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Evaluation of the details and importance of lymphatic, microvascular, and perineural invasion in patients with non-functioning pancreatic neuroendocrine neoplasms based on tumor size and the 2022 World Health Organization classification: a 23-year retrospective analysis

World Journal of Surgical Oncology volume 23, Article number: 79 (2025) Cite this article

Abstract

Background

Although, recently observation methods has been proposed as one of the treatment options for non-functioning pancreatic neuroendocrine neoplasms (NF-PanNENs), determining treatment strategies may be difficult for small and low-malignant NF-PanNENs; thus, clarifying the significance of lymphatic, microvascular, and perineural invasion in these patients is of great clinical importance. This study aimed to assess the incidence and role of lymphatic, microvascular, and perineural invasion in patients with NF-PanNENs based on tumor size and the 2022 World Health Organization classification.

Methods

From 2000 to 2023, we retrospectively investigated the incidence of lymphatic, microvascular, and perineural invasion and their impact on recurrence in 80 patients who underwent curative resection and were diagnosed with NF-PanNENs.

Results

Of the 80 patients, 14 (18%), 20 (25%), and six (9%) patients had lymphatic, microvascular, and perineural invasion. Patients with neuroendocrine tumor (NET) G1 had significantly fewer occurrences of lymphatic, microvascular, and perineural invasion than those with NET G2 (10%, 15%, and 7% vs. 40%, 55%, and 35%; all P < 0.05.). Patients with a tumor size < 20 mm had significantly lower rates of lymphatic and microvascular invasions than those with a tumor size ≥ 20 mm (12% and 17% vs 33% and 48%; P = 0.034 and 0.0073, respectively). In all patients, NET G2, tumor size ≥ 20 mm, local invasion T2–3, presence of lymph node metastasis, and presence of microvascular invasion were significant risk factors for shorter recurrence-free survival (RFS) (all P < 0.05). In patients with NET G1 and tumor size < 20 mm, five (10%), eight (16%), and four (8%) patients had lymphatic, microvascular, and perineural invasion. The presence of microvascular invasion was also an independent risk factor for RFS (P < 0.05).

Conclusions

Information on the frequency and role of lymphatic, microvascular, and perineural invasion based on tumor size and malignancy on recurrence may be useful when considering treatment strategies for small- and low-grade NF-PanNENs.

Background

Neuroendocrine neoplasms (NENs) are a general term for tumors arising from neuroendocrine cells. They are classified as Neuroendocrine tumor (NET) G1, NET G2, NET G3, neuroendocrine carcinoma (NEC), and mixed neuroendocrine and non-neuroendocrine neoplasm (MiNEN) based on the Ki-67 proliferation index, mitotic index, and histological differentiation grade; each has a different oncological malignancy and prognosis [1]. In addition, pancreatic NENs (PanNENs) include those accompanied by hormone production symptoms and those with genetic backgrounds, each of which is thought to have different malignancies and therapeutic indications [2,3,4,5].

In recent years, the number of patients with PanNENs has been increasing owing to advances in diagnostic imaging technologies and the widespread recognition of PanNEN [6,7,8,9,10]. The incidence of small, well-differentiated, localized, and non-functioning (NF)-type PanNENs (NF-PanNENs) has gradually increased. Radical surgical resection is the only curative and survival-prolonging treatment for localized NF-PanNENs [10, 11]. However, observation has recently been proposed as one of the treatment strategy or small and low-grade NF-PanNENs [2,3,4, 12]. This is thought to be due to the high rate of morbidity associated with surgical resection for NF-PanNENs [13], in addition to the possibility that these NF-PanNENs are not highly malignant [12]. However, it is still not clear whether this watchful waiting is acceptable.

Previous studies have reported that indicators, such as the World Health Organization (WHO) grading, local tumor invasion, synchronous lymph node metastasis (LNM), and liver metastasis, are associated with prognosis in patients with NF-PanNENs [14,15,16,17,18]; however, the relationship between lymphatic, microvascular, and perineural invasion and patient outcomes remains unclear.

