Microscopic venous invasion in patients with pancreatic neuroendocrine tumor as a potential predictor of postoperative recurrence

doi:10.1016/j.pan.2016.06.008

Pancreatology

Volume 16, Issue 5, September–October 2016, Pages 882-887

https://doi.org/10.1016/j.pan.2016.06.008 Get rights and content

Abstract

Background

Microscopic venous and lymphatic invasion is a known prognostic factor for various cancers, but its prognostic relevance for pancreatic neuroendocrine tumors (PNETs) is unclear.

Methods

Thirty-two consecutive patients with PNET who had complete resection were included in this study. Venous and lymphatic invasion was identified on elastic tissue or immunohistochemical staining, and correlated with other clinicopathological factors, including recurrence-free survival.

Results

Venous and lymphatic invasion was identified in nine (28%) and three (9%) patients, respectively. Tumors with venous invasion were of significantly larger size, higher Ki-67 index, and higher mitotic counts. Patients with venous invasion showed significantly worse prognosis than those without venous invasion (P = 0.001). Five of nine patients (56%) with venous invasion had tumor recurrence, while a relapse was found in one case in patients without venous invasion (n = 23). Lymphatic invasion was not correlated with any other clinicopathological parameters including lymph node metastasis and recurrence-free survival. Predictive factors for recurrence in univariate analysis included microscopic venous invasion, tumor size ≥ 20 mm, non-functionality, and WHO grades. In multivariate analysis where WHO grades and microscopic venous invasion were applied, venous invasion remained a significant predictor of poor recurrence-free survival (P = 0.021).

Conclusions

Microscopic venous invasion may serve as a predictive factor for tumor recurrence in patients with resectable PNET. The combination of WHO grades and microscopic venous invasion may assist in the stratification of the patients for risk of tumor recurrence.

Introduction

Pancreatic neuroendocrine tumor (PNET) is a rare form of epithelial neoplasm with histologic evidence of neuroendocrine differentiation. This unique neoplasm has been increasingly diagnosed in Japan and other countries [1], [2]. PNETs are classified into two groups based on histopathological findings. Well differentiated PNETs are characterized by relatively uniform, less dysplastic tumor cells arranged in a solid or trabecular pattern, while poorly differentiated PNETs are pancreatic equivalents of lung small cell carcinomas or large cell neuroendocrine carcinomas [3]. As mitotic counts and Ki-67 indices on tissue are currently the only reproducible prognostic factors for patients with PNET, these microscopic findings are currently endorsed for tumor grading by the World Health Organization (WHO) [4]. In the 2010 WHO classification, PNETs are graded on a three-tiered system [2], [5]. Although grade 3 (G3) PNETs are highly malignant neoplasms with aggressive clinical behavior, it is generally difficult to predict the prognosis of patients with G1/2 PNET. Identification of additional prognostic factors that can be used together with WHO grading will assist in the stratification of patients for the risk of tumor recurrence.

Lymphatic and venous drainage are primary routes of tumor dissemination from a primary tumor site to regional lymph nodes and distant organs. The presence of microscopic venous invasion is believed to be a histologic indicator of aggressive tumor behavior, and has been determined as an independent factor for poor prognosis for various cancers [6], [7], [8]. Previous studies on neuroendocrine tumors (NETs) of the lung has shown that microscopic venous and lymphatic invasion is significantly correlated with WHO histologic grades, tumor sizes, recurrence, and patients' survival [9]. However, this correlation remains controversial for PNETs. In the current study, we examined microscopic venous and lymphatic invasion in patients with resectable well differentiated PNET using immunohistochemistry for CD31 and D2-40, and correlated the results with other clinicopathologic parameters including recurrence-free survival.

