Ileal neuroendocrine tumors: clinicopathological features and associations with systemic inflammatory and nutritional markers

Abstract

Background: Ileal neuroendocrine tumors (NETs) are well-differentiated neoplasms with relatively indolent histological features but an often aggressive biological behavior, characterized by early lymphatic and hematogenous dissemination. Increasing evidence suggests that systemic inflammatory and nutritional status may influence tumor progression; however, data regarding these parameters in ileal NETs remain limited. Patients, Materials and Methods: A retrospective observational study was conducted on 12 consecutive patients with histologically confirmed ileal NETs who underwent surgical treatment between 2018 and 2024. Clinicopathological, morphological, immunohistochemical, and laboratory data were analyzed. Systemic inflammatory and nutritional indices, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, lymphocyte-to-monocyte ratio, and prognostic nutritional index, were calculated from preoperative blood tests and evaluated in relation to metastatic status. Results: The cohort comprised predominantly well-differentiated NETs classified as NET G1–G2. Most tumors showed deep wall infiltration and a high prevalence of regional lymph node and distant metastases at diagnosis. Patients with metastatic disease were significantly younger and had lower hemoglobin levels. Higher values of inflammatory indices and lower nutritional markers were consistently observed in the metastatic group, although these differences did not reach statistical significance. Conclusions: Ileal NETs exhibit a distinct biological behavior in which well-differentiated morphology frequently coexists with advanced disease. Systemic inflammatory and nutritional indices may reflect tumor burden and metastatic potential and could complement histopathological evaluation in the clinical assessment of ileal NETs. Larger prospective studies are warranted to clarify their prognostic value.

Introduction

Neuroendocrine tumors (NETs) comprise a diverse group of malignancies originating from neuroendocrine cells located throughout the gastrointestinal (GI) tract and various other organs. In recent decades, their reported incidence has increased significantly, a trend largely attributed to advances in diagnostic methods, imaging techniques, and pathological evaluation [1, 2]. Although many NETs display a relatively indolent histological appearance, their biological behavior is highly heterogeneous and depends on factors such as tumor location, grade, and stage at diagnosis.

Small intestinal neuroendocrine tumors (SI-NETs) are the most common malignant tumors of the small bowel and represent approximately one-third of all GI NETs. Within this category, the ileum is the predominant site of origin, with a particular predilection for the distal segment of the small intestine [3, 4].

Due to their subtle and often nonspecific clinical manifestations, ileal NETs are frequently identified at an advanced stage, when regional lymph node (LN) involvement and distant metastases are already present [3, 4].

From a histopathological (HP) perspective, ileal NETs are usually well-differentiated tumors, exhibiting trabecular, cribriform, or mixed architectural patterns and generally low to intermediate proliferative activity. Tumor grading, based on the Ki-67 labeling index (LI) and mitotic count according to the World Health Organization (WHO) Classification, remains essential for prognostic assessment and therapeutic planning [1, 5].

Immunohistochemical (IHC) evaluation is crucial for confirming the diagnosis, with typical expression of neuroendocrine markers such as chromogranin A, synaptophysin, and cluster of differentiation 56 (CD56). In addition, the assessment of somatostatin receptor (SSTR) status plays an important role in guiding functional imaging and targeted treatment strategies [3, 6]. Despite their well-differentiated morphology, SI-NETs frequently demonstrate early dissemination via lymphatic and hematogenous routes, resulting in a high rate of nodal and distant metastases, even in tumors classified as low-grade (G1–G2) [7, 8].

This characteristic pattern of metastatic spread, often disproportionate to the size of the primary lesion, represents a defining feature of ileal NETs and contributes to delayed diagnosis and complex clinical management [7, 8].

Beyond traditional clinicopathological parameters, increasing interest has focused on the influence of systemic inflammation and nutritional status on tumor progression. In several malignancies, inflammatory indices derived from routine laboratory tests, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and prognostic nutritional index (PNI), have been correlated with tumor burden, metastatic risk, and disease severity. However, data regarding the combined assessment of inflammatory and nutritional markers in ileal NETs remain limited, particularly in real-world surgical populations [2, 9].

