Context.—

Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous tumors with a wide range of malignant potential. Therefore, identification of prognostic factors is essential.

Objective.—

To systematically assess the significance of tumor border, a well-known prognostic indicator in other cancers, in PanNETs.

Design.—

We evaluated the macroscopic growth pattern (expansile [Exp] versus infiltrative [Inf]) and the microscopic tumor border (pushing [Pus] versus Inf) of 203 surgically resected PanNETs and compared them with other clinicopathologic factors.

Results.—

Based on macroscopic growth pattern, 83 cases had Exp patterns whereas 84 had Inf patterns. According to microscopic tumor border, 122 PanNETs had Pus borders whereas 81 had Inf borders. Combining macroscopic growth pattern and microscopic tumor border, 65 PanNETs had Exp/Pus, 34 had Inf/Pus, 18 had Exp/Inf, and 50 had Inf/Inf status. PanNETs with Inf/Inf status were associated with higher tumor grade, pT classification, and American Joint Committee on Cancer stage grouping; lymph node metastasis; and lymphovascular and perineural invasions (all P < .001). Patients with PanNET having Inf/Inf status had significantly shorter overall survival (OS) and recurrence-free survival (RFS; all P < .001). Further, using multivariate analysis, Inf/Inf status was identified as an independent poor prognostic factor of OS (P = .02) and RFS (P = .03).

Conclusions.—

In summary, combined Inf/Inf status was observed in approximately 25% of PanNETs and was associated with aggressive biological behavior and short OS and RFS. Therefore, assessing combined macroscopic growth pattern and microscopic tumor border can provide additional information regarding survival and recurrence in PanNET patients.

Pancreatic neuroendocrine tumor (PanNET) is the second most common solid neoplasm of the pancreas, accounting for 3% to 4% of all pancreas neoplasms.1  PanNET is a heterogeneous tumor composed of neuroendocrine cells.2  The incidence of this tumor has increased owing to advances in various imaging techniques and increasing awareness.3  Surgical resection is the main treatment option for localized PanNETs, both functioning and nonfunctioning, without distant metastasis.4,5  However, there is still ambiguity in the selection of patients who would benefit from surgery and/or adjuvant therapy. Further, deciding on the extent of surgery and optimal surveillance period remains a difficult task.3,69  These challenges are largely due to the wide-ranging malignant potential of PanNET and the limited effectiveness of the current classification in stratifying patients. Increased morbidity and long-term complications of surgical resection, such as diabetes or pancreatic exocrine insufficiency, should also be considered.6,10  Although complications after lymphadenectomy are high, there have been no preoperative predictors of lymph node metastasis.7 

The updated 2017 and 2019 World Health Organization (WHO) classification systems established the threshold of Ki-67 labeling index at 3% and 20% between grade 1 (G1) and grade 2 (G2) and between G2 and grade 3 (G3), respectively.1  G3 poorly differentiated neuroendocrine carcinomas (NECs) were categorized separately from G3 well-differentiated PanNETs.1  In addition to grading, prognostic factors, such as lymph node involvement, distant metastasis, or older age, have been used.5,1114  The expression of peptide hormones, such as insulin, glucagon-like peptide 1, and glucagon, is associated with prognosis.15,16  Similarly, several protein biomarkers, such as carbonic anhydrase 9 and C-kit expression, and the loss of progesterone receptor expression have been suggested to indicate aggressive behavior.1719  PanNETs with PTEN mutations display good prognosis, whereas ATRX and DAXX mutations, in accordance with the loss of ATRX and DAXX protein expression, respectively, have been associated with poor survival.2,2022  Owing to the heterogeneity of PanNETs, there is still no single specific prognostic criterion that leads to unanimity in an optimal management strategy.

The growth pattern of a tumor is one of the hallmarks used to differentiate benign from malignant tumors. In general, benign tumors have expansile growth, are well encapsulated, and are sharply demarcated from surrounding structures. Conversely, malignant tumors are characterized by poor demarcation and infiltration into surrounding structures.23  Microscopically, tumor borders can be divided into pushing and infiltrative borders. Patients with cancers of various organs with infiltrating tumor border, including endocervical adenocarcinoma, colorectal carcinoma, and tongue squamous cell carcinoma, show poor prognosis.2429  However, some malignant tumors show an expansile growth pattern with relatively pushing border and better prognosis than others. For example, medullary carcinomas of the colon, breast, and pancreas, which are characterized by well-circumscribed, syncytial growth of sheets of cancer cells with pushing border, tend to have a better prognosis than other histologic subtypes.3033  Similarly, the encapsulated follicular variant of papillary thyroid carcinomas tends to have pushing border with an indolent clinical behavior.34 

Well-differentiated PanNETs are generally known to have expansile growth pattern with pushing border with or without capsule of variable thickness.35  There have been a few previous reports regarding the microscopic tumor border of PanNETs3638 ; however, to the best of our knowledge, no previous studies have systematically evaluated the clinicopathologic aspects of PanNETs based on combined macroscopic growth pattern and microscopic tumor border. We investigated both the macroscopic growth patterns and microscopic tumor borders of PanNETs and evaluated the clinicopathologic and prognostic relevance of these factors to identify their role in better stratifying the survival of patients with PanNET.

Patient Selection

After approval with patient consent waiver from the institutional review board (approval number 2014-0580), surgically resected PanNET cases from 2000 to 2015 were selected. Patients with PanNETs who underwent neoadjuvant therapy or PanNET cases with unavailable paraffin-embedded blocks were excluded from this study. We sampled all areas of the tumor with different appearance, and at least one representative section per 1 cm of the tumor was submitted at the time of gross examination.39  In addition, poorly differentiated NECs, including small cell or large cell NECs, were excluded. Finally, a total of 203 PanNET cases were included for histopathologic review. Clinical data, including age, sex, symptoms, procedure, and survival outcomes, were obtained from reviewing electronic medical records.

