A Spotlight on Lung Neuroendocrine Neoplasms

Disclaimer:
The information in this Spotlight is for general education and awareness. It does not replace personalised medical advice, diagnosis, or treatment. Lung Neuroendocrine Neoplasms (NENs) are complex and highly variable, and individual cases may differ significantly from the patterns described here. Always discuss your own situation, test results, and treatment options with your specialist team, including your thoracic, oncology, endocrine, or NET multidisciplinary team (MDT). If you have concerns about symptoms, progression, or treatment decisions, please seek guidance from your clinical team without delay.

This 2026 updated spotlight summarises the latest understanding of Lung Neuroendocrine Neoplasms (NENs), including terminology, epidemiology, classification, functional syndromes, and emerging therapeutic targets. It remains based on the WHO Classification of Thoracic Tumours, 5th Edition (2021), with forward‑looking commentary anticipating the 2026 revision.

My advocacy position remains unchanged: the term “carcinoid” is an antiquated misnomer that should be retired. The 2021 WHO edition failed to take the final step, but it did leave the door open — and the NEN community should walk through it.

“The 2021 blue book index listed the section containing NET as ‘Carcinoid/Neuroendocrine Tumour’… i.e. it does provide a naming choice and I hope all those in the NEN community will now make the right one.”

This spotlight therefore uses 21st‑century nomenclature throughout.

1. Nomenclature: Why It Matters (and Why It Still Isn’t Fixed)

The 2021 WHO Thoracic volume correctly uses the umbrella term Neuroendocrine Neoplasms (NENs), grouping:

Well‑differentiated Neuroendocrine Tumours (NETs)
Poorly differentiated Neuroendocrine Carcinomas (NECs)

However, the committee retained the outdated term “carcinoid” in parallel with NET — a decision driven by concerns about “communication clarity” among thoracic physicians rather than scientific accuracy.

From your attached document:

“The refusal to remove the term Carcinoid completely is related to worry about the clarity of communication with the thoracic treating physicians.”

The 2026 edition is expected to correct this. Until then, I use Typical and Atypical Lung NET, not “carcinoid”.

2. WHO 2021 Classification: Key Features and Key Problems

Well‑differentiated Lung NETs

Typical Lung NET (Grade 1)
Atypical Lung NET (Grade 2)

Poorly differentiated Lung NECs

Small Cell Lung Cancer (SCLC)
Large Cell Neuroendocrine Carcinoma (LCNEC)

Major differences from GEPNENs

Lung uses mitotic count per 2 mm², not Ki‑67
No Grade 3 well‑differentiated NET category. Provisionally, the current WHO direction is to classify such tumours as ‘LCNEC with morphologic features of carcinoid tumour’, while more data is accumulated. Aggressive atypical Lung NETs (well‑differentiated tumours >10 mitoses/2 mm²) are placed into LCNEC category as a temporary fix. These aggressive Atypical Lung NETs are often called Supra‑carcinoids
Ki‑67 is acknowledged but not formally integrated

3. Epidemiology of Lung NENs (Including Carcinoid Syndrome & Cushing’s)

Overall burden

Lung NETs = 1–2% of all primary lung cancers
Lung NETs = ~25–30% of all NETs
Typical:Atypical ≈ 90:10
Incidence rising ~6% per year over 30 years

The NEC paradox (updated with molecular epidemiology)

Unlike GEPNENs, where NETs outnumber NECs, lung NENs are dominated by NECs:

SCLC ≈ 30,000+ cases/year (US)
LCNEC ≈ 7,000 cases/year (US)
Total lung NEC ≈ 38,000/year

These estimates are derived from US lung cancer incidence data (ACS/ASCO) combined with the known proportions of SCLC (~13% of all lung cancers) and LCNEC (~2–3%). Although approximate, they reflect the real‑world burden far more accurately than registry‑based NEN figures, which typically exclude lung NECs entirely.