Given the relatively low incidence of ileal NETs, most available evidence originates from retrospective single-center studies and institutional experiences, highlighting the continued importance of detailed monocentric analyses in improving the understanding of their biological behavior [7, 8].

Aim

The objective of this study was to characterize the clinicopathological, IHC, and proliferative profiles of patients with ileal NETs from a single-center cohort, while also examining the relationship between metastatic disease and systemic inflammatory and nutritional indicators. By correlating morphological findings with IHC data and hematological parameters, this case series aimed to offer additional insights into the biological behavior of ileal NETs in a real-world clinical context.

Patients, Materials and Methods

Study design and patient selection

This retrospective observational study included 12 consecutive patients diagnosed with ileal NETs who underwent primary surgical treatment at the Emergency County Clinical Hospital, Craiova, Romania, between January 2018 and December 2024.

Eligible patients were identified from institutional surgical and pathological databases. Inclusion criteria comprised histologically confirmed ileal NETs and availability of complete clinicopathological, IHC, and laboratory data at the time of diagnosis.

Patients with incomplete medical records, neuroendocrine neoplasms originating from other GI sites, or tumors managed non-surgically were excluded.

All included patients underwent initial tumor resection; no patients had received neoadjuvant systemic therapy prior to surgery. Surgical procedures were performed in both elective and emergency settings, according to clinical presentation.

Clinicopathological and immunohistochemical evaluation

Clinical data were retrieved from medical records and included demographic characteristics, surgical procedures, and length of hospital stay. Pathological evaluation was performed on formalin-fixed paraffin-embedded (FFPE) specimens according to standard protocols.

Tumor size, depth of wall invasion, serosal involvement, histological growth pattern, regional LN status, and presence of distant metastases were recorded. Tumor grading was performed according to the WHO Classification based on the Ki-67 LI and mitotic count.

IHC analysis included classical neuroendocrine markers, chromogranin A, synaptophysin, and CD56, as well as assessment of SSTR expression, when available. The Ki-67 LI was determined by counting positive tumor cell nuclei in areas of highest proliferative activity (“hot spots”) and expressed as a percentage.

Assessment of distant metastases and tumor staging

The presence of distant metastases was evaluated at diagnosis based on preoperative imaging and intraoperative assessment. All patients underwent contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis. In cases with suspected hepatic involvement, magnetic resonance imaging (MRI) was additionally performed. Functional imaging using SSTR-based techniques [68Ga-DOTATATE positron emission tomography (PET)/CT] was available for a subset of patients and, when performed, contributed to the identification of metastatic disease.

Distant metastases were defined as tumor spread beyond the primary ileal lesion and regional LNs, including involvement of the liver, peritoneum, or extra-abdominal sites, as demonstrated by imaging and/or confirmed intra-operatively or through HP examination when tissue samples were available. Metastatic status was determined at the time of initial diagnosis and surgical treatment, while postoperative progression was not included in this analysis.

Tumor staging followed the recommendations of the European Neuroendocrine Tumor Society (ENETS) for small intestinal NETs, considering tumor invasion depth, LN status, and the presence of distant metastases. Due to the retrospective nature of the study and variability in imaging data, formal stage grouping was not consistently applied across all cases. Consequently, metastatic status (present vs. absent) was used as the main variable for stratification in comparative analyses.

Laboratory parameters and inflammatory–nutritional indices

Preoperative laboratory data were obtained from routine blood tests performed at hospital admission. The following parameters were recorded: leukocyte count, neutrophil count, lymphocyte count, platelet count, hemoglobin (Hb) level, and red cell distribution width (RDW).

Systemic inflammatory and nutritional indices were calculated using standard formulas derived from routine peripheral blood parameters, as follows:

• NLR: absolute neutrophil count/absolute lymphocyte count.

• PLR: platelet count/absolute lymphocyte count.

• SII: (platelet count × absolute neutrophil count)/absolute lymphocyte count.

