Carbonic anhydrase 9 expression in well-differentiated pancreatic neuroendocrine neoplasms might be associated with aggressive behavior and poor survival

Although pancreatic neuroendocrine neoplasms (PanNENs) are generally indolent, patients with distant metastasis have a dismal prognosis. Recently, the autophagy inhibitor chloroquine (CQ) has been shown to suppress the tumour growth of PanNENs, but the detailed mechanisms have not been elucidated. Furthermore, these results were obtained from poorly differentiated cell lines rather than well-differentiated cell lines, which is the most prevalent type in this tumour. To explore the mechanism and efficacy of CQ on PanNENs, we applied CQ to cell lines and evaluated the resulting apoptosis and endoplasmic reticulum (ER) stress. CQ treatment induced ER stress, and an unfolded protein response was activated through the PERK-eIF2α-ATF4 pathway, resulting in the expression of the pro-apoptotic protein C/EBP homologous protein (CHOP), which reflects ER-stress-mediated apoptotic cell death. Furthermore, hydroxychloroquine (HCQ) was effective in Men1 heterozygous-deficient (Men1+/ΔN3-8) mice, a mouse PanNEN model that is considered to correspond to human low-grade PanNEN. HCQ administration decreased tumour size in Men1+/ΔN3-8 mice. In the HCQ group, histological analyses revealed that proliferative activity was unchanged, but apoptosis was accelerated, accompanied by CHOP expression. These results suggest that autophagy inhibition by CQ/HCQ could be used for the treatment of PanNEN, including the well-differentiated type.

Download Full-text

Pancreatic Neuroendocrine Neoplasms: Landscape and Horizon

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2019-0654-ra ◽

2020 ◽

Vol 144 (7) ◽

pp. 816-828

Author(s):

Laura H. Tang

Keyword(s):

Neuroendocrine Neoplasms ◽

Specific Gene ◽

Important Distinction ◽

Pancreatic Neuroendocrine Neoplasms ◽

Poorly Differentiated Neuroendocrine Carcinoma ◽

Poorly Differentiated ◽

Well Differentiated ◽

Initial Description ◽

Definition Of ◽

Hereditary Conditions

Context.— Since the initial description of pancreatic endocrine physiology and the recognition of islet cell tumors in the 1800s, there have been noteworthy advances in the pathobiology of pancreatic neuroendocrine neoplasms (PanNENs), and definition of the important distinction between well-differentiated neuroendocrine tumor (PanNET) and poorly differentiated neuroendocrine carcinoma (PanNEC). The evolving knowledge has resulted in a continuous update in terminology, classification, and grading system for this group of neoplasms. Pancreatic neuroendocrine tumors associated with hereditary conditions have been linked to unique molecular and genetic events, and sporadic PanNETs have specific gene signatures. Based on accumulative experience and knowledge, therapeutic strategies have been defined for this group of neoplasms. Objective.— To review the evolution and description of the pathologic-genomic evolution of PanNENs, and to facilitate accurate pathologic interpretation for the corresponding clinical management. Data Sources.— Literature review of published studies and author's own work. Conclusions.— Evolving experience and knowledge have established subtypes of pancreatic neuroendocrine neoplasms, based on their genotype and phenotype. Accurate pathologic interpretation of the specific neoplasm has significant implications for therapy and prognosis.

Download Full-text

Serum Elastase 1 Level as a Risk Factor for Postoperative Recurrence in Patients with Well-Differentiated Pancreatic Neuroendocrine Neoplasms

Annals of Surgical Oncology ◽

10.1245/s10434-018-6675-3 ◽

2018 ◽

Vol 25 (11) ◽

pp. 3358-3364 ◽

Cited By ~ 1

Author(s):

Yoshihide Nanno ◽

Hirochika Toyama ◽

Yoh Zen ◽

Masayuki Akita ◽

Yasuhisa Ando ◽

...

Keyword(s):

Risk Factor ◽

Postoperative Recurrence ◽

Neuroendocrine Neoplasms ◽

Pancreatic Neuroendocrine Neoplasms ◽

Elastase 1 ◽

Well Differentiated

Download Full-text

Clinical and biomarker evaluations of sunitinib in patients (pts) with advanced well-differentiated grade 3 (G3) and poorly differentiated neuroendocrine neoplasms (PD-NEN).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.274 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 274-274 ◽

Cited By ~ 2

Author(s):

Chantal Dreyer ◽

Anne Couvelard ◽

Thomas Walter ◽

Catherine Lombard Bohas ◽

Patricia Niccoli ◽

...

