Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3

Konukiewitz, Björn; Jesinghaus, Moritz; Steiger, Katja; Schlitter, Anna Melissa; Kasajima, Atsuko; Sipos, Bence; Zamboni, Giuseppe; Weichert, Wilko; Pfarr, Nicole; Klöppel, Günter

doi:10.1016/j.humpath.2018.03.018

Cited by 111 publications

(116 citation statements)

References 19 publications

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“…According to the current 2017 WHO classification, G3 Pan-NETs and PanNECs are two distinct entities that are genetically different and have different clinical implications. G3 PanNETs share morphological, immunophenotypical and genetic features with other low-grade PanNETs, while there is increasing evidence that PanNECs are genetically more closely related to conventional pancreatic carcinomas than to PanNETs [12]. With this background, the recent TNM classification for PanNECs follows the criteria for classifying PanNET PanNEC ductal adenocarcinomas [13].…”

Section: Discussionmentioning

confidence: 99%

“…Loss of Smad4 expression was seen in three PanNECs, all cases being SC-PanNECs, and in none of the G3 PanNETs. As MUC1 and p16 expression have recently been reported to be more frequent in PanNECs compared to PanNETs [12], we added these two markers to the immunohistochemical panel. We found similar findings to Konukiewitz et al [12]; diffuse p16 staining was present in 67% of PanNECs compared to 25% of G3 PanNETs, and MUC1 was also positive in 67% and 25% of PanNECs and G3 PanNETs, respectively.…”

Section: G3-pannet Pannecmentioning

confidence: 99%

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Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study

Kim

Lee

et al. 2020

Cancer Res Treat

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The most recent 2017 World Health Organization (WHO) classification of pancreatic neuroendocrine neoplasms (PanNENs) has refined the three-tiered 2010 scheme by separating grade 3 pancreatic neuroendocrine tumors (G3 PanNETs) from poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). However, differentiating between G3 Pan-NETs and PanNECs is difficult in clinical practice. Materials and Methods Eighty-two surgically resected PanNENs were collected from 16 institutions and reclassified according to the 2017 WHO classification based on the histological features and proliferation index (mitosis and Ki-67). Immunohistochemical stains for ATRX, DAXX, retinoblastoma, p53, Smad4, p16, and MUC1 were performed for 15 high-grade PanNENs. Results Re-classification resulted in 20 G1 PanNETs (24%), 47 G2 PanNETs (57%), eight G3 welldifferentiated PanNETs (10%), and seven poorly differentiated PanNECs (9%). PanNECs showed more frequent diffuse nuclear atypia, solid growth patterns and apoptosis, less frequent organoid growth and regular vascular patterns, and absence of low-grade PanNET components than PanNETs. The Ki-67 index was significantly higher in PanNEC (58.2%± 15.1%) compared to G3 PanNET (22.6%±6.1%, p < 0.001). Abnormal expression of any two of p53, p16, MUC1, and Smad4 could discriminate PanNECs from G3 PanNETs with 100% specificity and 87.5% sensitivity. Conclusion Histological features supporting the diagnosis of PanNECs over G3 PanNETs were the absence of a low-grade PanNET component in the tumor, the presence of diffuse marked nuclear atypia, solid growth pattern, frequent apoptosis and markedly increased proliferative activity with homogeneous Ki-67 labeling. Immunohistochemical stains for p53, p16, MUC1, and Smad4 may be helpful in distinguishing PanNECs from G3 PanNETs in histologically ambiguous cases, especially in diagnostic practice when only small biopsied tissues are available.

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Section: Discussionmentioning

confidence: 99%

Section: G3-pannet Pannecmentioning

confidence: 99%

Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study

Kim

Lee

et al. 2020

Cancer Res Treat

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“…Samples were amplified using a custom-designed gene panel for breast cancer 32 covering the most recurrent mutations 33 . Library preparation and sequencing were performed using the multiplex PCR-based Ion Torrent AmpliSeq ™ technology (Thermo Fisher Scientific) and Ion S5XL technology, with procedures already described 34 .…”