Section snippets

Patient selection

The study protocol was approved by the Ethics Committee at Kobe University, and written informed consents were obtained from all patients. During the study period from January 2008 to April 2014, 33 patients with PNET underwent surgical resection at our institute. One patient was excluded from this study due to the presence of multiple small metastatic nodules in the liver found during surgery that lead to incomplete resection. The remaining 32 patients who had complete resection were included

Clinical features

The study cohort consisted of 18 men and 14 women with a median age of 64 years (range: 29–87 years). The tumor sizes ranged from 10 to 156 mm (median 16 mm). Three patients had another primary NET in an extrapancreatic organ (the lung, duodenum, and stomach). Two patients had a history of von Hippel-Lindau disease, and another patient had multiple endocrine neoplasia type 1.

Based on WHO grading, 16 cases were graded as G1, and 13 were G2. The remaining three showed well differentiated

Discussion

The WHO grading scheme has been widely accepted as a good prognostic indicator for patients with PNET. In agreement with other studies, the current study also supports the prognostic value of the WHO system [12], [13]. Recently, however, some experts have argued that tumors categorized in each grade are heterogeneous in tumor biology and clinical behavior [14]. Therefore, it is likely that there are some other factors that can be used together with histologic grades for prognosis. This clinical

Acknowledgments

The authors declare that they have no conflict of interest.

References (26)

I.M. Modlin et al.
Gastroenteropancreatic neuroendocrine tumours
Lancet Oncol
(2008)
S.M. Bonsib
Renal veins and venous extension in clear cell renal cell carcinoma
Mod Pathol
(2007)
G. Tanaka et al.
Automatic quantification of the MIB-1 immunoreactivity in brain tumors
Int Congr Ser
(2004)
M. Qadan et al.
Reassessment of the current American Joint Committee on Cancer staging system for pancreatic neuroendocrine tumors
J Am Coll Surg
(2014)
H. Sorbye et al.
Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study
Ann Oncol
(2013)
S.M. Bonsib et al.
Retrograde venous invasion in renal cell carcinoma: a complication of sinus vein and main renal vein invasion
Mod Pathol
(2011)
T. Curran et al.
Importance of lymph node involvement in pancreatic neuroendocrine tumors: impact on survival and implications for surgical resection
J Gastroinestr Surg
(2015)
J. Wong et al.
Predictors of lymph node metastases and impact on survival in resected pancreatic neuroendocrine tumors: a single-center experience
Am J Surg
(2014)
J. Cherenfant et al.
Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors
Surgery
(2013)
T. Ito et al.
Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan
J Gastroenterol
(2010)

J.C. Yao et al.

One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States

J Clin Oncol

(2008)

M.T. Barakat et al.

Neuroendocrine tumours

Endocr Relat Cancer

(2004)

Cited by (32)

