Molecular reprogramming in thymic neuroendocrine tumors: a narrative review

Introduction

Thymic neuroendocrine tumors (tNETs) are exceedingly rare neoplasms arising from neuroendocrine cells of the anterior mediastinum. They constitute fewer than 5% of all primary thymic tumors and less than 1% of neuroendocrine neoplasms (NENs) across organ systems, yet their clinical behavior can be disproportionately aggressive, particularly in poorly differentiated subtypes such as large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SmCC) (1,2). Epidemiologically, tNETs occur more frequently in males, with the predominant age at diagnosis ranging between 40 and 60 years (3,4). A substantial proportion are associated with hereditary syndromes, particularly multiple endocrine neoplasia type 1 (MEN1) (5,6), and more recently atypical thymic carcinoids have also been reported in the context of MEN4 (7).

The World Health Organization (WHO) classified tNETs into typical carcinoid (TC), atypical carcinoid (AC), LCNEC, and SmCC (8), based on mitotic activity, presence of necrosis, and cytologic atypia. However, reliance on morphologic criteria alone often proves inadequate. Recent studies have described a subset of tNETs that display low-grade morphologic features with unexpectedly high proliferative activity (9,10), further challenging the traditional morphology-based classification.

Emerging molecular studies have been challenging the long-standing reliance on morphology and mitotic rate as primary determinants of tumor classification and prognosis. Recent whole-genome studies stratified tNETs into three distinct subgroups based on patterns of chromosomal instability (CNI) (9,11,12). In this framework, tumors are further stratified into three categories according to the extent of chromosomal copy number alterations: CNI-low (0–9 alterations), CNI-intermediate (>9–30 alterations), and CNI-high (>30 alterations). These thresholds were defined based on the degree of chromosomal instability observed in genomic studies, with higher levels of instability correlating with more aggressive clinical behavior and poorer prognosis. Such findings suggest molecular profiling may play a role in refining prognostic models and guiding therapeutic strategies.

Furthermore, the mutational landscape of tNETs remains less well defined than that of other neuroendocrine tumors. Early studies point to a low tumor mutational burden in TCs and more complex genomic alterations in high-grade variants (11,13). Alterations in chromatin remodeling and epigenetic regulation have also been observed, suggesting that these pathways may hold diagnostic and therapeutic relevance.

Against this background, there is growing interest in re-examining tNETs through a molecular lens. The aim of this review is to synthesize recent advances in the genomics, epigenetics, and transcriptomics of tNETs, and to propose an updated framework for their classification that integrates molecular features with traditional histologic findings. By doing so, we hope to facilitate a more nuanced understanding of these rare tumors and to lay the groundwork for future molecularly guided management strategies. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-25-40/rc).

Methods

Studies were identified in PubMed until 31 July 2025. The search keywords were “thymic neuroendocrine tumor”, “molecular”, “chromosomal instability”, “molecular profiling”, “epigenetics”, and “tumor microenvironment”. Reference lists of selected articles were reviewed for additional inclusion. Studies written in languages other than English were excluded (Table 1).

Discussion

Histologic spectrum

Histologically, thymic TC and AC consist of uniform tumor cells with neuroendocrine cytologic features, and a characteristic delicate vascular network. Growth patterns often include nests, trabeculae and organoid arrangements. Recent evidence has questioned the diagnostic value of necrosis in distinguishing ACs, suggesting that its presence may not reliably separate these tumors from TCs. As highlighted by Lang et al. (14) necrosis appears to be a less consistent histologic discriminator than previously assumed, reinforcing the need for integrating proliferative indices and molecular features into diagnostic assessment. LCNEC and SmCC represent the high-grade part of the spectrum, defined by a mitotic rate exceeding 10 per 2 mm² and often displayed extensive necrosis.

As noted in the introduction, accumulating evidence highlights a “grey zone” between carcinoids and neuroendocrine carcinomas, characterized by discordance between morphology and proliferative activity (10). This reinforces the notion that traditional morphology-based classifications, though useful, may not fully capture the true biological heterogeneity and prognostic variability of these tumors (12).

Molecular taxonomy

The molecular heterogeneity of tNETs has long been underappreciated, largely due to their rarity and the consequent lack of large-scale molecular studies. Over the past decade, molecular profiling studies have revealed that tNETs encompass a spectrum of genetically and epigenetically distinct subgroups, with implications that extend beyond simple histologic grading (14,15).

