scholarly journals How to Classify Pituitary Neuroendocrine Tumors (PitNET)s in 2020

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 514 ◽  
Author(s):  
Jacqueline Trouillas ◽  
Marie-Lise Jaffrain-Rea ◽  
Alexandre Vasiljevic ◽  
Gérald Raverot ◽  
Federico Roncaroli ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Early Recognition ◽  
Pituitary Tumors ◽  
Operative Management ◽  
Prognostic Impact ◽  
Null Cell ◽  
Ki 67 ◽  
Standardized Report ◽  
Proliferative Markers ◽  
Morphologic Type

Adenohypophyseal tumors, which were recently renamed pituitary neuroendocrine tumors (PitNET), are mostly benign, but may present various behaviors: invasive, “aggressive” and malignant with metastases. They are classified into seven morphofunctional types and three lineages: lactotroph, somatotroph and thyrotroph (PIT1 lineage), corticotroph (TPIT lineage) or gonadotroph (SF1 lineage), null cell or immunonegative tumor and plurihormonal tumors. The WHO 2017 classification suggested that subtypes, such as male lactotroph, silent corticotroph and Crooke cell, sparsely granulated somatotroph, and silent plurihormonal PIT1 positive tumors, should be considered as “high risk” tumors. However, the prognostic impact of these subtypes and of each morphologic type remains controversial. In contrast, the French five-tiered classification, taking into account the invasion, the immuno-histochemical (IHC) type, and the proliferative markers (Ki-67 index, mitotic count, p53 positivity), has a prognostic value validated by statistical analysis in 4 independent cohorts. A standardized report for the diagnosis of pituitary tumors, integrating all these parameters, has been proposed by the European Pituitary Pathology Group (EPPG). In 2020, the pituitary pathologist must be considered as a member of the multidisciplinary pituitary team. The pathological diagnosis may help the clinician to adapt the post-operative management, including appropriate follow-up and early recognition and treatment of potentially aggressive forms.

scholarly journals MON-287 Expression of Programmed Death-Ligand 1 (PD-L1) in Human Pituitary Neuroendocrine Tumor

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Valentine Suteau ◽  
Alexandre Collin ◽  
Philippe Menei ◽  
Patrice Rodien ◽  
Marie-Christine Rousselet ◽  
...  
Keyword(s):  
Pituitary Tumors ◽  
Human Pituitary ◽  
Ki 67 ◽  
Programmed Death Ligand 1 ◽  
Standard Management ◽  
Programmed Death ◽  
In Vitro Diagnostic ◽  
Proliferative Markers ◽  
Grade 3

Abstract Introduction Some Pituitary NeuroEndocrine Tumors (PitNET) present an aggressive evolution and are resistant to standard management. Immunotherapy have shown durable efficacy in a variety of malignancies. The aim of this study was to explore the programmed death-ligand 1 (PD-L1) expression in varied subtypes of pituitary adenomas with assessment of their clinical behavior at diagnosis and follow-up. Methods We conducted a retrospective monocentric study, including all patients operated a PitNET between 2012 and 2018. PDL-1 immunostaining were performed using an European Conformity-In-Vitro-Diagnostic labeled anti-PDL1 antibody (Clone 22C3). PD-L1 immunostaining was evaluated as the percentage of tumor cell showing positive membrane staining, into four grades: grade 0 = <1%, grade 1 = 1 to 5%, grade 2 = 6 to 49% and grade 3 = ≥ 50%. PD-L1 expression was compared with tumor features (secretion, proliferation, invasion) and outcome. Results The study included one hundred and thirty-nine PitNET, including 84 (60%) nonfunctioning adenomas. Twenty-five PitNET were PD-L1 positive (18%), including 3 grade 3, 8 grade 2 and 14 grade 1. PD-L1 expression was not different between functioning and non-functioning adenomas (p=0.26). Among sixteen tumors with proliferative markers (Ki-67 ≥ 3% and p53 positive), only one was PD-L1 positive. Conclusion In our series, pituitary tumors rarely exhibit PD-L1 expression and this immune marker did not seem to be associated with any biological characteristic or behavior of the pituitary tumors. Thus, PD-L1 staining is necessary before considering PD-L1 blockage in PitNET, in case of therapeutic impasse.

scholarly journals Predictive value of morphological features and proliferative markers (mitotic index, Ki-67, PHH3) in bronchopulmonary neuroendocrine tumors

Pathologia ◽  
2021 ◽  
Vol 18 (3) ◽  
pp. 254-262
Author(s):  
L. M. Zakhartseva ◽  
H. Ye. Chytaieva
Keyword(s):  
Mitotic Index ◽  
Neuroendocrine Tumors ◽  
Survival Data ◽  
Predictive Value ◽  
Survival Rates ◽  
Metastatic Lesion ◽  
Morphological Features ◽  
Biopsy Material ◽  
Ki 67 ◽  
Proliferative Markers