Keyword(s):

Previous Treatment ◽

Progression Free Survival ◽

Roc Curves ◽

Threshold Value ◽

Neuroendocrine Neoplasms ◽

Tumor Biomarkers ◽

Prospective Phase ◽

Carbonic Anhydrase 9 ◽

Well Differentiated ◽

Grade 3

274 Background: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumors (PNET) where sunitinib was showed to prolong progression-free survival leading to FDA and EMA approval. However, clinical experience in pts with well-differentiated G3 & PD-NEN remains limited. Methods: This prospective phase II trial evaluate potential biomarkers correlating with sunitinib activity in pts with advanced well differentiated G3 or PD-NEN. Sunitinib was given at the dose of 37.5 mg/d as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAEv4. Pharmacokinetics (PK) of sunitinib and SU12662 (main active metabolite) were evaluated. Tumor biomarkers (PDGFR-b, VEGFR2, Carbonic Anhydrase 9, Ki67 and p-AKT) were evaluated in tumor tissues, quantified in tumor cells and stroma (vessels, fibroblasts) using immunohistochemistry and correlated with response by RECIST. Results: Among 31 pts (M/F: 18/13, median age 61), 13 pancreatic, 5 gastric, 5 rectal, 4 colonic, and 4 other G3 & PD-NEN were entered. 27 pts had previous treatment with chemotherapy (mainly platinum/VP16). Among 26 pts evaluable for safety and activity, 7 pts (23%, 95%CI: 6.9%-39.3%), including 3 pts classified as well-differentiated G3 neoplasms) experienced partial responses and tumor stabilizations (clinical benefit). Safety and PK exposure to sunitinib and SU12662 in those pts was consistent with that experienced in PNET. Among the above evaluated tumor biomarkers, only Ki67 correlated with sunitinib activity. The median Ki67 was 20% and 77.5% in pts with CB versus non-responders (p=.002), respectively. ROC curves showed correlations between lower Ki67 in tumors and sunitinib activity (OR:0.9; IC95%:0.831-0.9, p=.039). With a threshold value of Ki67 of 47%, sensitivity and specificity were 80%, the predictive positive value was 67% and the negative predictive value was 86%. Conclusions: In pts with well-differentiated G3 & PD-NEN, sunitinib showed evidence of activity that was more pronounced in pts with Ki67<47%. Clinical trial information: NCT01215578.

Download Full-text

Alterations in Cancer-related Genes Associated with Grading of Well Differentiated Pancreatic Neuroendocrine Neoplasms

Pancreatic Disorders and Therapy ◽

10.4172/2165-7092.1000189 ◽

2017 ◽

Vol 07 (03) ◽

Author(s):

Yudai Yokota ◽

Mitsuharu Fukasawa ◽

Shinichi Takano ◽

Hiroko Shindo ◽

Ei Takahashi ◽

...

Keyword(s):

Neuroendocrine Neoplasms ◽

Pancreatic Neuroendocrine Neoplasms ◽

Well Differentiated

Download Full-text

A simple and practical index predicting the prognoses of the patients with well-differentiated pancreatic neuroendocrine neoplasms

Journal of Gastroenterology ◽

10.1007/s00535-019-01570-0 ◽

2019 ◽

Vol 54 (9) ◽

pp. 819-828 ◽

Cited By ~ 4

Author(s):

Bo Liu ◽

Atsushi Kudo ◽

Yuko Kinowaki ◽

Toshiro Ogura ◽

Kosuke Ogawa ◽

...

Keyword(s):

Neuroendocrine Neoplasms ◽

Pancreatic Neuroendocrine Neoplasms ◽

Well Differentiated

Download Full-text

Neuroendocrine neoplasms of the pancreas: diagnosis and pitfalls

Virchows Archiv ◽

10.1007/s00428-021-03211-5 ◽

2021 ◽

Author(s):

Björn Konukiewitz ◽

Moritz Jesinghaus ◽

Atsuko Kasajima ◽

Günter Klöppel

Keyword(s):

Neuroendocrine Tumors ◽

Chromogranin A ◽

Molecular Profile ◽

Neuroendocrine Neoplasms ◽

Histological Differentiation ◽

Pancreatic Neuroendocrine Neoplasms ◽

Poorly Differentiated ◽

Well Differentiated ◽

Diagnostic Pitfalls ◽

Neuroendocrine Carcinomas

AbstractCommon to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological differentiation and molecular profile. Three groups can be distinguished: well-differentiated neuroendocrine neoplasms (neuroendocrine tumors), poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas), and mixed neuroendocrine-non-neuroendocrine neoplasms. However, the expression of synaptophysin and, to a lesser extent, also chromogranin A is not restricted to the neuroendocrine neoplasms, but may also be in a subset of non-neuroendocrine epithelial and non-epithelial neoplasms. This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high-grade neuroendocrine tumors from neuroendocrine carcinomas and an algorithm avoiding diagnostic pitfalls in the delineation of non-neuroendocrine neoplasms with neuroendocrine features from pancreatic neuroendocrine neoplasms.

Download Full-text