One of the most important contributions in recent years has been the introduction of CNI as a molecular framework for subclassifying tNETs. In a comprehensive genomic analysis of a large cohort of tNETs, Dinter et al. (9) identified three reproducible molecular subgroups: CNI-low, CNI-intermediate, and CNI-high, based on the extent and pattern of chromosomal copy number alterations. These subtypes aligned with tumor histology, but more importantly, they were associated with distinct prognostic patterns.

CNI-low tumors, predominantly TC, exhibited minimal chromosomal alterations and a relatively stable genome, associating with more favorable clinical outcomes and lower rates of recurrence. In contrast, the CNI-intermediate group, composed mostly of AC, some LCNEC, displayed a moderate burden of copy number changes, often involving chromosomes 5q, 11q, and 16q. These tumors displayed variable clinical behavior, underscoring the limitations of purely morphological classification. The CNI-high group, which included most cases of SmCC and LCNEC demonstrated widespread chromosomal alterations and aggressive clinical phenotypes.

In addition to chromosomal instability patterns, high-grade tNETs frequently harbor mutations in TP53 and RB1, mirroring the molecular profile of small cell lung carcinoma and other extrapulmonary high-grade neuroendocrine carcinomas (16). These alterations play a central role in tumor biology and highlight the shared pathogenesis of high-grade NETs across organ systems.

Beyond copy number alterations, the mutational landscape of tNETs remains partially characterized. TC and AC generally exhibit a low tumor mutational burden, with few recurrently mutated genes identified to date (10). MEN1 alterations are recurrent in a subset of tNETs, particularly in AC. Chromatin-modifying genes such as ATRX have been reported in smaller series, although without frequency or specificity to serve as reliable biomarkers. High-grade tNETs, particularly those within the CNI-high category, tend to harbor more complex genomic rearrangements and occasional actionable mutations, including MYC amplification and alterations in the PI3K-AKT-mTOR pathway (11,13,17).

Collectively, the molecular taxonomy of tNETs gives new insight into how to interpret these tumors. Incorporating genomic data and histology may allow clinicians to stratify patients by risk more accurately, identify those who may benefit from targeted therapies, and design more rational clinical trials. Despite remaining challenges, particularly the need for multi-institutional collaboration and validation, these early findings appear to lay the groundwork for a more refined and biologically meaningful classification of thymic NENs.

Epigenetic and transcriptomic landscape

Although genetic alterations offer valuable insights into tumor evolution, the epigenetic landscape of tNETs is being increasingly recognized as equally informative, especially in the context of low mutational burden. Epigenomic profiling of tNETs has revealed differential DNA methylation patterns across histologic subtypes, with global hypomethylation often seen in high-grade tumors and promoter-specific hypermethylation in lower-grade variants, such as RASSF1A silencing (18,19). Alterations in chromatin-related genes are also relevant. The involvement of MEN1 is well established in the thoracic neuroendocrine spectrum, including loss of heterozygosity at the MEN1 locus in thymic tumors arising in MEN1 syndrome (20,21). ATRX abnormalities have been reported, though their frequency and clinical significance in tNETs remain to be defined (17).

Transcriptomic studies further support molecular heterogeneity across TC, AC, and high-grade tumors, with programs related to endocrine differentiation, immune regulation, and proliferation described in thoracic NENs (10,12,14,21,22). In thymic neuroendocrine carcinomas, particularly SmCC and LCNEC, occasional MYC amplifications and alterations in cell cycle regulators such as E2F have been observed, although these are less consistent than in pulmonary SmCC (11,13). With respect to neuroendocrine markers, chromogranin A expression is often reduced or absent in high-grade tNETs, whereas synaptophysin remains more consistently expressed, in contrast to the uniform positivity typically observed in carcinoids (10,17).

The reversibility of epigenetic changes opens the door to potential therapies targeting histone deacetylases (HDACs) or DNA methyltransferases. Preclinical studies in related NENs have demonstrated sensitivity to these agents, though clinical data specific to tNETs remain sparse (23). Nevertheless, incorporating epigenetic profiling into diagnostic workflows may enhance stratification, especially in tumors of ambiguous histology or borderline mitotic activity.