• LMR: absolute lymphocyte count/absolute monocyte count.

• PNI: serum albumin (g/L) + 5 × absolute lymphocyte count (×109/L).

All indices were analyzed in relation to metastatic status.

Histopathological and immunohistochemical assessment

HP examination showed well-differentiated NETs of the small bowel, corresponding to NET G1–G2. The tumors exhibited infiltrative growth pattern and were composed of small, monomorphic cells arranged in clusters, islands, short trabeculae, and organoid structures. The neoplastic proliferation predominantly occupied the submucosa and frequently extended into the muscularis propria, while the overlying intestinal mucosa was largely preserved (Figure 1A). Invasion of the muscularis propria was characterized by small nests and short trabeculae of tumor cells infiltrating between smooth muscle fascicles (Figure 1B).

Figure 1.

(A and B) Ileal neuroendocrine tumor with organoid architecture and irregular nests of monomorphic small cells with salt-and-pepper chromatin. Hematoxylin–Eosin (HE) staining: (A) ×100; (B) ×200.

At intermediate magnification, the tumors displayed organoid structures and irregular islands of uniform small cells, consistent with well-differentiated neuroendocrine morphology (Figure 2A). Higher magnification revealed small tumor cells with round, hyperchromatic, monotonous nuclei showing characteristic salt-and-pepper chromatin and moderate eosinophilic granular cytoplasm (Figure 2B). Mitotic activity was generally low, with only rare mitotic figures identified in most cases; focal paranuclear cytoplasmic densification was also observed (Figure 2B).

Figure 2.

(A and B) Ileal neuroendocrine tumor: organoid architecture with irregular nests of monomorphic small cells. HE staining: (A) ×100; (B) ×200.

Immunohistochemically, tumor cells showed diffuse cytoplasmic positivity for chromogranin A (Figure 3A, 3B) and synaptophysin (Figure 4A, 4B), confirming neuroendocrine differentiation. In the adjacent normal intestinal epithelium, only scattered neuroendocrine cells were identified. The Ki-67 LI ranged from very low values to intermediate levels, in keeping with the NET G1–G2 spectrum, whereas the normal intestinal epithelium exhibited a higher proliferative activity (Figure 5A, 5B).

Figure 3.

(A and B) Chromogranin A immunostaining in ileal neuroendocrine tumor: (A) ×40; (B) ×400.

Figure 4.

(A and B) Synaptophysin immunostaining in ileal neuroendocrine tumor: (A) ×40; (B) ×200.

Figure 5.

(A and B) Ki-67 immunostaining in ileal neuroendocrine tumor: (A) ×40; (B) ×200.

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Emergency County Clinical Hospital, Craiova (Protocol No. 55516/2025; Approval date: November 18, 2025). Written informed consent was obtained from all patients prior to surgical intervention.

Statistical analysis

Given the limited sample size, statistical analyses were primarily descriptive and exploratory in nature. Continuous variables were expressed as median and interquartile range (IQR), while categorical variables were reported as frequencies and percentages.

Inferential statistical tests were applied selectively to a limited number of clinically relevant comparisons, including age, Hb level, and metastatic status, using the Mann–Whitney U-test for continuous variables and Fisher’s exact test for categorical variables.

For systemic inflammatory and nutritional indices, statistical comparisons were interpreted cautiously, and observed differences were considered hypothesis-generating trends rather than definitive associations. Statistical significance was set at p<0.05; however, results were interpreted in a biological and exploratory context due to the small cohort size.

Results

The study cohort included 12 patients with ileal NETs, with a median age of 65 years (IQR 62.75–69.25) (Table 1). Male patients predominated (58.3%), and most patients originated from urban areas (58.3%). All patients underwent segmental ileal resection, with enteroenteric end-to-end anastomosis performed in two-thirds (66.7%) of cases, while ileostomy was required in the remaining (33.3%) patients. The median length of hospital stay was 10.5 days (IQR 8–11.75).

Table 1.