Section: Methodsmentioning

confidence: 99%

Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer

Eichelberger

Saini

Moreno³

et al. 2020

Preprint

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scheel@helmholtz-muenchen.de and 39 Martin R. Sprick, m.sprick@Dkfz-Heidelberg.de and 40 Andreas Trumpp, a.trumpp@Dkfz-Heidelberg.de 41 42 Running title: 43 Epithelial gene expression in EMT is required for breast cancer metastasis. 44 45 Abstract 48Despite important advances in the treatment of breast cancer, the 5-year survival rate 49 for patients with distant metastasis remains less than 30%. Metastasis is a complex, 50 multi-step process beginning with local invasion and ending with the outgrowth of 51 systemically disseminated cells into actively proliferating metastases that ultimately 52 cause the destruction of vital organs. It is this last step that limits patient survival and, 53 at the same time, remains the least understood mechanistically. Here, we focus on 54 understanding determinants of metastatic outgrowth using metastatic effusion biopsies 55 from stage IV breast cancer patients. By modelling metastatic outgrowth through 56 xenograft transplantation, we show that tumour initiation potential of patient-derived 57 metastatic breast cancer cells across breast cancer subtypes is strongly linked to high 58 levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly 59 plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt 60 mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels 61 are caused by the irreversible reprogramming to a mesenchymal state with 62 concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to 63 retain epithelial traits is tied to a global epigenetic program that limits the actions of 64 EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide 65 direct evidence that maintenance of epithelial identity is required for metastatic 66 outgrowth while concomitant expression of mesenchymal markers enables plasticity. 67In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal 68 reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our 69 data provide a framework for the intricate intercalation of mesenchymal and epithelial 70 traits in metastatic growth. 71Other studies emphasize that a transient, rather than permanent expression of EMT-87 transcription factors is crucial for the outgrowth of metastases 4,6,7 . This is supported by 88 the finding that most macroscopic metastases generated by carcinomas display an 89 epithelial morphology 8 . However, a strict requirement for EMT at any time during the 90 metastatic process is called into question by the finding that overexpression of micro 91RNAs that inhibit EMT does not affect metastasis 9 and loss of Twist1 and Snai1 92 expression in a pancreatic cancer mouse model does not change invasion and disease 93 progression 10 . 94More complication has recently arisen from the observation that tumour cells with an 95 intermediate, often termed hybrid epithelial-mesenchymal phenotype, are the most 96 competent in colonization and metastasis fo...

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“…A PanNET G3 constitutes a newly introduced category with a Ki67 index > 20% and mitotic count > 20/2 mm 2 [8]. It has been shown that PanNET G3 largely shares its molecular and genetic characteristics with PanNET G1/G2, while it profoundly differs from PanNECs [9-12]. Clinically, the outcome of the patients seems to be worse than that of patients with NET G1/2 but still better than that of NEC patients [11, 13, 14].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index > 20%

et al. 2018

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The clinicopathological features of lung neuroendocrine neoplasms (NEN) with a high proliferative index at the border area between atypical carcinoid and neuroendocrine carcinoma have not been investigated so far. The aim of this study was, therefore, to search for lung NENs which are well differentiated but show Ki67 values that overlap with those of poorly differentiated (PD)-NENs. Resected lung NENs from 244 Japanese patients were reviewed, and Ki67 indices were assessed in all tumors. The data were then correlated to clinicopathological parameters and patient outcome. Among 59 (24%) well-differentiated (WD)-NENs and 185 (76%) lung PD-NENs, 7 were defined as WD-NENs with Ki67 indices > 20%. The Ki67 indices of these tumors (mean 29%, range 24–36) were significantly lower than those of PD-NENs (mean 74%, range 34–99). All WD-NENs with Ki67 > 20% lacked abnormal p53 and loss of retinoblastoma 1 (Rb1) expression. In contrast, many PD-NENs expressed p53 (48%) and showed loss of Rb1 (86%). The 2- and 5-year disease-free survival rates in WD-NEN patients with Ki67 > 20% were lower than those of WD-NEN patients with Ki67 ≤20% (p < 0.01 for disease-free and overall survival). No statistical differences were detected between outcome of WD-NEN patients with Ki67 > 20% and those of PD-NEN. It is concluded that WD-NEN patients with Ki67 > 20% share the morphological and immunohistochemical features of WD-NEN patients with Ki67 ≤20%, but they have a worse prognosis, suggesting that this tumor group requires particular attention in future classifications and probably new therapeutic regimes.

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Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3

Cited by 111 publications

References 19 publications

Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study

Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study

Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer

Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index > 20%

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Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3

Cited by 111 publications

References 19 publications

Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study

Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study

Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer

Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index &#x3e; 20%

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Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index > 20%