However, modern molecular profiling shows that not all SCLC are equally neuroendocrine. Based on the best available immunohistochemical and genomic studies, around 70–85% of SCLC are genuinely neuroendocrine (NE‑high), driven by ASCL1 or NEUROD1. The remaining 15–30% fall into NE‑low or non‑neuroendocrine categories, typically associated with POU2F3 or YAP1 expression.

Even so, the WHO classification remains morphology‑based, and all SCLC are classified as Neuroendocrine Carcinomas (NECs) because they share the same architectural patterns, mitotic activity, and clinical behaviour. This means that, even after accounting for NE‑low subtypes, lung NECs still vastly outnumber lung NETs, and the overall burden of lung NENs remains significantly under‑recognised in epidemiologic reporting.

Reference 9, the 2024 ENETS position paper (J Neuroendocrinology, DOI: 10.1111/jne.70174) reinforces this distinction, noting that SCLC comprises both neuroendocrine‑high and non‑neuroendocrine molecular subtypes. However, ENETS also emphasises that WHO classification remains morphology‑based, and therefore all SCLC continue to be classified as Neuroendocrine Carcinomas (NECs). This aligns with clinical behaviour, treatment response, and the architectural patterns seen on pathology.

Even after accounting for NE‑low subtypes, lung NECs still vastly outnumber lung NETs, and the overall burden of lung NENs remains significantly under‑recognised in epidemiologic reporting.

4. Functional Syndromes in Lung NENs

Carcinoid Syndrome (rare in lung NETs)

More than 90% of lung NETs are non‑functional. Carcinoid syndrome occurs in a small minority, usually when:

There is liver or widespread metastasis
The tumour secretes serotonin or histamine
The tumour is centrally located (more common in Typical NETs)

From your attached document:

“Although more than 90% of lung NETs are non-functional, functional lung NETs may present with hormonal symptoms…”

Ectopic ACTH & Cushing’s Syndrome

Occurs in:

A small fraction of Typical/Atypical Lung NETs
1–5% of SCLC cases (varies by series)

Your attached text:

5. Well‑Differentiated Lung NETs

Typical Lung NET (Grade 1)

~90% of lung NETs
<2 mitoses per 2 mm²
No necrosis
Often central; obstructive symptoms common

Atypical Lung NET (Grade 2)

2–10 mitoses per 2 mm²
Focal necrosis
More aggressive; higher rates of nodal and distant spread

Staging & Imaging

Both can metastasise
80% express somatostatin receptors → SSTR PET useful
Higher‑grade atypical NETs may benefit from FDG PET

Hereditary associations

~5% linked to MEN1

5A. Ki‑67 vs Mitotic Count in Lung NETs (Why It Matters)

Unlike GEPNENs, where Ki‑67 is central to grading, the 2021 WHO Thoracic classification mandates mitotic count per 2 mm² as the grading criterion for Lung NETs. Ki‑67 is not a formal grading tool, but it remains clinically valuable.

Ki‑67 is particularly useful when:

mitotic figures are difficult to assess
biopsies are crushed or limited
distinguishing high‑grade NET from NEC
identifying aggressive well‑differentiated tumours (“Supra‑carcinoids”)

Your WHO text acknowledges this role:

“The updated 2021 WHO classification for lung NETs provides guidance on the use of the Ki‑67 cell proliferation labelling index to distinguish between what appears to be high-grade lung NETs and Typical/Atypical Lung NETs…”

The controversy

Ki‑67 is not yet standardised in lung pathology because:

different labs use different clones and counting methods
Ki‑67 often reads higher than mitotic count
WHO has not defined Ki‑67 cut‑offs for lung NETs
thoracic pathology has historically relied on mitoses, not proliferation indices

The emerging consensus

Mitotic count = the rule
Ki‑67 = the reality

And for “Supra‑carcinoids”:

Ki‑67 >30% is increasingly recognised as a meaningful threshold
These tumours behave like well‑differentiated high‑grade NETs, not LCNEC
WHO 2026 is expected to clarify the use of Ki‑67 more formally

6. The Missing Grade 3 Lung NET (“Supra‑carcinoids”)

One of the most significant gaps in the 2021 WHO Thoracic classification is the absence of a Grade 3 well‑differentiated Lung NET category. GEPNENs have had this category since 2017/2019, but lung NETs were left behind — creating a diagnostic and therapeutic no‑man’s‑land.