Clinical and surgical characteristics of patients with ileal NETs (n=12)

Variable	Value
Age [years], median (IQR)	65 (62.75–69.25)
Sex, n (%)
• Male	7 (58.3)
• Female	5 (41.7)
Living environment, n (%)
• Urban	7 (58.3)
• Rural	5 (41.7)
Length of hospital stay [days], median (IQR)	10.5 (8–11.75)
Surgical procedure	Segmental ileal resection (100%)
Type of reconstruction, n (%)
• Enteroenteric end-to-end anastomosis	8 (66.7)
• Ileostomy	4 (33.3)

IQR: Interquartile range; n: No. of cases.

The median tumor size was 5.5 cm (IQR 3.75–7.0), with tumor dimensions ranging from 2 to 12 cm (Table 2). Most tumors showed deep wall infiltration, with complete invasion of the muscularis propria observed in 75% of cases. Serosal involvement was identified in two-thirds (66.7%) of patients. Histologically, the most frequent growth pattern was trabecular (33.3%), followed by cribriform (25.0%) and mixed trabecular–alveolar architecture (16.7%). Less common patterns included pseudoacinar, tubulovillous, and small round cell morphology.

Table 2.

Morphological characteristics of ileal neuroendocrine tumors (n=12)

Variable	Value
Tumor size [cm], median (IQR)	5.5 (3.75–7.0)
Tumor size [cm], range (min.–max.)	2–12
Muscularis propria invasion, n (%)
• Partial	3 (25.0)
• Complete	9 (75.0)
Serosal involvement, n (%)
• Present	8 (66.7)
• Absent	4 (33.3)
Histological growth pattern, n (%)
• Trabecular	4 (33.3)
• Cribriform	3 (25.0)
• Trabecular–alveolar	2 (16.7)
• Pseudoacinar	1 (8.3)
• Tubulovillous	1 (8.3)
• Small round cell pattern	1 (8.3)

IQR: Interquartile range; n: No. of cases.

Distant metastases were identified in eight (66.7%) patients, while four (33.3%) patients showed no evidence of metastatic disease at diagnosis (Table 3). Regional LN metastases were present in seven (58.3%) cases, reflecting a high rate of nodal involvement within the study cohort.

Table 3.

Metastatic status and LN involvement (n=12)

Variable	Value
Distant metastases, n (%)
• Present	8 (66.7)
• Absent	4 (33.3)
Regional LN metastases, n (%)
• Present	7 (58.3)
• Absent	5 (41.7)

LN: Lymph node; n: No. of cases.

All tumors demonstrated diffuse immunoreactivity for classical neuroendocrine markers, including chromogranin A, synaptophysin, and CD56 (Table 4). SSTR expression was identified in 66.7% of cases. The Ki-67 LI ranged from 0.5% to 12%, with a median value of 4.5% (IQR 1.5–8.0). According to the WHO Classification, five (41.7%) tumors were graded as NET G1 and seven (58.3%) tumors as NET G2, while no NET G3 tumors were identified.

Table 4.

Immunohistochemical profile, Ki-67 PI, and tumor grading of ileal NETs (n=12)

Marker/parameter	Result
Chromogranin A, n (%)	12 (100)
Synaptophysin, n (%)	12 (100)
CD56 (NCAM), n (%)	12 (100)*
SSTRs, n (%)
• Positive	8 (66.7)
• Negative	4 (33.3)
Ki-67 LI
• Median (IQR)	4.5% (1.5–8.0)
• Range	0.5–12%
Tumor grade (WHO Classification)
• NET G1 (≤2%)	5 (41.7)
• NET G2 (3–20%)	7 (58.3)
• NET G3 (>20%)	0 (0)

*One case showed weak and/or diffuse immunoreactivity. CD56: Cluster of differentiation; IQR: Interquartile range; LI: Labeling index; n: No. of cases; NET: Neuroendocrine tumor; NCAM: Neural cell adhesion molecule; SSTRs: Somatostatin receptors; WHO: World Health Organization.