Growth Pattern and Histologic Evaluation

Pathologic data of PanNETs, including tumor location and size, were retrieved from the surgical pathology reports. Gross examination of the tumor border was reviewed in cases with available gross images of the cut surface of the PanNET. All hematoxylin and eosin–stained slides were carefully reevaluated by 3 pathologists blinded to the clinicopathologic information.

Growth pattern and tumor border were evaluated at the junctions between tumor and normal pancreatic parenchyma or between tumor and other adjacent organs by both gross and microscopic examination. First, macroscopic growth pattern was evaluated in PanNET cases with available gross images of the cut surface of the PanNETs and was classified as expansile or infiltrative pattern. Expansile growth pattern was defined when the tumor had well-delineated margin from adjacent parenchyma (Figure 1, A and B), whereas infiltrative growth pattern was defined when there were any foci of poorly demarcated margin from surrounding structure (Figure 1, C and D). All available gross images were examined. Tumors with even a small focus of macroscopic infiltrating growth pattern were considered to have an infiltrative growth pattern.

Figure 1

Representative gross images of pancreatic neuroendocrine tumors with expansile and infiltrative growth patterns. (A and B) Tumors with expansile growth have well-demarcated margins from adjacent pancreatic parenchyma. Tumors with infiltrative pattern possess foci of poorly demarcated margins (indicated by white arrows) from (C) surrounding pancreatic parenchyma or (D) duodenum and peripancreatic adipose tissue.

Figure 1

Representative gross images of pancreatic neuroendocrine tumors with expansile and infiltrative growth patterns. (A and B) Tumors with expansile growth have well-demarcated margins from adjacent pancreatic parenchyma. Tumors with infiltrative pattern possess foci of poorly demarcated margins (indicated by white arrows) from (C) surrounding pancreatic parenchyma or (D) duodenum and peripancreatic adipose tissue.

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Second, microscopic tumor border was categorized as pushing or infiltrative. When the tumor boundary was well circumscribed under microscopic examination, this was referred to as a pushing border (Figure 2, A). PanNETs with smooth, well-circumscribed border by the well-demarcated fibrotic tumor capsule with inclusion of small irregular clusters or cords of infiltrating tumor cells within the fibrotic tumor capsule without accompanying frank tumor cell invasion to adjacent normal pancreatic parenchyma or other organs were also classified as having a pushing border (Figure 2, B). Multinodular tumor with clear delineation of the invasive edge from the adjacent tissue was also considered as pushing border. In contrast, infiltrative border was defined when irregular tonguelike projections of tumor cells or clusters were dissecting through normal pancreatic parenchyma (Figure 2, C) or surrounding structure without a recognizable, distinct delineation of the tumor (Figure 2, D). For better interobserver reproducibility, the tumor border was evaluated with this 2-tier system by assigning tumors with at least focal infiltrative growth pattern to infiltrative border.40  All available slides were examined. Areas difficult to interpret were reevaluated via discussion to arrive at a consensus interpretation among the 3 pathologists.

Figure 2

Representative microscopic images of pancreatic neuroendocrine tumors with microscopic pushing and infiltrative tumor borders. Tumors with pushing border showed (A) a margin well demarcated from surrounding tissue or (B) small irregular clusters or cords of tumor cells (arrows) infiltrating within a well-demarcated fibrotic tumor capsule with an overall smooth, well-circumscribed border. Tumors with infiltrative border showed (C) an ill-demarcated border with tumor clusters or individual cells dissecting through the pancreatic parenchyma or (D) surrounding peripancreatic adipose tissue (hematoxylin-eosin, original magnification ×200 [A through D]).

Figure 2

Representative microscopic images of pancreatic neuroendocrine tumors with microscopic pushing and infiltrative tumor borders. Tumors with pushing border showed (A) a margin well demarcated from surrounding tissue or (B) small irregular clusters or cords of tumor cells (arrows) infiltrating within a well-demarcated fibrotic tumor capsule with an overall smooth, well-circumscribed border. Tumors with infiltrative border showed (C) an ill-demarcated border with tumor clusters or individual cells dissecting through the pancreatic parenchyma or (D) surrounding peripancreatic adipose tissue (hematoxylin-eosin, original magnification ×200 [A through D]).

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Tumor grade was evaluated by counting mitoses per 10 high-power fields (HPFs) and Ki-67 labeling index according to the current guidelines of the 2017 and 2019 WHO classification systems.41,42  G1 was assigned to tumors with a mitotic rate of less than 2/10 HPFs and/or a Ki-67 labeling index lower than 3%, G2 to tumors with a mitotic rate of 2 to 20/10 HPFs and/or a Ki-67 labeling index of 3% to 20%, and G3 to tumors with a mitotic rate more than 20/10 HPFs and/or a Ki-67 labeling index higher than 20%.1,42  Lymphovascular and perineural invasions, marginal status, lymph node, and distant metastatic status were also evaluated. Tumor stage was evaluated based on the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual.43 

Tissue Microarray and Immunohistochemistry Analysis for Peptide Hormones

Tissue microarrays (TMAs) were constructed from archived, formalin-fixed, paraffin-embedded tissue blocks with a manual tissue microarrayer (Uni TMA Co Ltd, Seoul, Korea).15  Three representative cores from areas of the PanNET and one core from normal pancreas parenchyma were punched from the donor block of each PanNET case and transferred to a recipient TMA block to obtain uniform immunohistochemical labeling and normal control, respectively.