Venous invasion and lymphatic invasion are correlated with the postoperative prognosis of pancreatic neuroendocrine neoplasm
2023, Surgery (United States)
Citation Excerpt :
Previous research, especially outside Japan, has analyzed LVI as a prognostic factor in patients with PNENs (Supplementary Table S1). In Japan, it is customary to use immunostaining to distinguish between venous invasion and lymphatic invasion,27–29 and the current study especially emphasized that these 2 factors should be separately evaluated when estimating the prognosis of patients with PNENs. To support this, the 5-year cumulative liver and lymph node metastasis rates in the LVI 2 group were 33.3% and 70.0%, respectively, which were both higher than those in the LVI 1 group (15.8% and 23.1%, respectively).
To determine treatment strategies corresponding to a wide range of pancreatic neuroendocrine neoplasms staging, easier-to-use and detailed prognostic classification is required.
Patients with pancreatic neuroendocrine neoplasms who underwent curative-intent surgery at the University of Tokyo Hospital between 2000 and 2018 were retrospectively reviewed. The presence or absence of venous and lymphatic invasion was assessed. Multivariable analysis was performed to identify the risk factors of shorter overall survival and recurrence-free survival. Patients were classified into the following 3 groups: a lymphovascular invasion 0 group, whereby both venous and lymphatic invasion were negative; an lymphovascular invasion 1 group, where either of the 2 was positive; and an lymphovascular invasion 2 group, where both were positive. The survival curves and recurrence patterns of the 3 groups were compared.
Eighty-nine patients were analyzed. Multivariable analysis revealed that lymphatic invasion and Ki-67 index (≥ 3.0%) were independent prognostic factors of recurrence-free survival (hazard ratio: 5.2 and 3.6). Fifty-three patients were classified as lymphovascular invasion 0, 26 as lymphovascular invasion 1, and 10 as lymphovascular invasion 2. The recurrence-free survival curves of the 3 groups were significantly stratified (10-year recurrence-free survival: 89.1% in lymphovascular invasion 0, 57.1% in lymphovascular invasion 1, and 18.3% in lymphovascular invasion 2). Five-year cumulative liver and lymph node metastasis of lymphovascular invasion 0, lymphovascular invasion 1, and lymphovascular invasion 2 were well stratified at 0% and 3.8%, 15.8% and 23.1%, and 33.3% and 70.0%, respectively.
Postoperative prognosis of resected pancreatic neuroendocrine neoplasms could be finely classified by venous invasion and lymphatic invasion. Management after curative-intent surgery for pancreatic neuroendocrine neoplasms may be changed by this new classification.
Prognostic factors for relapse in resected gastroenteropancreatic neuroendocrine neoplasms: A systematic review and meta-analysis
2021, Cancer Treatment Reviews
Citation Excerpt :
The included studies (n = 63) [7,9,13-16,18-75] include 64 datasets (one study [54] provided separate analyses for a cohort of patients with pancreatic NENs and a cohort of patients with duodenal NENs within the same article) and 13,715 patients. Of these 64 datasets, 56 reported on pancreatic NENs only [9,14,16,19-21,23-31,33-60,62-64,66-70,72-75] (12,418 patients), 3 reported on duodenal NENs (155 patients)[18,54,61] and 5 reported on mixed primary sites including pancreatic, gastroduodenal, gastric and small bowel NENs (1,142 patients) [7,15,32,65,71]. Of the 64 datasets included, 24 reported on grade 1–2 tumours only [9,15,16,21,22,29,32,38,40,45,46,48,49,53,54,57,61,64,65,69-71,74] (4,735 patients) and 40 included grade 1–3 tumours [7,13,14,18,19,21-24,27-32,34,35,37-41,43,45-48,51,54-56,59,60,62-64,66,67,69-71,75] (8,980 patients).
Gastroenteropancreatic neoplasms (GEP-NENs) can potentially be cured through surgical resection, but only 42–57% achieve 5-year disease-free survival. There is a lack of consensus regarding the factors associated with relapse following resection of GEP-NENs.
A systematic review identified studies reporting factors associated with relapse in patients with GEP-NENs following resection of a primary tumour. Meta-analysis was performed to identify the factors prognostic for relapse-free survival (RFS) or overall survival (OS).