Patients with distant metastases were younger than those without metastases (median 63.5 vs. 71 years, p=0.041) and had significantly lower Hb levels (median 12.00 vs. 13.79 g/dL, p=0.027) (Table 5). Regional LN metastases were strongly associated with distant metastatic disease (87.5% vs. 0%, p=0.010), while serosal involvement did not differ significantly between groups.

Table 5.

Comparison between patients with and without distant metastases

Variable	No metastases (n=4)	Metastases present (n=8)	p-value
Age [years], median (IQR)	71 (68–74.25)	63.5 (61–65.75)	0.041a
Hb [g/dL], median (IQR)	13.79 (13.35–14.20)	12.00 (11.15–12.55)	0.027a
Serosal involvement, n (%)	2 (50.0)	6 (75.0)	0.547b
Positive LNs, n (%)	0 (0)	7 (87.5)	0.010b

aMann–Whitney U-test, bFisher’s exact test. Hb: Hemoglobin; IQR: Interquartile range; LN: Lymph node; n: No. of cases.

Patients with distant metastases tended to exhibit higher leukocyte, neutrophil, platelet, RDW, NLR, PLR, and SII values, along with lower lymphocyte counts, LMR, and PNI (Table 6). Although none of these differences reached statistical significance, consistent trends toward increased systemic inflammation and impaired nutritional status were observed in the metastatic group.

Table 6.

Systemic inflammatory, hematological and nutritional markers according to metastatic status

Parameter	No metastases (n=4), median (IQR)	Metastases present (n=8), median (IQR)	p-value
Leukocytes (×109/L)	7.25 (5.36–8.45)	9.50 (6.31–12.00)	0.393
Neutrophils (×109/L)	4.84 (4.64–5.83)	6.92 (4.56–7.12)	0.269
Lymphocytes (×109/L)	1.71 (1.23–2.31)	1.10 (1.05–1.20)	0.107
Platelets (×109/L)	235.0 (209.5–261.8)	276.5 (231.5–333.8)	0.441
RDW (%)	13.13 (11.99–14.38)	17.65 (15.50–19.00)	0.106
NLR	2.78 (2.16–4.29)	5.84 (2.79–6.36)	0.552
PLR	136.0 (107.4–206.3)	227.0 (149.3–277.5)	0.202
SII	427.4 (157.7–1097.5)	968.5 (697.8–1590.9)	0.269
LMR	2.95 (2.01–3.87)	1.57 (1.12–1.94)	0.107
PNI	36.30 (29.70–47.00)	33.98 (32.38–40.75)	1.000

Due to the limited sample size, inflammatory and nutritional markers were analyzed descriptively and interpreted in a biological context. IQR: Interquartile range; LMR: Lymphocyte-to-monocyte ratio; n: No. of cases; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; PNI: Prognostic nutritional index RDW: Red cell distribution width; SII: Systemic immune-inflammation index.

Discussions

In this single-center case series, we present a detailed clinicopathological and IHC analysis of ileal NETs, incorporating routinely available systemic inflammatory and nutritional parameters in relation to metastatic status. The results confirm several well-recognized characteristics of ileal NETs while also providing additional insights derived from real-world clinical practice.

Overall, our findings illustrate the complex biological profile of ileal NETs, in which relatively well-differentiated histological features coexist with advanced local extension and a substantial metastatic burden. These observations offer a useful framework for interpreting our data within the context of existing literature and for exploring the interplay between clinicopathological features and systemic factors involved in disease progression.

Recent epidemiological evidence has challenged the traditional view of SI-NETs as rare and indolent entities. Both population-based and institutional studies have reported a steady rise in incidence over time, with a significant proportion of patients presenting with regional LN and/or distant metastases at diagnosis, particularly involving the liver [4, 7, 10, 11, 12, 13].

Given the relatively low frequency of ileal NETs and their heterogeneous clinical presentation, large prospective studies remain difficult to perform. As a result, much of the available evidence is based on retrospective single-center analyses, highlighting the ongoing importance of detailed monocentric studies such as the present one [4, 7].