Subsequently, 4-μm-thick tissue sections were deparaffinized and hydrated in xylene and serially diluted in ethanol. Endogenous peroxidase was blocked via incubation in 3% H2O2 for 10 minutes. Thereafter, heat-induced antigen retrieval was performed. Primary antibodies were used with a Benchmark autostainer (Ventana Medical Systems, Tucson, Arizona) following the manufacturer's protocol. Sections were incubated at room temperature for 32 minutes in primary antibodies for insulin (1:100; 2D11-H5, Novocastra, Newcastle, United Kingdom), somatostatin (1:4000; A0566, DakoCytomation, Glostrup, Denmark), serotonin (1:200; 5HTH209, DakoCytomation), gastrin (prediluted; A0568, DakoCytomation), and glucagon (1:400; 295A-15, Cell Marque, Rocklin, California). The sections were then labeled with an automated immunostaining system with an I-View detection kit (Benchmark XT; Ventana). The immunolabeled sections were lightly counterstained with hematoxylin, dehydrated in ethanol, and cleared in xylene. Immunoreactivity was interpreted by light microscopic examination and independently evaluated by 2 pathologists, who were blinded to the clinicopathologic information. The results were interpreted as positive for diffuse cytoplasmic positivity.

Statistical Analysis

Continuous variables were compared using the independent Student t test or the Mann-Whitney U test. Categorical variables were examined using the χ2 test or the Fisher exact test. Concordances of the macroscopic and microscopic patterns between pathologists were evaluated using the Cohen κ statistic.44  The κ value was interpreted as follows: 0, no agreement; 0.20 or less, slight agreement; 0.21 to 0.40, fair agreement; 0.41 to 0.60, moderate agreement; 0.61 to 0.80, substantial agreement; and 0.81 to 1, almost perfect agreement.44  Survival curves were estimated using the Kaplan-Meier method, and differences between the curves were compared using the log-rank test. The prognostic potential of the factors was evaluated using univariate and multivariate Cox proportional hazards regression analyses. All statistical evaluations were performed using R (version 4.0.3; The R Foundation for Statistical Computing, Vienna, Austria). A P value < .05 was considered to indicate statistical significance.

Patient Characteristics

The mean age of patients was 59.0 ± 12.8 years (median, 60.5 years; range, 35–85 years). There were 96 men (47.3%) and 107 women (52.7%). One hundred sixty-one patients (79.3%) did not display any symptoms, whereas 42 patients (20.7%) had symptoms specific to functioning PanNETs. Forty-eight (23.6%), 41 (20.2%), 5 (2.5%), 5 (2.5%), and 9 cases (4.4%) were immunolabeled to insulin, glucagon, gastrin, serotonin, and somatostatin, respectively. Mean tumor size was 3.0 ± 2.2 cm. When dichotomization was performed, 90 cases (44.3%) were smaller than 2 cm and 113 (55.7%) were 2 cm or larger. There were 130 G1 (64.0%), 61 G2 (30.0%), and 12 G3 (6.0%) PanNETs. Eighty-eight (43.3%) were pT1, 52 (25.6%) were pT2, 57 (28.1%) were pT3, and 6 (3.0%) were pT4 cases based on the T classification of the 8th edition of the AJCC Cancer Staging Manual.43  Thirty (14.7%) and 6 cases (3.0%) showed lymph node metastasis and distant metastasis at the time of diagnosis, respectively. Lymphovascular and perineural invasions were noted in 55 (27.1%) and 30 cases (14.8%), respectively. Eighteen cases (8.9%) had a positive resection margin. The median follow-up period was 71 months (range, 1–137 months).

Macroscopic Growth Pattern and Its Association With Clinicopathologic Factors

Macroscopic growth pattern evaluation was performed with 167 cases (82.3%) that had available images of the cut surface of the PanNETs. Of these cases, 83 (49.7%) had an expansile growth pattern whereas 84 (50.3%) displayed an infiltrative pattern to surrounding pancreatic parenchyma or adjacent organs (Figure 1). The associations between growth pattern and clinicopathologic factors are summarized in Table 1. Briefly, PanNETs with grossly infiltrative growth pattern were correlated with tumors that had the following features: nonfunctioning (P < .001), larger size (P = .02), microscopic infiltrative tumor border (P < .001), higher tumor grade (P = .01), higher pT classification (P = .007), lymph node metastasis (P < .001), distant metastasis (P = .04), higher AJCC stage grouping (P < .001), lymphovascular (P = .007) and perineural (P < .001) invasions, and no insulin expression (P = .001).

Table 1

Correlation of the Macroscopic Growth Pattern With Other Clinicopathologic Variables

Correlation of the Macroscopic Growth Pattern With Other Clinicopathologic Variables
Correlation of the Macroscopic Growth Pattern With Other Clinicopathologic Variables

Microscopic Tumor Border and Its Association With Clinicopathologic Factors

Microscopic tumor borders were evaluated in the 203 PanNETs. The pushing-type tumor border was observed in 122 cases (60.1%), whereas the infiltrative tumor border was identified in 81 cases (39.9%), based on microscopic examination (Figure 2). The correlation of microscopic tumor border with the clinicopathologic factors of the PanNET cases is summarized in Table 2. PanNETs with infiltrative tumor border were more frequently observed in patients of older age (P = .04) and men (P < .001), and were associated with tumors with the following features: nonfunctioning (P = .03), larger size (P = .003), macroscopic infiltrative growth pattern (P < .001), higher tumor grade (P < .001), higher pT classification (P < .001), lymph node metastasis (P < .001), higher AJCC stage grouping (P < .001), lymphovascular (P < .001) and perineural (P < .001) invasions, involvement of resection margin (P = .007), and no insulin expression (P = .004).