Clinically and pathologically, we now recognise a group of tumours that:

Have well‑differentiated morphology
Have mitotic counts above 10 per 2 mm²
Often have Ki‑67 >30%
Behave more aggressively than Atypical NETs
But do not fit the biology of LCNEC or SCLC

These tumours are increasingly referred to as “Supra‑carcinoids” — a term that acknowledges their NET‑like architecture but recognises their higher proliferative activity.

This is a temporary workaround, not a biologically accurate solution.

What might we see in the next WHO Thoracic ‘blue book’ edition?

A formal Grade 3 Lung NET category
Integration of Ki‑67 into lung grading
Removal of the “LCNEC with carcinoid morphology” stop‑gap
Alignment with GEPNEN classification principles

This will finally give “Supra‑carcinoids” a proper home.

7. Poorly Differentiated Lung NECs

Small Cell Lung Cancer (SCLC)

~15% of all lung cancers
Extremely high mitotic rate
Often presents with bulky central disease
Paraneoplastic syndromes: SIADH, Cushing’s

Large Cell Neuroendocrine Carcinoma (LCNEC)

~3% of lung cancers
High mitotic rate (median ~70/2 mm²)
Requires at least one neuroendocrine marker (synaptophysin, chromogranin A, CD56)

Why NECs dominate lung NEN epidemiology

Because SCLC is so common, lung NECs are most likely the most common NENs in the body — a fact almost never reflected in NEN statistics. Based on the best available molecular and immunohistochemical studies, around 70–85% of SCLC are genuinely neuroendocrine, while 15–30% fall into the “non‑neuroendocrine” or “NE‑low” categories. These figures come from subtype analyses using ASCL1, NEUROD1, POU2F3, and YAP1 expression

8. DIPNECH

A rare, pre‑invasive neuroendocrine proliferation, usually in:

Women
In their 50s–60s
With chronic cough or airflow obstruction

“DIPNECH remains a rare disease… Overall, DIPNECH appears to have a low risk of progressing to Lung NET.”

9. Combined NECs

Defined as:

SCLC or LCNEC plus any NSCLC component
Most common combination: SCLC + LCNEC
Thresholds differ from GEPNEN MINEN rules

Amphicrine tumours are rare but recognised.

10. MDT Oversight & Guidelines

Many lung NECs are managed in lung MDTs, not NET MDTs
UKINETS confirms SCLC sits firmly in lung MDT territory, at least in UK
This contributes to the under‑recognition of lung NECs in NEN statistics

Your attached text:

Guidelines

NCCN: Lung NETs covered; lung NECs not
ENETS 2015: Still relevant; update expected
2024 ENETS Lung Task Force: Confirms ongoing divergence in MDT oversight

11. DLL3 and Emerging Targets

DLL3 is highly expressed in:

SCLC
LCNEC
Some aggressive lung NETs

It is a major therapeutic target for:

Antibody–drug conjugates
Bispecific T‑cell engagers
Radiopharmaceuticals (future)

This is far more relevant to lung NENs than GEPNENs. I wanted to include DLL-3 as it relates more to Lung NENs that it does to GEPNENs. Read more by clicking here or on the graphic below.

12. Why Terminology Matters (Advocacy)

The persistence of “carcinoid” in lung medicine:

Confuses patients
Obscures the relationship between lung NETs and other NETs
Reinforces outdated clinical assumptions
Hinders unified research and guideline development

The WHO has already given us the correct umbrella term: Neuroendocrine Neoplasms. The community should use it — consistently, confidently, and without apology.

13. Resources and References Used to Compile this Summary

14. See more of my Spotlight series

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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.

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