The demographic profile of our cohort aligns with previously published data, indicating that ileal NETs predominantly affect individuals in the sixth and seventh decades of life, with a slight male predominance [3, 4, 7, 14, 15, 16].

All patients in our study underwent segmental ileal resection, reflecting the standard surgical management for localized small intestinal NETs. The relatively high rate of ileostomy formation observed in this cohort likely reflects advanced disease at presentation and the need for staged or damage-control surgical approaches in selected cases with extensive mesenteric involvement or compromised intestinal viability [8, 17].

From a morphological standpoint, our results highlight the tendency of ileal NETs to present advanced local diseases. The relatively large tumor size, frequent invasion of the muscularis propria, and common involvement of the serosa are consistent with previous reports emphasizing delayed diagnosis, often related to nonspecific symptoms, submucosal tumor growth, and slow tumor progression [3, 18].

The predominance of trabecular and cribriform architectural patterns corresponds to the classic histological appearance of well-differentiated NETs, while the presence of less common patterns reflects the inherent morphological heterogeneity of these neoplasms [1, 5, 19, 20].

Despite their well-differentiated morphology and generally low-to-intermediate proliferative activity, a notable finding in our cohort was the high frequency of both regional LN and distant metastases. This supports the concept that ileal NETs have a distinct biological behavior characterized by early lymphatic and hematogenous spread, often disproportionate to the size or grade of the primary tumor [21, 22].

A key biological feature of these tumors is their ability to metastasize at an early stage, even when lesions are small and low-grade. This phenomenon is thought to be related to early vascular and lymphatic invasion, as well as complex interactions between the tumor and mesenteric environment, including desmoplastic responses [8, 23, 24, 25, 26, 27, 28].

The strong correlation between LN involvement and distant metastases observed in our study further emphasizes the importance of lymphatic dissemination in disease progression. It also highlights the need for systematic LN dissection and careful pathological staging during surgical management [29, 30].

IHC analysis demonstrated diffuse positivity for chromogranin A, synaptophysin, and CD56 in all cases, confirming neuroendocrine differentiation and supporting the diagnostic value of these markers in ileal NETs [31, 32].

SSTR positivity was observed in most cases, in agreement with previously published data, and underscores the importance of receptor evaluation for functional imaging, treatment with somatostatin analogs, and theranostic strategies such as peptide receptor radionuclide therapy [3, 33, 34, 35].

The Ki-67 LI indicated that all tumors in our cohort were well-differentiated NETs (G1–G2), consistent with WHO Classification criteria, despite the frequent presence of advanced-stage disease [1, 5]. Recent studies emphasize that Ki-67 should not be interpreted as isolation but rather in conjunction with tumor size and anatomical location, particularly in small intestinal tumors. Larger tumor dimensions have been associated with increased malignant potential even within well-differentiated categories, suggesting that tumor burden and depth of invasion may better reflect clinical aggressiveness than proliferative activity alone [33, 36, 37, 38]. This observation is supported by our findings of relatively large tumors presenting with advanced disease, despite predominantly low-to-intermediate Ki-67 LI.

Comparative analysis revealed several clinicopathological differences between patients with and without distant metastases. Those with metastatic disease were, on average, younger and exhibited lower Hb levels. These findings likely reflect underlying biological heterogeneity, chronic inflammatory processes, occult GI blood loss, and impaired nutritional status, rather than any protective effect associated with older age [2, 39, 40]. The association between anemia and metastatic spread may therefore serve as an indirect indicator of systemic tumor burden and inflammatory activity.

In addition to conventional parameters, we evaluated the relationship between metastatic status and systemic inflammatory as well as nutritional markers derived from routine laboratory tests. Patients with distant metastases consistently demonstrated higher values of leukocytes, neutrophils, platelets, RDW, NLR, PLR, and SII, along with reduced lymphocyte counts, LMR, and PNI. Although these differences did not reach statistical significance, likely due to the limited sample size, the observed trends suggest a more pronounced inflammatory response and compromised nutritional status in metastatic disease. Similar correlations between inflammatory markers, immune dysregulation, and tumor burden have been described in other GI malignancies, including small bowel tumors [2, 41, 42, 43, 44].