Table 2

Correlation of the Microscopic Tumor Border With Other Clinicopathologic Variables

Correlation of the Microscopic Tumor Border With Other Clinicopathologic Variables
Correlation of the Microscopic Tumor Border With Other Clinicopathologic Variables

Combined Macroscopic Growth Pattern and Microscopic Tumor Border Status and Its Association With Clinicopathologic Factors

Combined macroscopic growth pattern and microscopic tumor border analysis was performed with 167 cases (82.3%) that had available images of the cut surface of the PanNETs. Based on combined macroscopic growth pattern and microscopic tumor border status, 65 cases (38.9%) were classified as having expansile growth and pushing border (Exp/Pus), 34 (20.4%) had infiltrative growth and pushing border (Inf/Pus), 18 (10.8%) had expansile growth and infiltrative border (Exp/Inf), and 50 (29.9%) had infiltrative growth and infiltrative border (Inf/Inf) (Table 3). PanNETs with Exp/Pus status were more commonly observed in female patients (P = .01) and were associated with tumors of smaller size (<2 cm; P = .01), lower pT classification (T1; P = .004), no lymph node metastasis (P < .001), no distant metastasis (P = .03), lower AJCC stage grouping (P < .001), and insulin expression (P = .001). In contrast, PanNETs with Inf/Inf status were more frequently associated with tumors with no symptoms (P = .01) and lymphovascular and perineural invasions (both P < .001).

Table 3

Correlation of the Combination of Growth Pattern and Tumor Border With Other Clinicopathologic Variables

Correlation of the Combination of Growth Pattern and Tumor Border With Other Clinicopathologic Variables
Correlation of the Combination of Growth Pattern and Tumor Border With Other Clinicopathologic Variables

We also assessed the 2-tier classification of combined macroscopic growth pattern and microscopic tumor border status after merging Exp/Pus, Inf/Pus, and Exp/Inf into “others” and then compared PanNETs having the “others” pattern with those having Inf/Inf. PanNETs with Inf/Inf status were more frequently observed in male patients (P = .01) and were associated with tumors with no symptoms (P = .01), larger size (≥2 cm; P = .002), higher tumor grade (P < .001), higher pT classification (P < .001), lymph node metastasis (P < .001), distant metastasis (P = .01), higher AJCC stage grouping (P < .001), lymphovascular and perineural invasions (both P < .001), and no insulin expression (P = .007).

Interobserver Variability in Assessing Macroscopic and Microscopic Tumor Borders

Interobserver variability was tested in 100 representative cases by 2 pathologists for tumor border assessment. Interobserver agreement was almost perfect for macroscopic growth pattern (κ = 0.86), moderate for microscopic tumor border (κ = 0.58), and substantial for combined macroscopic and microscopic tumor border (κ = 0.75).

Survival Impact of Macroscopic Growth Pattern

Patients with PanNET having the expansile growth pattern (5-year survival rate, 98.7%) had significantly better overall survival (OS) than those having the infiltrative pattern (76.2%; P < .001; Figure 3, A). Similarly, patients with PanNET having the expansile growth pattern (5-year survival rate, 90.3%) had significantly better recurrence-free survival (RFS) than those having the infiltrative pattern (68.1%; P < .001; Figure 3, B).

Figure 3

Overall survival (OS) and recurrence-free survival (RFS) of patients with pancreatic neuroendocrine tumor (PanNET) based on macroscopic growth patterns and microscopic tumor borders. Patients with PanNET having an infiltrative growth pattern showed (A) significantly worse OS (5-year survival rate, 76.2% versus 98.7%; P < .001) and (B) significantly shorter RFS (5-year survival rate, 68.1% versus 90.3%; P < .001) than those having an expansile pattern. Patients with PanNET having an infiltrative tumor border showed (C) significantly worse OS (72.5% versus 90.7%; P < .001) and (D) significantly shorter RFS (62.1% versus 83.9%; P < .001) than those having a pushing border.

Figure 3

Overall survival (OS) and recurrence-free survival (RFS) of patients with pancreatic neuroendocrine tumor (PanNET) based on macroscopic growth patterns and microscopic tumor borders. Patients with PanNET having an infiltrative growth pattern showed (A) significantly worse OS (5-year survival rate, 76.2% versus 98.7%; P < .001) and (B) significantly shorter RFS (5-year survival rate, 68.1% versus 90.3%; P < .001) than those having an expansile pattern. Patients with PanNET having an infiltrative tumor border showed (C) significantly worse OS (72.5% versus 90.7%; P < .001) and (D) significantly shorter RFS (62.1% versus 83.9%; P < .001) than those having a pushing border.

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Survival Impact of Microscopic Tumor Border

Patients with PanNET having the pushing tumor border (5-year survival rate, 90.7%) had significantly better OS than those having the infiltrative border (72.5%; P < .001; Figure 3, C). Similarly, patients with PanNET having the pushing tumor border (5-year survival rate, 83.9%) had significantly better RFS than those having the infiltrative border (62.1%; P < .001; Figure 3, D).