In various gastroenterological cancers and NENs, if histopathological factors, including lymphatic and/or microvascular invasion, are detected after endoscopic treatment, radical surgery with lymph node dissection is an additional treatment option to improve outcomes [5, 19,20,21]. Conversely, if pathological examination after endoscopic local resection shows no lymphatic or microvascular invasion, the possibility of metastasis is low and additional treatment may not be necessary [5, 19,20,21]. This recommendation is based on the oncological role of lymphatic and/or microvascular invasion in these cancers and neoplasms, which has been investigated and discovered to be suggestive of potential LNM and poor prognosis. Lymphatic and microvascular invasion are essential for tumor metastasis from local areas to other sites [5, 19,20,21]. To become a selective option for some NF-PanNENs, which are considered low-grade malignancies, it is important to clarify the role and frequency of lymphatic, microvascular, and perineural invasions, which are potential indicators of distant metastasis.

Moreover, although a few previous studies have reported the frequency of these invasions in patients with PanNENs, these studies included a mixture of various PanNENs, some of which contained functionality, hereditary disease, and different WHO grades [22,23,24,25,26]. Owing to the diversity of the patient backgrounds, it is difficult to draw clear conclusions from these previous studies regarding the role of lymphatic, microvascular, and perineural invasion in patients with NF-PanNET G1 and G2 without genetic backgrounds. Because NF-PanNET G1 and G2 are the most common type of PanNEN and determining treatment strategies may be difficult, clarifying the significance of lymphatic, microvascular, and perineural invasion in these patients is of great clinical importance.

Therefore, we aimed to reveal the detailed features and prognostic significance of lymphatic, microvascular, and perineural invasion in patients with NF-PanNET G1 and G2 without genetic diseases, especially based on tumor size and the WHO 2022 classification. Large-scale observational studies are required to clarify the oncological significance of these findings. Therefore, a preliminary pilot study was conducted.

Methods

Study design

This study was approved by the institutional review board of Yamanashi University (approval number: H30897). The requirement for informed consent was waived due to the retrospective nature of this study. In this retrospective study, we analyzed the medical records of 94 patients who underwent curative surgical resection for PanNEN at the Department of Digestive Surgery, University of Yamanashi Hospital between 2000 and 2022. We excluded patients who underwent residual tumor resection; had hormone-producing symptoms; had genetic diseases, such as multiple endocrine neoplasia type 1 (MEN type 1) and von Hipple Lindau (VHL); a pathological grade NET G3, NEC, and MiNEN; or had an unknown examination status. Finally, 80 patients who underwent curative surgical resection of G1 and G2 NF-PanNETs were retrospectively analyzed. We analyzed the frequency of lymphatic, microvascular, and perineural invasion and evaluated the association between clinicopathological factors and recurrence-free survival (RFS) based on tumor size and malignant grade, as defined by the 2022 WHO classification [1].

The clinicopathological data were collected and examined. The preoperative parameters included age, sex, diagnostic opportunity, and tumor location. Intraoperative parameters included the type of surgical procedure and number of dissected lymph nodes. Postoperative parameters included postoperative complication grade defined by the Clavien–Dindo classification [27]; Ki-67 index of pathological tumor specimens; 2022 WHO classification [1]; pathological tumor size; grade of local invasion; the existence of LNM; the presence of lymphatic, microvascular, and perineural invasion; recurrence; recurrence period; and prognosis.

Definition of NF-PanNEN

PanNEN was defined as exhibiting cord-like, rosette-like, and alveolar-like structures detected using hematoxylin and eosin staining; immunohistochemical staining for chromogranin A and synaptophysin protein markers was positive; and other pancreatic tumors were excluded by histopathological examination. We defined PanNEN without clinical symptoms of hormone production as NF-PanNEN. Based on the 2022 WHO classification [1], well-differentiated NF-PanNENs with Ki-67 proliferation indices < 3%, 3–20%, and > 20% were defined as NET G1, NET G2, and NET G3, respectively. In addition, poorly differentiated NF-PanNEN with a Ki-67 proliferation index > 20% was defined as NEC G3. PanNENs containing 30% or more of each neuroendocrine and non-neuroendocrine component were classified as MiNENs.

