitoses per 2 mm2, but generally substantially exceeding this threshold (median 70 mitoses/2 mm2). It accounts for approximately 15% of all primary tumours of the lung.  Given those potential numbers, it makes SCLC the most common type of NEN. 

Location. Lung NEC usually begin in the large airways (bronchi) of the lungs. 

Grading.  Lung NEC pathology is normally based on mitotic count measurement rather than Ki67 used in GEPNENs.  However, the updated 2021 WHO classification for lung NETs provides guidance on the use of the Ki-67 cell proliferation labeling index to distinguish between what appears to be high-grade lung NETs and Typical/Atypical Lung NETs, particularly in crushed biopsy specimens, in which some well-differentiated NETs may be mistaken for poorly differentiated Lung NEC (in particular SCLC).  The IHC for this sub-type is complex, e.g.

– 15–20% of SCLC are negative for the 2 most widely used neuroendocrine markers—synaptophysin and chromogranin A. Although most are positive for CD56 and/or INSM1 in these cases.
– entirely neuroendocrine-negative SCLC may still occur, plus some SCLC have only minimal neuroendocrine marker labeling (e.g., CD56-only in rare cells).
– TTF-1 is positive in the majority of SCLC (~80%), but it is usually associated with high neuroendocrine marker expression. 

I emphasise again, this is a very complex diagnosis; more exceptions can be found in reference 2 below. 


Standard Stages I to IV apply but the terms below are also frequently used for SCLC. 

  • Limited-Stage Disease. No universally accepted definition of this term is available. Limited-stage disease (LD) SCLC is confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port. Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups.
  • Extensive-Stage Disease. Extensive-stage disease (ED) SCLC has spread beyond the supraclavicular areas and is too widespread to be included within the definition of LD. Patients with distant metastases (M1 as part of the TNM staging definition) are always considered to have ED.

Secretory Syndromes associated with Lung NECs

Infrequently, patients with SCLC may present with symptoms and signs of a paraneoplastic hormonal syndrome, e.g:

  • Syndrome of Inappropriate antidiuretic hormone (SIADH).
  • Cushing syndrome from the secretion of adrenocorticotropic hormone.

Hereditary Syndromes associated with Lung NECs

Information is scant. 

Combined Neuroendocrine Carcinomas

Combined neuroenocrine carcinomas are defined by the WHO as tumors containing both SCLC or LCNEC components plus any type of NSCLC component (adenocarcinoma, Squamous cell carcinoma (SqCC), large cell carcinoma, rarely other). For combined SCLC, the most common combination is with LCNEC or large cell carcinoma (~10% of cases), whereas combination with other NSCLC components is uncommon (3–9%). Given the common presence of occasional large cells in SCLC, only if they exceed 10% is it recommended by the WHO to classify as combined carcinoma (with MINENS in GEPNETs, the threshold is 30%). For adenocarcinoma or SqCC, any amount of such component qualifies for combined SCLC diagnosis.

Carcinomas with co-existing neuroendocrine and mucinous differentiation in the same cell rather than in distinct geographic areas (so-called amphicrine carcinomas) do rarely occur in the lung although they are better described in the digestive tract. The WHO taxonomy for these is currently lacking, but conceptually such tumour may be regarded as a type of combined carcinomas.

Unlike carcinomas, well-differentiated Lung NETs generally do not occur in combination with NSCLC, supporting their highly distinct histogenesis, with only rare exceptions documented in case reports.

MDT/Tumor Board/Centre of Excellence Oversight

I’m fairly certain that many Lung NECs are looked after by Lung MDTs rather than NET MDTs. UKINETS guidance confirms this is the case for SCLC (SC Lung NEC) in the UK. I suspect that is not an uncommon situation. I also suspect that many Lung NEN patients find themselves in the same situation. For complex lung NEC such as SCLC, this is not necessarily a bad thing but that is only my layman’s perspective.


I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me. 

Neither should any post or comment made by a follower or member of my private group be assumed to be medical advice, even if that person is a healthcare professional.   

Please also note that mention of a clinical service, trial/study or therapy does not constitute an endorsement of that service, trial/study or therapy by Ronny Allan, the information is provided for education and awareness purposes and/or related to Ronny Allan’s own patient experience. This element of the disclaimer includes any complementary medicine, non-prescription over the counter drugs and supplements such as vitamins and minerals.

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