Spotlight on Thymic Neuroendocrine Neoplasms (Thymic NENs)

Spotlight on Thymic Neuroendocrine Neoplasms (Thymic NENs)

A rare but important member of the NEN family

What Are Thymic Neuroendocrine Neoplasms?

Thymic neuroendocrine neoplasms (tNENs) — often referred to as thymic carcinoids when well‑differentiated, are rare tumours arising from neuroendocrine cells in the anterior mediastinum. They represent less than 5% of all primary thymic tumours and well under 1% of all NENs.

Lung NENs and Thymic NENs share the 2021 WHO Thoracic Tumours (5th edition) and they both follow a similar top level classification which includes four subtypes:

• Typical carcinoid (TC) – NET G1
• Atypical carcinoid (AC) – NET G2*
• Large‑cell neuroendocrine carcinoma (LCNEC) – NEC
• Small‑cell carcinoma (SmCC) – NEC

* Experts acknowledge that some atypical thymic NETs behave like high‑grade NETs without meeting criteria for NEC. i.e. Atypical Thymic NET morphology and a higher proliferative index (>10 mitosis/2 mm²) and/or Ki67 proliferation index >20%This remains an area of active discussion, and future WHO updates may address it as more molecular data emerge, hopefully in the 6th Edition of the WHO Thoracic Tumours.

ENETS 2025 guidance continues to treat TC and AC as thymic NETs, and LCNEC/SmCC as thymic NEC, reflecting their distinct biology.  In line with the Lung NENs Spotlight, I will use 21st century nomenclature rather than the archaic ‘carcinoid‘. Hopefully in the 6th Edition of the WHO Thoracic Tumours, nomenclature will be aligned with the rest of the NEN family.

How Common Are They?

Thymic NENs are among the rarest thoracic malignancies.

A key epidemiological feature is their association with MEN1:

• Around 25% of thymic and lung NETs occur in MEN1
• Thymic NETs show a male predominance, especially in MEN1 families

ENETS 2025 guidance update: thymic NETs contribute disproportionately to MEN1‑related mortality, and thymic imaging is recommended as part of MEN1 surveillance in expert centres.

Clinical Presentation

Symptoms usually relate to mass effect in the mediastinum:

• Chest pain
• Cough
• Breathlessness
• Superior vena cava obstruction

Paraneoplastic syndromes are more frequently reported in thymic NETs than in many other NET sites, driven mainly by ectopic ACTH production (Cushing’s syndrome). Hypercalcaemia (PTHrP) is rare but recognised, and ADH‑related hyponatraemia is very uncommon, with only isolated case reports.  Carcinoid syndrome is rare.

In terms of frequency:

1. Cushing’s syndrome (ectopic ACTH)
2. Hypercalcaemia (PTHrP) — rare but recognised
3. Hyponatraemia (ADH/SIADH) — very rare
4. Carcinoid syndrome — exceptionally rare

Pathology and Grading

Thymic NENs share morphological features with pulmonary NENs but show three copy‑number instability (CNI) groups:

• CNI‑low → typical Thymic NET
• CNI‑intermediate → atypical Thymic/LCNEC
• CNI‑high → small‑cell carcinoma

Ki‑67 is not part of WHO grading, but typical values are:

• TC: <20%
• AC: up to 30%
• LCNEC/SmCC: >50–80%

ENETS 2025 guidance continues to emphasise mitotic count and necrosis as the primary grading criteria for thymic NETs.

Small‑Cell Carcinoma (SmCC) — The High‑Grade End of the Spectrum

Thymic small‑cell carcinoma is a genuine tNEN subtype, representing less than 10% of cases and forming the CNI‑high molecular group. It is characterised by:

• RB1 and TP53 loss
• Ki‑67 >80%
• Extensive necrosis
• Rapid local invasion and early metastasis

Unlike pulmonary SmCC, no smoking association has been identified.

Most patients present with unresectable disease, and response to chemoradiotherapy is limited. Median survival is approximately 14 months, with no long‑term survivors reported.

Staging

The TNM system (UICC/IASLC/ITMIG) is the recommended staging system for thymic epithelial tumours, including thymic NENs.

Metastatic Patterns

• Regional lymph nodes: up to 50% at diagnosis
• Distant metastases: bone, lung, liver
• Pleural involvement: less common than thymic carcinoma

Treatment Overview (Aligned with ENETS 2025 guidance paper)

Surgery

Surgery remains the cornerstone of treatment for thymic NETs.

ENETS recommends:

• Complete thymectomy
• Systematic lymph‑node dissection
• Surgery performed in high‑volume thoracic or NEN centres

Systemic Therapy for Well‑Differentiated Thymic NETs (TC/AC)

ENETS supports a structured approach:

• Somatostatin analogues (SSAs) for SSTR‑positive, slowly progressive disease
• Everolimus for progressive disease
• Temozolomide‑based chemotherapy (e.g., CAPTEM)
• PRRT for SSTR‑positive disease progressing despite SSA

Systemic Therapy for Thymic NEC (LCNEC/SmCC)

• Platinum–etoposide chemotherapy
• Radiotherapy for local control
• Surgery rarely feasible

Follow‑Up

ENETS emphasises long‑term surveillance, as recurrences can occur many years after apparently curative surgery.

Thymic Cancer vs Thymic NENs — Why the Distinction Matters

Thymic neuroendocrine neoplasms (tNENs) are often confused with “thymic cancer,” but they are biologically and clinically distinct. Thymic cancer refers specifically to thymic carcinoma, a non‑neuroendocrine epithelial malignancy that behaves more like an aggressive squamous carcinoma. Thymic NENs arise from neuroendocrine cells and include typical Thymic NET, atypical Thymic NET, LCNEC and small‑cell carcinoma. Although both fall under the umbrella of thymic epithelial tumours, they differ in cell of origin, morphology, molecular features, paraneoplastic profiles and treatment pathways. Thymic carcinoma tends to show rapid local invasion, early nodal spread, and poorer prognosis, whereas thymic NETs — especially TC and AC — may follow a more indolent but unpredictable course. Thymic MiNENs blur this boundary but remain exceptionally rare.

Thymic MiNENs — What Do We Know?

MiNENs (Mixed Neuroendocrine–Non‑Neuroendocrine Neoplasms) are exceptionally rare in the thymus, with only isolated case reports.

Key points:

• Defined by ≥30% neuroendocrine and ≥30% non‑neuroendocrine components
• Non‑neuroendocrine elements usually squamous carcinoma or adenocarcinoma
• Behaviour driven by the highest‑grade component, typically the NEC element
• Managed according to thymic NEC, not thymic NET
• NCRAS includes MiNENs in incidence analyses but excludes them from survival modelling

For patient education: thymic MiNENs are not typical NENs and require a different treatment mindset.