Assessment of lymphatic, microvascular, and perineural invasion

Lymphatic invasion was indicated by the presence of cancer cells and nests in the interstitial space. A space filled with lymph and lymphocytes is likely to be a lymphatic vessel, and this space was concluded to represent a lymphatic vessel when the endothelial cells were identified around the space. The presence or absence of lymphatic invasion was evaluated using D2-40 immunohistochemical staining. Microvascular invasion is likely when a circular, semicircular, or oblong tumor cell nest with regular margins is located in the vicinity of the vessels and distant from the main lesion. When a tumor cell nest is surrounded by venous wall structures, such as an internal elastic membrane or perivascular smooth muscle, it is considered to represent microvascular invasion. Victoria blue and/or Elastica Van Gieson staining was used to elucidate the elastic fibers in the vessel walls. Perineural invasion was detected based on the presence of tumor cells in the perineural space and nerve fiber bundles. S-100 protein staining was used to assist in the diagnosis of perineural invasion. Perineural invasion was defined as an invasion distinct from the extrapancreatic plexus nerve invasion. Immunohistochemical staining, which aids in the diagnosis of lymphatic, microvascular, and perineural invasion, was routinely performed as necessary to aid in the interpretation of hematoxylin and eosin staining and evaluated by staining representative cut sections of the tumor. Representative immunohistochemical images of lymphatic, microvascular, and perineural invasions are show in Fig. 1.

Fig. 1
figure 1

Representative histologic and immunohistochemical images of lymphatic, microvascular, and perineural invasions. a Presence of lymphatic invasion using D2-40 immunohistochemical staining. b Presence of microvascular invasion using Elastica Van Gieson staining. c Presence of perineural invasion using S-100 protein staining

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Surgical procedure

In this study, pancreaticoduodenectomy (PD), distal pancreatectomy (DP), and total pancreatectomy (TP) were the major resection procedures. Spleen-preserving DP, central pancreatectomy, enucleation, and partial pancreatectomy were defined as limited resection procedures. Regional LND was performed with major resection. In patients who underwent PD, the LND region included the area around the subpyloric, infrapyloric, common hepatic artery (CHA), hepatoduodenal ligament, anterior and posterior surfaces of the pancreatic head, and the superior mesenteric artery (SMA). In patients who underwent DP, the LND regions included the areas along the left gastric artery, CHA, celiac artery, splenic hilum, splenic artery, SMA, and the inferior margin of the pancreas. In the patients who underwent TP, the LND regions included the PD and DP. In limited resections, LND was only partially performed around the NF-PanNEN, such as LN sampling resection; regional LND was not performed. This was because the Japanese guidelines allow for limited resection with partially LND for small NF-PanNEN [5]. We performed major resection with regional LND for large tumors and/or NET G2, which were preoperatively diagnosed using endoscopic ultrasonography-guided fine-needle aspiration. Conversely, limited resection was performed in patients with small tumors and NET G1 in whom LNM was not suspected in preoperative imaging studies. In addition, limited resection is sometimes performed, depending on the patient’s background and tumor location. Particularly, in cases of tumor lesions in the pancreatic head, limited resection is sometimes performed instead of major resection.

Follow-up

After surgery, the patients underwent laboratory examinations and imaging studies every 3–6 months as a standard follow-up strategy for the first 5 years. In principle, imaging studies, including ultrasonography (US), contrast-enhanced computed tomography (CT), contrast-enhanced magnetic resonance imaging (MRI), somatostatin receptor scintigraphy, and positron emission tomography, were performed when indicated. The choice of imaging modality ultimately depended on the discretion of the attending physician and the patient's general condition. The follow-up strategy continued beyond 5 years after surgery, as long as the patients were able to attend a hospital, and the patients who were followed up at other hospitals were referred back to our hospital when necessary. Five years postoperatively, patients underwent the same examinations every 6–12 months. A tumor initially identified in postoperative imaging studies was considered a recurrence. Elevations in tumor markers alone, such as neuron-specific enolase and pro-gastrin-releasing peptide, were not considered to indicate recurrence. All sites were counted when two or more recurrence sites were simultaneously observed. After NF-PanNEN recurrence, drug therapy, surgical resection, and/or peptide receptor radionuclide therapy (PRRT) were planned and performed according to the patient’s background and tumor status. RFS time was calculated from the day of surgery until the diagnosis of recurrence or the last follow-up day if there was no recurrence.