Survival Impact of Combined Macroscopic Growth Pattern and Microscopic Tumor Border

The overall 5-year survival rates in patients with PanNET having Exp/Pus, Inf/Pus, Exp/Inf, and Inf/Inf status were 98.4%, 89.7%, 100%, and 67.2%, respectively (overall comparison, P < .001; Figure 4, A). In the pairwise comparisons, patients with PanNET having Inf/Inf status had significantly worse OS than those having Exp/Pus (P < .001), Inf/Pus (P = .01), and Exp/Inf (P = .04) status. However, no survival difference was observed between patients with PanNET having Exp/Pus and Inf/Pus (P = .32), Exp/Pus and Exp/Inf (P = .53), or Inf/Pus and Exp/Inf status (P = .65). Also, the recurrence-free 5-year survival rates of patients with PanNET having Exp/Pus, Inf/Pus, Exp/Inf, and Inf/Inf status were 92.0%, 82.5%, 83.6%, and 56.7%, respectively (overall comparison, P < .001; Figure 4, B). In the pairwise comparisons, patients with PanNET having Inf/Inf status had significantly worse RFS than those having Exp/Pus (P < .001) and Inf/Pus (P = .004) status, but had a marginally significant difference from patients with Exp/Inf status (P = .05). In contrast, no survival difference was observed between patients with PanNET having Exp/Pus and Inf/Pus (P = .31), Exp/Pus and Exp/Inf (P = .4), or Inf/Pus and Exp/Inf status (P = .98).

Figure 4

Overall survival (OS) and recurrence-free survival (RFS) of patients with pancreatic neuroendocrine tumor (PanNET) based on 4-tier and 2-tier combined macroscopic and microscopic tumor border. (A) In the 4-tiered comparison, patients with PanNET having an infiltrative macroscopic growth pattern and infiltrative microscopic tumor border (Inf/Inf) status showed significantly worse OS (5-year survival rate, 67.2%; P < .001) than those having expanding/pushing (Exp/Pus; 98.4%), expanding/infiltrative (Exp/Inf; 89.7%), and infiltrative/pushing (Inf/Pus; 100%) status. (B) Patients with PanNET having Inf/Inf status showed significantly worse RFS (5-year survival rate, 56.7%; P < .001) than those having Exp/Pus (92.0%), Exp/Inf (82.5%), and Inf/Pus (83.6%) status. In the pairwise comparison, patients with PanNET having Inf/Inf status showed (C) significantly worse OS (67.2% versus 96.2%; P < .001) and (D) significantly shorter RFS (56.7% versus 88.4%; P < .001) than those with other growth patterns and borders.

Figure 4

Overall survival (OS) and recurrence-free survival (RFS) of patients with pancreatic neuroendocrine tumor (PanNET) based on 4-tier and 2-tier combined macroscopic and microscopic tumor border. (A) In the 4-tiered comparison, patients with PanNET having an infiltrative macroscopic growth pattern and infiltrative microscopic tumor border (Inf/Inf) status showed significantly worse OS (5-year survival rate, 67.2%; P < .001) than those having expanding/pushing (Exp/Pus; 98.4%), expanding/infiltrative (Exp/Inf; 89.7%), and infiltrative/pushing (Inf/Pus; 100%) status. (B) Patients with PanNET having Inf/Inf status showed significantly worse RFS (5-year survival rate, 56.7%; P < .001) than those having Exp/Pus (92.0%), Exp/Inf (82.5%), and Inf/Pus (83.6%) status. In the pairwise comparison, patients with PanNET having Inf/Inf status showed (C) significantly worse OS (67.2% versus 96.2%; P < .001) and (D) significantly shorter RFS (56.7% versus 88.4%; P < .001) than those with other growth patterns and borders.

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Therefore, we merged Exp/Pus, Inf/Pus, and Exp/Inf groups into one group, categorized them as “others,” and compared the OS of patients in this group with that of patients with PanNET having Inf/Inf status. Patients with PanNET having Inf/Inf status (5-year survival rate, 67.2%) had significantly worse OS than those having other growth patterns and/or tumor borders (96.2%; P < .001; Figure 4, C). Also, patients with PanNET having Inf/Inf status (5-year survival rate, 56.7%) had significantly worse RFS than those having other growth patterns and/or tumor borders (88.4%, P < .001; Figure 4, D).

Univariate and Multivariate Survival Analysis of OS

Infiltrative macroscopic growth pattern (hazard ratio [HR], 5.249; 95% CI, 1.794–15.36; P = .002), infiltrative microscopic tumor border (HR, 3.211; 95% CI, 1.655–6.228; P < .001), and Inf/Inf status (HR, 6.094; 95% CI, 2.525–14.7; P < .001) predicted poor OS based on univariate analysis (Table 4). Other factors associated with the OS of patients with PanNETs included age (P < .001), symptoms (P = .02), tumor size (P = .01), tumor G3 (P < .001), pT classification (P < .001), lymph node metastasis (P < .001), distant metastasis (P = .04), lymphovascular and perineural invasions (both P < .001), resection marginal status (P < .001), and glucagon expression (P = .03).

Table 4

Univariate and Multivariate Analysis of Overall Survival

Univariate and Multivariate Analysis of Overall Survival
Univariate and Multivariate Analysis of Overall Survival

Multivariate analyses were performed to determine whether combined macroscopic growth pattern and microscopic tumor border status would remain a predictor of OS after adjusting for these factors. As T classification, lymph node metastasis, and distant metastasis are components of the AJCC stage group, the AJCC stage group was not included in the multivariate analysis. Similarly, as macroscopic growth pattern and microscopic tumor border were components of combined macroscopic growth pattern and microscopic tumor border status, macroscopic growth pattern and microscopic tumor border were excluded from the multivariate analysis. Based on multivariate analysis, Inf/Inf status (P = .02), higher tumor grade (P = .04), and the involvement of resection margin (P = .04) were identified as independent poor prognostic factors of PanNETs (Table 4).