Systemic inflammation and host nutritional status are increasingly recognized as key determinants of immune function and clinical resilience across multiple disease states. Evidence from non-oncological contexts also supports this concept, as micronutrient deficiencies, such as reduced vitamin C levels, have been linked to enhanced inflammatory responses and less favorable microbiological outcomes [45].

In our cohort, metastatic cases consistently showed higher platelet-related inflammatory indices, including PLR and SII, suggesting a more pronounced systemic inflammatory phenotype. Platelet activation and endothelial dysfunction are central components of inflammation-driven thrombo-inflammatory pathways, providing a plausible biological explanation for why platelet-based composite indices may serve as relevant markers of inflammatory burden in oncologic patients [46].

From an anatomical standpoint, the ileum represents a highly active immunological environment, where continuous interactions with the intestinal microbiota influence systemic immune regulation through gut–organ communication pathways. Within this context, circulating inflammatory indices may reflect not only tumor-related processes but also the complex interplay between neoplastic activity and host immune responses, particularly in ileal tumors [47].

Importantly, systemic inflammatory and nutritional markers are low-cost and widely accessible parameters that can complement standard HP evaluation. Unlike advanced molecular or experimental biomarkers, which may have limited availability, these indices can be easily incorporated into routine clinical workflows and may enhance risk stratification in ileal NETs, especially in real-world settings and in healthcare systems with constrained resources [48, 49].

Proinflammatory status may be further influenced by prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or by coexisting conditions, including the association between oncological disease and depressive disorders [50]. Depression is known to promote activation of inflammatory pathways, and persistently elevated inflammatory markers may signal an increased risk of adverse outcomes, including disease progression or severe behavioral complications such as suicidal tendencies [51]. In this context, therapeutic approaches combining anti-inflammatory and antidepressant effects may offer additional clinical benefits in selected patients [52].

Overall, this study contributes real-world evidence by combining detailed morphological and IHC analysis with accessible inflammatory and nutritional indices, such as SII, LMR, RDW, and PNI, in relation to metastatic status in ileal NETs. The results support a multidimensional understanding of ileal NET biology, in which metastatic potential reflects a complex interaction between tumor morphology, mesenteric involvement, immune-inflammatory dynamics, and host nutritional status, rather than being determined solely by proliferative activity. These findings provide a basis for future prospective studies and hypothesis-driven research.

Strengths and limitations

The principal strength of this study is its comprehensive real-world analysis of ileal NETs, combining clinicopathological, morphological, IHC, proliferative, and systemic inflammatory and nutritional parameters within a single, anatomically uniform cohort. The inclusion of routinely accessible laboratory markers further enhances the practical applicability and translational relevance of the findings.

Nevertheless, several limitations should be considered. The retrospective design and relatively small sample size, inherent to a single-center study, restrict statistical robustness and limit the generalizability of the results. Moreover, the exploratory nature of the analysis does not allow definitive conclusions regarding the prognostic significance of inflammatory and nutritional indices. The absence of survival data and long-term follow-up also precludes correlation with clinical outcomes. Despite these limitations, given the rarity of ileal NETs and the predominance of retrospective institutional data in the literature, carefully conducted monocentric studies continue to provide valuable insights into the biological behavior of these neoplasms.

Conclusions

Well-differentiated ileal NETs (G1–G2) in our cohort were often diagnosed at an advanced stage, with significant local invasion and a high prevalence of metastatic disease. Regional LN involvement showed a strong correlation with the presence of distant metastases. Patients with metastatic spread generally exhibited elevated systemic inflammatory markers alongside reduced nutritional indices, suggesting a potential relationship between tumor dissemination, inflammatory response, and nutritional status. Although these observations are exploratory, they indicate that routinely available inflammatory and nutritional parameters may serve as useful adjuncts to HP evaluation in ileal NETs. Further prospective investigations are required to validate their prognostic significance.

Conflict of interests

The authors declare that they have no conflict of interests.