Statistical analyses

We selected factors that seemed to be clinically and pathologically relevant to the prognosis as the factors to be examined. Univariate analysis was performed to determine independent predictors of RFS in patients with NF-PanNENs. RFS rates were compared based on the presence or absence of risk factors identified in the univariate analysis. Because only a small number of recurrences were caused by NF-PanNENs, only the univariate analysis was performed for RFS. Survival analyses were performed using the Kaplan–Meier method, log-rank test, and Cox proportional hazards model. The Chi-square test was used to analyze the frequency between the two groups. Statistical significance was set at P < 0.05. All analyses were performed using JMP 17.0.0 for Windows (SAS Institute Inc., Cary, NC, USA).

Results

Patient characteristics are shown in Table 1. Based on the 2022 WHO classification, 60 (75%) and 20 (25%) patients had NET G1 and NET G2. The median tumor size was 12 (2–80) mm and the number of patients with tumor size < 20 mm and ≥ 20 mm was 59 (74%) and 21 (26%), respectively. Fourteen (18%), 20 (25%), and 6 (9%) patients had lymphatic, microvascular, and perineural invasion. The correlation between microvascular, lymphatic, and perineural invasion is shown in Supplemental Table 1. Regarding the local invasion, 58 (73%), 13 (16%), and nine (11%) had T1, T2, and T3, respectively. Four patients (5%) had synchronous LNM. Six patients (9%) experienced recurrence, and the median recurrent period after surgery was 2.0 years (range: 0.6–11.6). The 1-, 3-, and 5-year RFS rates were 98.7, 93.2, and 93.2%, respectively. Recurrence (with duplication) predominantly occurred in the liver (six patients), followed by the para-aortic LN (one patient). Only two patients (3%) died from NF-PanNENs, whereas nine patients (11%) died from another disease.

Table 1 Patient characteristics
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Frequency of lymphatic, microvascular, and perineural invasion based on the tumor size and WHO grading

Based on the 2022 WHO classification, patients with NET G1 had significantly fewer occurrences of lymphatic, microvascular, and perineural invasion than those with NET G2 (NET G1: 10, 15, and 7%. NET G2: 40, 55, and 35%; P = 0.004, < 0.001, and 0.0031, respectively) (Table 2a). From the viewpoint of tumor size, patients with tumor size < 20 mm had significantly lower rates of lymphatic and microvascular invasion than those with tumor size ≥ 20 mm (< 20 mm: 12 and 17%; ≥ 20 mm: 33 and 48%; P = 0.034 and 0.0073, respectively) (Table 2b). Moreover, the incidence rates of these invasions in patients with tumor size < 10 mm were 14%, 14%, and 5%, respectively, and microvascular invasion was significantly less prevalent in smaller tumor sizes (Supplemental Table 2). The frequency of these invasions in patients with a combination of the 2022 WHO classification and tumor size is shown in Table 2c. Even among patients with NET G1 and tumor size < 20 mm, lymphatic, microvascular, and perineural invasion was observed in 10, 16, and 8% of cases, respectively.

Table 2 Frequency of lymphatic, microvascular, and perineural invasion based on the 2022 World Health Organization classification and tumor size
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Risk factors and scoring system for RFS