63 studies comprising 13,715 patients were included; 56 studies reported on pancreatic NENs (12,418 patients), 24 reported on patients with grade 1–2 tumours (4,735 patients). Median follow-up was 44.2 months, median RFS was 32 months. Pooling of multivariable analyses of GEP-NENs (all sites and grades) found the following factors predicted worse RFS (all p values < 0.05): vascular resection performed, metastatic disease resected, grade 2 disease, grade 3 disease, tumour size > 20 mm, R1 resection, microvascular invasion, perineural invasion, Ki-67 > 5% and any lymph node positivity. In a subgroup of studies comprising exclusively of grade 1–2 GEP-NENs, R1 resection, perineural invasion, grade 2 disease, any lymph node positivity and tumour size > 20 mm predicted worse RFS (all p values < 0.05). Few OS data were available for pooling; in univariable analysis (entire cohort), grade 2 predicted worse OS (p = 0.007), while R1 resection did not (p = 0.14).
The factors prognostic for worse RFS following resection of a GEP-NEN identified in this meta-analysis could be included in post-curative treatment surveillance clinical guidelines and inform the stratification and inclusion criteria of future adjuvant trials.
Prediction of lymph node metastasis in pancreatic neuroendocrine tumors by contrast enhancement characteristics
2017, Pancreatology
Citation Excerpt :
The presence of microscopic tumor invasion into the adjacent pancreatic parenchyma, lymphovascular invasion, LN metastasis, and tumor grade were analyzed for pathological evaluation. Lymphovascular invasion was assessed by visualizing microvascular and lymphatic vessels via immunostaining for CD31 and D2-40 as previously described [10]. Tumor grades were evaluated according to the World Health Organization (WHO) 2010 classification, which is based on mitotic counts and Ki-67 indices (G1: mitotic count < 2 per 10 high-power fields [HPFs] and/or Ki-67 ≤ 2%; G2: mitotic count 2–20 per 10 HPFs and/or Ki-67 3–20%; and G3: mitotic count > 20 per 10 HPFs and/or Ki-67 > 20%) [11].
Iso- or hypo-attenuating areas in the arterial phase on contrast-enhanced computed tomography (CE-CT) have been reported to be negative prognostic features in pancreatic neuroendocrine tumors (PNETs). Given that the optimal indication for lymph node dissection in patients with PNET remains unclear, we sought to utilize enhancement characteristics on CE-CT as a preoperative predictor of regional lymph node metastasis in PNETs.
The medical records of patients with well-differentiated PNETs who underwent pancreatectomy along with lymphadenectomy were retrospectively analyzed. We divided PNETs into two groups based on the extent of attenuation in the late arterial phase on CE-CT imaging. PNETs that showed hyper-attenuation over the entire area compared to the adjacent normal pancreas were categorized as hyper-PNETs. PNETs that contained both hyper and iso- or hypo-attenuation regions as well as those that showed only iso- or hypo-attenuation over the entire area were categorized as hetero/hypo-PNETs.
Forty-one patients with a median age of 64 years were enrolled, including 11 with hyper-PNETs and 30 with hetero/hypo-PNETs. Hetero/hypo-PNETs were significantly larger than hyper-PNETs (P = 0.022), and the former group more frequently comprised G2 tumors, according to the World Health Organization 2010 classification (P < 0.001). On univariate and multivariate analyses, hetero/hypo-PNETs were independently associated with regional lymph node metastasis.
The presence of iso- or hypo-attenuating regions appears to be associated with regional lymph node metastasis in PNETs. Tumor enhancement characteristics should be assessed in patients with PNET so as not to miss those at high risk of lymph node metastasis.
The Usefulness of Elastin Staining to Detect Vascular Invasion in Cancer
2023, International Journal of Molecular Sciences
A Machine Learning Approach Using [<sup>18</sup>F]FDG PET-Based Radiomics for Prediction of Tumor Grade and Prognosis in Pancreatic Neuroendocrine Tumor
2023, Molecular Imaging and Biology
Venous Invasion in Pancreatic Neuroendocrine Tumors Is Independently Associated With Disease-free Survival and Overall Survival
2023, American Journal of Surgical Pathology

View all citing articles on Scopus

^☆: Institute where the work was conducted: Kobe University Hospital.

View full text

Original articleMicroscopic venous invasion in patients with pancreatic neuroendocrine tumor as a potential predictor of postoperative recurrence☆

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Patient selection

Clinical features

Discussion

Acknowledgments

Lancet Oncol

Mod Pathol

Int Congr Ser

J Am Coll Surg

Ann Oncol

Mod Pathol

J Gastroinestr Surg

Am J Surg

Surgery

Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan

J Gastroenterol

One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States

J Clin Oncol

Neuroendocrine tumours

Endocr Relat Cancer

Original article
Microscopic venous invasion in patients with pancreatic neuroendocrine tumor as a potential predictor of postoperative recurrence☆