Univariate and Multivariate Survival Analysis of RFS

Survival analysis of RFS was performed with 185 PanNET cases with clear resection margin, and 18 cases with involvement of resection margin were excluded (Table 5). Infiltrative macroscopic growth pattern (HR, 4.456; 95% CI, 1.821–10.91; P = .001), infiltrative microscopic tumor border (HR, 3.438; 95% CI, 1.839–6.427; P < .001), and Inf/Inf status (HR, 5.893; 95% CI, 2.755–12.61; P < .001) significantly predicted shortened RFS based on univariate analysis (Table 5). Other factors that predicted the RFS of patients with PanNETs included age (P < .001), symptoms (P = .04), tumor size (P < .001), tumor grade (G2, P = .02; G3, P < .001), pT classification (P < .001), lymph node metastasis (P < .001), and perineural invasion (P = .001).

Table 5

Univariate and Multivariate Analysis of Recurrence-Free Survival

Univariate and Multivariate Analysis of Recurrence-Free Survival
Univariate and Multivariate Analysis of Recurrence-Free Survival

AJCC stage group, lymphovascular invasion, and glucagon and gastrin expression were not included in the multivariate analysis, as these factors can affect pT classification, lymph node metastasis, and symptoms, respectively. Similarly, as macroscopic growth pattern and microscopic tumor border were components of combined macroscopic growth pattern and microscopic tumor border status, they were excluded from the multivariate analysis. As a result, Inf/Inf status (HR, 2.807; 95% CI, 1.097–7.184; P = .03) was the only independent prognostic factor significantly correlated with a short RFS.

Subgroup Survival Analyses of Combined Macroscopic Growth Pattern and Microscopic Tumor Border

Patients were further stratified based on tumor grade, pT classification, lymphovascular invasion, and nodal metastasis status because Inf/Inf status was the only independent poor prognostic factor based on multivariate analysis. Patients were well stratified by tumor grading based on the 2019 WHO classification scheme; patients with a higher grade had worse OS (5-year survival rate, G1, 88.5%; G2, 84.3%; G3, 25.0%; P < .001; Figure 5, A) and RFS (5-year survival rate, G1, 82.8%; G2, 65.3%; G3, 33.3%; P < .001; Figure 5, B). In G1, patients with PanNET having Inf/Inf status showed the tendency of worse OS (5-year survival rate, 85.9% versus 97.0%; P = .06; Figure 6, A) and significantly shorter RFS (5-year survival rate, 80.0% versus 91.2%; P = .04; Figure 6, B) than those with PanNET having other patterns or borders. Similarly, in higher grades (G2 and G3), patients with PanNET having Inf/Inf status showed significantly worse OS (5-year survival rate, 52.6% versus 94.4%; P < .001; Figure 6, C) and RFS (5-year survival rate, 35.0% versus 82.7%; P < .001; Figure 6, D) than those with PanNET having other growth patterns or borders.

Figure 5

Overall survival (OS) and recurrence-free survival (RFS) of patients with pancreatic neuroendocrine tumor (PanNET) by tumor grade. Patients with grade 3 (G3) PanNET showed (A) significantly worse OS (5-year survival rate, G1, 88.5%; G2, 84.3%; G3, 25.0%; overall comparison, P < .001) than those with G1 (G1 versus G3, P < .001) and G2 (G2 versus G3, P < .001) and (B) significantly shorter RFS (G1, 82.8%; G2, 65.3%; G3, 33.3%; overall comparison, P < .001; G1 versus G2, P = .02) than those with G1 (G1 versus G3, P < .001) and G2 (G2 versus G3, P = .02).

Figure 5

Overall survival (OS) and recurrence-free survival (RFS) of patients with pancreatic neuroendocrine tumor (PanNET) by tumor grade. Patients with grade 3 (G3) PanNET showed (A) significantly worse OS (5-year survival rate, G1, 88.5%; G2, 84.3%; G3, 25.0%; overall comparison, P < .001) than those with G1 (G1 versus G3, P < .001) and G2 (G2 versus G3, P < .001) and (B) significantly shorter RFS (G1, 82.8%; G2, 65.3%; G3, 33.3%; overall comparison, P < .001; G1 versus G2, P = .02) than those with G1 (G1 versus G3, P < .001) and G2 (G2 versus G3, P = .02).

Close modal
Figure 6

Overall survival (OS) and recurrence-free survival (RFS) of the 2-tier combined macroscopic growth pattern and microscopic tumor border of patients with pancreatic neuroendocrine tumor (PanNET) based on tumor grade. Patients with grade 1 PanNET having infiltrative macroscopic growth pattern and infiltrative microscopic tumor border (Inf/Inf) status showed (A) marginally significant worse OS (5-year survival rate, 85.9% versus 97.0%; P = .06) and (B) significantly shorter RFS (80.0% versus 91.2%; P = .04) than those with other macroscopic growth patterns and microscopic tumor borders. Patients with grades 2 and 3 PanNET having Inf/Inf status showed (C) significantly worse OS (52.6% versus 94.4%; P < .001) and (D) significantly shorter RFS (35.0% versus 82.7%; P < .001) than those with other macroscopic growth patterns and microscopic tumor borders.

Figure 6

Overall survival (OS) and recurrence-free survival (RFS) of the 2-tier combined macroscopic growth pattern and microscopic tumor border of patients with pancreatic neuroendocrine tumor (PanNET) based on tumor grade. Patients with grade 1 PanNET having infiltrative macroscopic growth pattern and infiltrative microscopic tumor border (Inf/Inf) status showed (A) marginally significant worse OS (5-year survival rate, 85.9% versus 97.0%; P = .06) and (B) significantly shorter RFS (80.0% versus 91.2%; P = .04) than those with other macroscopic growth patterns and microscopic tumor borders. Patients with grades 2 and 3 PanNET having Inf/Inf status showed (C) significantly worse OS (52.6% versus 94.4%; P < .001) and (D) significantly shorter RFS (35.0% versus 82.7%; P < .001) than those with other macroscopic growth patterns and microscopic tumor borders.