In the univariate analysis, NET G2 (vs. NET G1, P < 0.001), tumor size ≥ 20 mm (vs. < 20 mm, P = 0.03), local invasion T2–3 (vs. T1, P = 0.038), LNM (vs. absence, P = 0.0012), and presence of microvascular invasion (vs. absence, P = 0.0079) were significant risk factors for shorter RFS (Table 3). When each assigned risk score was one point, the 5-year RFS rates of patients with risk scores of 0 (n = 42), 1 (n = 14), 2 (n = 11), 3 (n = 4), 4 (n = 6), and 5 (n = 3) were 100%, 91.7%, 90.0%, 80.0%, 66.7%, and 66.7, respectively (P = 0.014). Moreover, the 5-year RFS rates of patients with risk scores of 0–1 (n = 56) and 2–5 (n = 24) were 98.1% and 81.7% (P = 0.0046) (Fig. 2). The hazard ratio (HR) of the risk score groups 2–5 was 2.8 times higher than that of risk score groups 0–1 (P = 0.040). Similarly, in patients with NET G1 and a tumor size < 20 mm, LNM (vs. absence, P < 0.001) and microvascular invasion (vs. absence, P = 0.020) were independent risk factors for RFS (Supplemental Table 3). When each assigned risk score was one point, the 5-year RFS rates of patients with risk scores of 0 (n = 43) and 1–2 (n = 8) were 100% and 87.5% (P = 0.020).

Table 3 Univariate analysis of risk factors for recurrence-free survival in all patients
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Fig. 2
figure 2

Kaplan–Meier analyses of recurrence-free survival (RFS) rates in patients with non-functioning pancreatic neuroendocrine neoplasms (NF-PanNENs) depending on the risk score. The 5-year RFS rates of patients with risk scores of 0–1 and 2–5 were 98.1% and 81.7% (P = 0.0046). The hazard ratio (HR) of risk score groups 2–5 was 1.8 times higher than that of risk score groups 0–1 (P = 0.040)

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Discussion

This study is the first to clarify the detailed frequency of lymphatic, microvascular, and perineural invasion according to tumor size and latest WHO grading in patients with NF-PanNENs based on a uniform pathological diagnostic method. We revealed that even in patients with NET G1 and tumor size < 20 mm, microvascular invasion was a risk factor for recurrence, with an incidence of 16%. Moreover, a risk-scoring system that includes the presence of microvascular invasion may be useful for predicting recurrence. These findings are novel and may be informative when considering treatment strategies for patients with NF-PanNENs, especially for those with small- and low-grade malignancies.

NENs were previously called carcinoids [28]; however, they are now classified according to the 2022 WHO definition based on the Ki-67 proliferation index, mitotic index, and histological degree of differentiation. According to the latest 2022 WHO classification [1], PanNEN is classified into NET G1, NET G2, NET G3, NEC, and MiNEN, which have different oncological malignancies and prognoses. NET has a histologically well-differentiated type and initially has low-grade nuclear features; however, as it progresses from NET G1 to NET G2 and NET G3, the prognosis becomes poor. In contrast, NEC is a high-grade malignancy at an early stage and clinically exhibits aggressive behavior and poor survival [29]. NECs containing certain amounts of adenocarcinoma, squamous cell carcinoma, acinar cell carcinoma, or other components are known as MiNENs. Recently, genetic analysis demonstrated that the genetic mutations and onset mechanisms of NET and NEC are different [30]. In addition, there are two types of PanNENs: functioning-PanNENs, which have hormone-producing symptoms, such as insulinoma and gastrinoma, and NF-PanNENs, which do not have different oncological malignancies, prognoses, or treatment strategies [2,3,4,5]. It is also known that NF-PanNENs coexist with hereditary diseases, such as MEN Type 1 and VHL, and the malignancies and treatment strategies differ depending on the presence or absence of these genetic backgrounds [2,3,4,5]. Thus, PanNEN should be considered a comprehensive collective term for tumors with diverse oncological and clinical characteristics derived from neuroendocrine cells. Individual treatment strategies are needed for each PanNEN.

PanNEN was previously considered a rare malignant neoplasm; however, recently, its incidence has gradually increased [6,7,8,9,10]. As the frequency of PanNENs increases, several clinicopathological factors associated with the prognosis of PanNENs, such as WHO grading, tumor size, LNM, liver metastasis, and some immune nutritional indices, have been reported [14,15,16,17,18]. However, these studies examined a variety of PanNENs together, and careful consideration is required for interpretation because of the diversity of PanNENs.