Tumor microenvironment and immune evasion

The immune contexture of tNETs is another frontier that has begun to reveal tumor-intrinsic differences and potential avenues for immunotherapy. Unlike classic thymomas or thymic carcinomas, neuroendocrine tumors of the thymus are typically less inflamed, and exhibit reduced immune cell infiltration, particularly in high-grade forms (24). Multiplex immunohistochemistry and transcriptomic analyses have identified two immune phenotypes: immune-infiltrated and immune-excluded, which often correspond with tumor grade and CNI status (25).

PD-L1 expression has been detected in up to approximately one-third of high-grade tNETs, but is uncommon in low-grade carcinoids. This heterogeneity may explain the modest and inconsistent responses seen in early-phase immunotherapy trials involving thymic neoplasms. In addition to PD-L1, other mechanisms of immune escape, including human leukocyte antigen (HLA) class I downregulation, B2M mutations, and TGF-β signaling, have been noted in aggressive tNETs, paralleling mechanisms seen in extrapulmonary NECs (26). Distinct metabolic programs influencing γδ T cell subsets further highlight the complexity of the thymic tumor immune microenvironment (27).

Understanding these features is essential for the rational development of immunotherapies. Combinatorial approaches, such as combine immune checkpoint inhibitors with anti-angiogenics or epigenetic modulators, may enhance efficacy, particularly in tumors with intermediate immunogenicity. However, the rarity of tNETs continues to limit the feasibility of large-scale clinical trials, underscoring the need for collaborative consortia.

Targetable molecular alterations and therapeutic implications

In terms of systemic therapy, evidence specific to tNETs remains limited, and most treatment approaches have been extrapolated from pulmonary and extrapulmonary NETs. Recent studies, however, suggest that everolimus and temozolomide may provide meaningful benefit in subsets of patients with tNETs, consistent with reports in other thoracic and pancreatic NETs (28,29). In contrast, peptide receptor radionuclide therapy (PRRT), while effective in gastroenteropancreatic NETs, appears less promising in tNETs based on early prospective series (14). Clinical trials such as the LUNA study and the recent cabozantinib trial included both pulmonary and thymic NETs, yet subgroup analyses were not performed, and therefore the results cannot be directly applied to tNETs (3,30,31). These limitations highlight the ongoing challenge of defining evidence-based treatment algorithms for such a rare disease and underscore the need for future trials designed to evaluate therapeutic efficacy specifically in tNETs.

Beyond conventional systemic therapies, the reversibility of epigenetic alterations offers a promising avenue for therapeutic intervention in tNETs. Frequent events such as RASSF1A promoter hypermethylation and MEN1-associated dysregulation suggest that epigenetic reprogramming plays a central role in tumor biology (19,32). Preclinical studies in related NENs have demonstrated sensitivity to histone deacetylase inhibitors (HDACis) and DNA methyltransferase inhibitors (DNMTis), underscoring the potential to translate these findings into clinical application for tNETs (20,25). Although data are still limited, the incorporation of epigenetic modulators—either alone or in rational combinations with molecularly targeted or immune-based therapies—represents a promising strategy for future precision oncology approaches in these rare tumors.

Molecular profiling has also begun to uncover a spectrum of potentially targetable alterations (Table 2). In high-grade tNETs, TP53 and RB1 mutations, MYC amplification, and loss of heterozygosity across multiple chromosomal arms are frequent (12,30). These alterations mirror findings in pulmonary SmCC and suggest potential benefit from targeted agents such as CDK4/6 inhibitors, aurora kinase inhibitors, or PARP inhibitors in select contexts (33). Low-grade tumors, on the other hand, may harbor alterations in mTOR signaling and respond to rapalogues or PI3K inhibitors, though predictive biomarkers remain elusive (33,34).

The challenge lies in matching molecular findings with effective therapies in the context of ultra-rare disease. Tumor-agnostic trials, while promising, may underrepresent tNETs due to their low incidence. As such, an international registry or biomarker-driven basket trials focusing on thymic and thoracic rare tumors could offer a more inclusive and effective platform for therapeutic exploration.

Emerging diagnostic algorithms

Given the limitations of morphology alone, several groups have proposed integrated diagnostic frameworks that combine histologic and molecular features. One of the most influential contributions was made by Dinter et al., who first described a three-tiered classification based on copy number instability (CNI). This framework, later refined by Bohnenberger and colleagues, stratifies tNETs into CNI-low, CNI-intermediate, and CNI-high subgroups, with thresholds defined by the extent of chromosomal copy number alterations. These categories have shown prognostic relevance and may guide therapeutic stratification beyond conventional histology (9,12).