Close modal

In the lower pT (pT1–2) classification, patients with PanNET having Inf/Inf status had worse OS (5-year survival rate, 78.3% versus 96.2%; P = .001; Figure 7, A) and RFS (5-year survival rate, 71.9% versus 93.8%; P < .001; Figure 7, B) than those with PanNET having other patterns or borders. Also, in the higher pT (pT3–4) classification, patients with PanNET having Inf/Inf status showed significantly worse OS (5-year survival rate, 57.7% versus 96.0%; P = .02; Figure 7, C) and shorter RFS (5-year survival rate, 41.6% versus 71.4%; P = .02; Figure 7, D) than those with PanNET having other growth patterns or borders.

Figure 7

Overall survival (OS) and recurrence-free survival (RFS) of the 2-tier combined macroscopic growth pattern and microscopic tumor border of patients with pancreatic neuroendocrine tumor (PanNET) based on tumor pT classification. Patients with PanNET having the pT1–pT2 classifications with infiltrative macroscopic growth pattern and infiltrative microscopic tumor border (Inf/Inf) status showed (A) significantly worse OS (5-year survival rate, 78.3% versus 96.2%; P = .001) and (B) significantly shorter RFS (71.9% versus 93.8%; P < .001) than those with other macroscopic growth patterns and microscopic tumor borders. Patients with PanNET having the pT3–pT4 classifications with Inf/Inf status also showed (C) significantly worse OS (5-year survival rate, 57.7% versus 96.0%; P = .02), (D) and significantly shorter RFS (41.6% versus 71.4%; P = .02) than those with other macroscopic growth patterns and microscopic tumor borders.

Figure 7

Overall survival (OS) and recurrence-free survival (RFS) of the 2-tier combined macroscopic growth pattern and microscopic tumor border of patients with pancreatic neuroendocrine tumor (PanNET) based on tumor pT classification. Patients with PanNET having the pT1–pT2 classifications with infiltrative macroscopic growth pattern and infiltrative microscopic tumor border (Inf/Inf) status showed (A) significantly worse OS (5-year survival rate, 78.3% versus 96.2%; P = .001) and (B) significantly shorter RFS (71.9% versus 93.8%; P < .001) than those with other macroscopic growth patterns and microscopic tumor borders. Patients with PanNET having the pT3–pT4 classifications with Inf/Inf status also showed (C) significantly worse OS (5-year survival rate, 57.7% versus 96.0%; P = .02), (D) and significantly shorter RFS (41.6% versus 71.4%; P = .02) than those with other macroscopic growth patterns and microscopic tumor borders.

Close modal

Subgroup analyses according to lymphovascular invasion status also revealed that patients with PanNET having Inf/Inf status had worse OS and RFS than those with other patterns or borders. First, in cases without lymphovascular invasion, patients with Inf/Inf showed significantly worse OS than those with other patterns or borders (5-year survival rate, 80.4% versus 96.5%; P = .01; Supplemental Figure 1, A [see supplemental digital content containing 8 figures at https://meridian.allenpress.com/aplm in the January 2023 table of contents]). Similarly, patients with Inf/Inf status showed significantly shorter RFS than those with other patterns or borders (5-year survival rate, 67.7% versus 89.8%; P < .001; Supplemental Figure 1, B). In cases with lymphovascular invasion, patients with Inf/Inf status showed significantly worse OS than those with other patterns or borders (5-year survival rate, 57.8% versus 94.4%; P = .04; Supplemental Figure 1, C). Similarly, patients with Inf/Inf status showed significantly shorter RFS than those with other patterns or borders (5-year survival rate, 47.0% versus 80.8%; P = .04 Supplemental Figure 1, D).

In the pN0 classification, patients with PanNET having Inf/Inf status had worse OS (5-year survival rate) than those with other patterns or borders (73.7% versus 96.0%; P < .001; Supplemental Figure 2, A). Similarly, patients with Inf/Inf showed significantly shorter RFS than those with other patterns or borders (5-year survival rate, 67.5% versus 90.0%; P < .001; Supplemental Figure 2, B). In the pN1–2 classification, there was no statistically significant difference in OS (5-year survival rate, 56.4% versus 100.0%; P = .29, Supplemental Figure 2, C) or RFS (37.5% versus 53.3%; P = .43; Supplemental Figure 2, D) between Inf/Inf status and other patterns or borders. These results might be due to the small number of these cases.

To the best of our knowledge, this study is the first to assess the clinicopathologic significance and prognostic value of both macroscopic growth pattern and microscopic tumor border using a large number of PanNET cases. Infiltrative macroscopic growth pattern and infiltrative microscopic tumor border were both significantly correlated with aggressive clinicopathologic factors, such as tumor being nonfunctioning, larger size, higher grade, higher pT classification, higher AJCC stage, presence of nodal metastasis, lymphovascular and perineural invasions, and no insulin expression. Patients with infiltrative macroscopic growth pattern and infiltrative microscopic tumor border showed significantly worse OS and shorter RFS than those with expansile macroscopic growth pattern and pushing microscopic tumor border, respectively. Furthermore, when these 2 factors were combined, infiltrative combined macroscopic growth pattern and microscopic tumor border status was identified as an independent prognostic factor for poor OS and the only independent predictor for short RFS. In addition, interobserver agreement could be increased substantially by combining both factors. Finally, combined macroscopic growth pattern and microscopic tumor border status could predict survival and tumor recurrence in patients based on tumor grading and pT classification. Our findings suggest that assessing both macroscopic growth pattern and microscopic tumor border in daily pathology practice is a simple, feasible, and economic strategy for predicting different biological features and the prognosis of patients with PanNETs.