The standard treatment for NF-PanNENs is radical surgical resection [10, 11]. In recent years, some guidelines have proposed observation as an optional treatment strategy for small, low-grade NF-PanNENs [2,3,4]. The National Comprehensive Cancer Network guidelines mention that in patients with NF-PanNENs with tumor size < 2 cm and incidental detection, observation is considered a treatment option based on estimated surgical risk, tumor location, and patient comorbidities [2]. The European Neuroendocrine Tumor Society guideline stated that non-operative management was tolerable in patients with NF-PanNENs with a tumor size ≤ 20 mm, NET G1, low malignant NET G2, asymptomatic, and located in the pancreatic head [3]. The North American Neuroendocrine Tumor Society guidelines described that initial observation is an acceptable treatment strategy for NF-PanNENs that are asymptomatic and with a tumor size < 1 cm, and recommended that the decision to observe or resect an asymptomatic NF-PanNET 1–2 cm in size be individualized [4]. A large multicenter study from Japan proposed observational treatment in patients with NF-PanNET G1 and tumor size < 20 mm or NF-PanNET G2 and tumor size < 10 mm, based on the outcome after curative surgery [12]. A past report from Brazil showed that both observation and surgical resection were same outcome in patients with NF-PanNET and tumor size < 20 mm [31]. From Chinese literature, a monogram predicting prognosis has been reported, with the cut-off value for tumor size set at 26 mm [32]. Furthermore, a nationwide survey in Korea reported that tumor size was not a significant risk factor for recurrence [33]. However, all these suggestions are based on retrospective studies, and their reliability is unclear. Currently, a nationwide prospective cohort study of watchful waiting for small NF-PanNENs in the Netherlands [34], and a comparative prospective multicenter cohort study of resection versus observation for small, asymptomatic, and sporadic NF-PanNENs in Europe [35], are being conducted, the results of which should be closely monitored.

Metastasis of malignant neoplasms from the primary site to other organs can occur via hematogenous and/or lymphatic routes, while local recurrence can occur via infiltration of surrounding nerve plexuses; however, microvascular, lymphatic, and perineural invasion are prerequisites for these events. In some gastrointestinal cancers and NETs, the presence of lymphatic and/or microvascular invasion is used to determine whether additional radical resection with regional LND is indicated after endoscopic local treatment [5, 19,20,21]. The impact of these factors on prognosis has been clarified; however, there has been insufficient research on the frequency and role of these factors in NF-PanNENs. In particular, if an observation strategy is to be accepted as an option for small, low-grade NF-PanNENs, the incidence and prognostic impact of lymphatic, microvascular, and perineural invasion must be clarified. Furthermore, in NF-PanNENs, there is still no evidence that additional radical resection with regional LND based on pathological factors after local resection improves the prognosis, and it is not realistic to perform it in clinical practice. Therefore, the presence of lymphatic, microvascular, and perineural invasion should be used as predictors of recurrence rather than as indications for additional resection after minimally invasive local treatment. In this study, considering the oncological diversity of PanNENs, we clarified the frequency of these invasions, and the importance of recurrence based on tumor size and malignant grade. The fact that microvascular invasion is a risk factor for recurrence and has an incidence of 16%, even in patients with NF-PanNENs with NET G1 and tumor size < 20 mm, should be taken into consideration when selecting treatment strategies for small, low-grade NF-PanNENs. Postoperative adjuvant therapy improves recurrence rates and prognosis for many cancers [19,20,21], and is therefore implemented; however, no adjuvant therapy has been proven to be effective for NF-PanNENs. Future clinical trials are required to demonstrate the significance of adjuvant therapy in NF-PanNENs and to identify cases with a high risk of recurrence and poor prognosis. Our proposed risk-scoring system, which includes microvascular invasion, may help identify patients who are candidates for adjuvant therapy.

In clinical practice, CT, MRI, and US are often used as routine postoperative imaging modalities and are performed every 3–12 months based on the WHO grading. Recently, somatostatin receptor scintigraphy has been recommended every 2 years for NET G1 and every year for NET G2 and G3 [3]. Furthermore, in patients undergoing non-operative management, these examinations should be performed periodically during the follow-up period. However, these imaging techniques are expensive and physically invasive. Therefore, indiscriminately using these imaging modalities is undesirable. The recurrence risk scoring system and the incidence of microvascular invasion identified in this study may also be useful when considering the frequency of these examinations.