The clinical indications for molecular profiling in tNETs are evolving (16,35). At present, molecular testing is primarily used in cases with ambiguous histology, discordant proliferative indices, or when tumor morphology does not align with clinical behavior. Targeted next-generation sequencing (NGS), copy number profiling, and methylation-based assays are the most frequently applied modalities in this context (36,37). Although molecular profiling is not yet standardized across all institutions, its adoption is increasing in specialized centers where access to advanced genomic platforms is available.

The current evidence base consists largely of retrospective multi-institutional series, smaller single-center studies, and expert consensus statements, rather than randomized controlled trials (36,38). Nevertheless, these studies collectively support the incorporation of molecular tools into diagnostic workflows, particularly to refine risk stratification and inform treatment planning. Prospective validation will be required, but early results suggest that combined histologic and molecular algorithms can provide a more biologically meaningful classification of tNETs than morphology alone.

Future directions and research gaps

Despite recent advances in molecular characterization, several key gaps remain in the study of tNETs. The foremost challenge is their rarity, which limits the assembly of adequately powered genomic datasets and clinical trials. Establishing international consortia, centralized biobanks, and collaborative registries will be essential to enable large-scale, pooled analyses and the development of standardized diagnostic algorithms.

Liquid biopsy represents an emerging and highly relevant tool for rare thoracic tumors such as tNETs, where repeated tissue sampling can be technically challenging. Although direct evidence in thymic tumors is lacking, several studies in related entities provide a strong rationale for translation. In pulmonary carcinoids and high-grade pulmonary neuroendocrine carcinomas, circulating tumor DNA (ctDNA) sequencing and exosomal RNA profiling have demonstrated feasibility for non-invasive molecular characterization, monitoring of disease burden, and early relapse detection (39). Similar approaches have also been reported in extrapulmonary NENs, highlighting their broader applicability across molecularly defined tumor groups. Given that liquid biopsy methodologies are not site-specific, their application to tNETs is both feasible and promising, particularly as a means of overcoming the limitations of limited tissue availability and enabling longitudinal monitoring in clinical practice. Importantly, the combined loss of TP53 and RB1 has emerged as a robust two-gene signature for high-grade neuroendocrine tumors, irrespective of anatomic site. In the context of liquid biopsy, detection of this signature in ctDNA can provide a strong diagnostic clue and may also serve as a marker of disease progression, underscoring its potential utility for molecular monitoring in tNETs.

Artificial intelligence (AI)-based image analysis is another emerging tool that may support molecular stratification in tNETs. In lung and thymic epithelial tumors, deep learning algorithms applied to digitized histology slides have shown promise in predicting mutational status, CNI, and even treatment outcomes (39). Extending such approaches to tNETs could provide a cost-effective and rapid adjunct to molecular testing, particularly in settings where tissue material is scarce or sequencing resources are limited.

In parallel, the design of clinical trials for ultra-rare tumors such as tNETs requires adaptation beyond traditional randomized controlled models. Basket trials, in which patients are enrolled based on shared molecular alterations rather than tumor site, and adaptive platform studies, which allow parallel testing of multiple agents with real-time modifications, have emerged as feasible strategies in rare tumor research (30,40). Incorporating tNETs into such biomarker-driven trial frameworks, alongside the establishment of international registries, may provide the most practical route for generating evidence-based treatment strategies in this rare entity.

Together, these strategies highlight the importance of integrating emerging technologies—such as liquid biopsy, AI, and basket trial methodologies—into future research, with the overarching goal of establishing biomarker-driven, precision oncology approaches tailored to the unique biology of tNETs.

Conclusions

This review consolidates current knowledge on the molecular taxonomy and therapeutic landscape of tNETs while highlighting critical research gaps. By expanding the discussion on diagnostic algorithms, liquid biopsy applications, epigenetic modulation, and trial design, we provide an updated framework that emphasizes both present clinical practice and future directions. The addition of a molecular summary table further contextualizes key genetic and epigenetic alterations across tumor subtypes, supporting efforts toward biomarker-driven stratification. In doing so, this review aims to serve as a resource for clinicians and researchers while underscoring the need for collaborative studies to advance precision oncology in this ultra-rare disease.

Acknowledgments

This article was prepared with the assistance of Scientific Editor 2nd Brain, an AI-powered academic writing tool, used to support literature organization, language refinement, and structural editing.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-25-40/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-25-40/coif). The authors have no conflicts of interest to declare.

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