The growth pattern based on gross examination and tumor border based on microscopic examination could provide important information on the biological behavior of mass-forming lesions and have previously been emphasized as valuable prognostic factors in cancers of several other organs.24,27,40,4550  In the case of macroscopic growth pattern, the infiltrative pattern of cervical cancer on preoperative magnetic resonance images was a significant independent factor for poor OS.50  Similarly, hepatocellular carcinoma with an infiltrative growth pattern was associated with shorter RFS with more frequent vascular invasion than that with other gross patterns.46,47  Zlobec et al24  demonstrated the additive effect of microscopic tumor border for stratifying OS in patients with stage II colorectal cancer, and adverse molecular alteration, such as BRAFV600 mutation, was correlated with infiltrative tumor border of colorectal cancer.40  Similarly, infiltrating tumor border of breast cancer and papillary thyroid carcinoma was correlated with aggressive behavior with lymph node metastasis.48,49  In particular, a 3-tiered, pattern-based classification system of tumor infiltration in endocervical adenocarcinoma, named the Silva system, is widely used today in daily diagnosis of endocervical adenocarcinoma to better predict patients' prognosis and aid physicians in deciding further treatment, especially lymphadenectomy.27 

Likewise, we attempted to stratify patients with PanNET by the tumor border based on pattern of invasion to correctly stratify patients who need additional intervention after surgical resection. There have been few studies on the immune microenvironment of PanNETs at the invasive margin,45,51  and infiltrative microscopic tumor border of PanNETs was emphasized previously in a few studies,3638  with correlation of adverse clinicopathologic factors, such as higher risk of metastasis, recurrence, and lymphovascular invasion. However, there have been no previous reports systematically reviewing both the macroscopic and microscopic tumor border of PanNETs for survival analysis and correlation with various clinicopathologic factors. We sampled all areas of the tumor with different appearance, and at least one representative section per 1 cm of the tumor was submitted at the time of gross examination. Our results demonstrated that 1 section per centimeter was enough for microscopic evaluation of the tumor border. However, there may not be a single answer, because the appropriate number of sections depends on the type of specimen. Further study is required for solving this issue.

In the present study, PanNET with an infiltrative macroscopic growth pattern was correlated with tumors with the following features: nonfunctioning, larger size, higher tumor grade, higher pT classification, lymph node metastasis, distant metastasis, higher AJCC stage grouping, lymphovascular and perineural invasions, and no insulin expression. Similarly, PanNET with an infiltrative microscopic tumor border was more frequently observed in patients of older age and in men, and infiltrative border status was associated with tumors with the following features: nonfunctioning, larger size, higher tumor grade, higher pT classification, lymph node metastasis, higher AJCC stage grouping, lymphovascular and perineural invasions, involvement of resection margin, and no insulin expression. These clinicopathologic factors, including patients with older age, tumors being nonfunctioning, higher tumor grade, lymph node metastasis, and lymphovascular invasion, were reported to be independent poor prognostic factors in patients with PanNETs in previous studies.12,13,16  To our knowledge, our study is the first to assess the combined macroscopic growth pattern and microscopic tumor border in PanNETs. Our observations of shorter survival in patients with microscopic infiltrative border were consistent with those of the previous studies of PanNETs.3638  In addition, we have confirmed that interobserver agreement in assessing microscopic tumor border can be substantially increased by combining macroscopic growth pattern with microscopic tumor border. By combining macroscopic growth pattern and microscopic tumor border, additional information can be provided; both features when combined can be used as an independent prognostic factor of the survival and tumor recurrence in patients with PanNET.

Our study has several limitations. First, only a few cases in each of the prognostic groupings, especially patients with G3, pT4, pN1 to 2, and AJCC stage IV tumors, were included. Nonetheless, based on subgroup analysis of our cohort, relatively accordant survival and recurrence data were found. Further, the importance of the tumor border was highlighted in further stratification of these groups. Second, this was a retrospective study with a limited number of available gross images of the cross section and tumor sections of the PanNETs, which may have led to missing a few cases with focal infiltrative growth pattern. Last, the macroscopic growth pattern and microscopic tumor border cannot be assessed in endoscopic ultrasound-guided fine needle aspiration biopsy specimens. Therefore, further studies on the role of preoperative imaging and combined macroscopic growth pattern and microscopic tumor border status in patients with PanNETs are needed.

In summary, PanNETs with combined infiltrative macroscopic growth pattern and infiltrative microscopic tumor border were observed in approximately one-quarter of the PanNET cases evaluated in this study and were associated with aggressive behavior and short OS and RFS. Therefore, assessment of the macroscopic growth pattern and microscopic tumor border status, which is a simple, reproducible, and cost-saving method, can provide additional information and improve current prognostic classification of the recurrence and survival of patients with surgically resected PanNETs.

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The authors have no relevant financial interest in the products or companies described in this article.

This work was supported by a grant (2015-554; to S.M.H.) from the Asan Institute for Life Sciences (Seoul, Republic of Korea), and by the National Research Foundation of Republic of Korea (NRF-2016R1A2B4009381; to S.M.H.).

Presented in part at the 73rd Annual Fall Meeting of the Korean Society of Pathologists; October 27–29, 2021; Seoul, Republic of Korea.

Author notes

Supplemental digital content is available for this article at https://meridian.allenpress.com/aplm in the January 2023 table of contents.