This study had some limitations. First, this observational study spanned over a long period of 23 years. The patients received different diagnoses and treatments at various times. In particular, changes in imaging modalities and surgical procedures were significant and may have affected patient outcomes. Second, because the number of recurrences and deaths from NF-PanNENs was low and the number of deaths due to other diseases was higher, RFS was analyzed only in the univariate analysis, and disease-specific survival and overall survival rates were not analyzed, rendering these evaluations insufficient. Finally, given that our investigation was retrospective and conducted at a single institution, the inherent biases in such settings cannot be excluded. These results are satisfactory as a pilot study to clarify the details and oncological importance of lymphatic, microvascular, and perineural invasion based on tumor size and malignancy; however, large-scale research is required to confirm these results.

Conclusions

In conclusion, we revealed the details and importance of lymphatic, microvascular, and perineural invasion based on tumor size and the 2022 WHO classification, and subsequently developed a recurrence predictive score. These results may be useful when considering treatment strategies, particularly for small and low-grade NF-PanNENs.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

NET:

Neuroendocrine tumor

NEC:

Neuroendocrine carcinoma

MiNEN:

Mixed neuroendocrine neoplasm

PanNEN:

Pancreatic neuroendocrine neoplasm

NF-PanNEN:

Non-functioning-type pancreatic neuroendocrine neoplasm

WHO:

World Health Organization

LNM:

Lymph node metastasis

MEN type 1:

Multiple endocrine neoplasia type 1

VHL:

Von Hipple Lindau

RFS:

Recurrence-free survival

PD:

Pancreaticoduodenectomy

DP:

Distal pancreatectomy

TP:

Total pancreatectomy

CHA:

Common hepatic artery

SMA:

Superior mesenteric artery

US:

Ultrasonography

CT:

Computed tomography

MRI:

Magnetic resonance imaging

PRRT:

Peptide receptor radionuclide therapy

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Acknowledgements

The authors thank Editage (www.editage.jp) for the English language editing.

Funding

This study did not receive any specific grants from funding agencies in the public, commercial, or non-profit sectors.

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Authors and Affiliations

  1. Department of Digestive Surgery, University of Yamanashi Hospital, 1110 Shimokato, Chuo-Shi, Yamanashi, 409-3898, Japan

    Wataru Izumo, Hiromichi Kawaida, Ryo Saito, Yuki Nakata, Hidetake Amemiya, Suguru Maruyama, Koichi Takiguchi, Katsutoshi Shoda, Kensuke Shiraishi, Shinji Furuya, Yoshihiko Kawaguchi & Daisuke Ichikawa

  2. Department of Human Pathology, University of Yamanashi Hospital, 1110 Shimokato, Chuo-Shi, Yamanashi, 409-3898, Japan

    Kunio Mochizuki & Tetsuo Kondo

Authors
  1. Wataru Izumo
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  2. Hiromichi Kawaida
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  14. Daisuke Ichikawa
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Contributions

WI, HK, and DI contributed to conception and design. WI, HK, RS, YN, HA, and DI contributed to development of methodology. WI, KM, and TK contributed to pathological considerations. WI, HK, RS, YN, HA, SM, KT, KS, KS, SF, YK, and DI contributed to development of data acquisition and analysis. WI, HK, KM and DI contributed to, writing, reviewing, and/or revising of the manuscript. All authors have read, reviewed, and approved the final manuscript.

Corresponding author

Correspondence to Daisuke Ichikawa.

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Ethics approval and consent to participate

This study was approved by the institutional review board of Yamanashi University (approval number: H30897). The requirement for informed consent was waived due to the retrospective nature of this study.

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The authors declare no competing interests.

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Izumo, W., Kawaida, H., Saito, R. et al. Evaluation of the details and importance of lymphatic, microvascular, and perineural invasion in patients with non-functioning pancreatic neuroendocrine neoplasms based on tumor size and the 2022 World Health Organization classification: a 23-year retrospective analysis. World J Surg Onc 23, 79 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12957-025-03734-0

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Keywords

World Journal of Surgical Oncology

ISSN: 1477-7819

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