The aim of this study was to evaluate relations of mitotic index (MI), necrosis, IHC proliferative markers Ki-67 and PHH3, and their predictive value for lung neuroendocrine tumors (NETs) aggressiveness. Materials and methods. The study used surgical and biopsy material from 64 patients with lung NETs before chemotherapy prescribing. Morphological study and IHC was performed. MI, necrosis, Ki-67 and PHH3 expression and metastatic disease and survival were estimated using nonparametric statistics. Results. Statistically significant association of necrosis severity and survival rates was found (P = 0.021). This was true for comparing patients with no necrosis in tumor tissue and extensive foci of necrosis (P = 0.023). MI appeared to be associated with metastases in lymph nodes (P = 0.003) and with distant metastatic lesions (P = 0.029). Significant, direct association of Ki-67 and MI (P < 0.001), MI and PHH3 expression (P < 0.001) was found. However, there was no significant link between Ki-67 and PHH3 rates (P = 0.240). Ki-67 didn’t show any significant association with necrosis and metastases. Also, Ki-67 rates didn’t affect the patient survival. Data on PHH3 expression and their estimation appeared to be rather contradictory. PHH3 expression rates were lower than expected and did not exceed neither Ki-67 rates, nor MI. Conclusions. MI and necrosis are reliable markers for the assessment of lung NETs aggressiveness. MI is statistically associated with metastatic lesion, while extensive necrosis – with survival rates. Ki-67 expression was significantly associated with MI. No significant association of Ki-67 and PHH3 expression, tumor’s morphological features, disease progression and prognosis was found. Contrary to our expectations, PHH3 showed no diagnostic and prognostic value in lung NETs.

Clinical Implications of the New WHO Classification 2017 for Pituitary Tumors

2021 ◽  
Vol 129 (03) ◽  
pp. 146-156 ◽  
Author(s):  
Wolfgang Saeger ◽  
Arend Koch
Keyword(s):  
Transcription Factors ◽  
Who Classification ◽  
Cell Lineage ◽  
Pituitary Tumors ◽  
Pituitary Hormones ◽  
Null Cell ◽  
Cell Adenoma ◽  
Ki 67 ◽  
Worse Prognosis

AbstractAccording to the WHO classification 2017 of Pituitary Tumors adenomas are classified not only by structure and immunostaining for pituitary hormones but also by expression of the pituitary transcription factors Pit-1, T-pit and SF-1. By these factors, three cell lineages can be identified: Pit-1 for the GH-, Prolactin- and TSH-cell lineage, T-pit for the ACTH-cell lineage, and SF-1 for the gonadotrophic cell lineage. By this principle, all GH and/or Prolactin producing and all TSH producing adenomas must be positive for Pit-1, all corticotrophic adenomas for T-pit, and all gonadotrophic for SF-1. In adenomas without expression of pituitary hormones immunostainings for the transcription factors have to be examined. If these are also negative the criteria for an endocrine inactive null cell adenoma are fulfilled. If one transcription factor is positive the corresponding cell lineage indicates a potential hormonal activity of the adenoma. So Pit-1 expressing hormone-negative adenomas can account for acromegaly, hyperprolactinemia, or TSH hyperfunction. T-pit positive hormone negative adenomas can induce Cushing’s disease, and SF-1 positive hormone negative tumors indicate gonadotrophic adenomas. Instead of the deleted atypical adenoma of the WHO classification of 2004 now (WHO classification 2017) criteria exist for the identification of aggressive adenomas with a conceivably worse prognosis. Some adenoma subtypes are described as aggressive “per se” without necessity of increased morphological signs of proliferation. All other adenoma subtypes must also be designated as aggressive if they show signs of increased proliferation (mitoses, Ki-67 index>3–5%, clinically rapid tumor growth) and invasion. By these criteria about one third of pituitary adenoma belong to the group of aggressive adenomas with potentially worse prognosis. The very rare pituitary carcinoma (0.1 % of pituitary tumors) is defined only by metastases. Many of them develop after several recurrences of Prolactin or ACTH secreting adenomas. The correlation of clinical findings and histological classification of pituitary adenomas is very important since every discrepancy has to be discussed between clinicians and pathologists. Based on data of the German Registry of Pituitary Tumors a table for examinations of correlations is shown in this review.

Small Neuroendocrine Tumors of the Whole Gastrointestinal Tract Performed Endoscopic or Surgical Resections Also Show Positive for Lymphovascular Invasion

Digestion ◽  
2021 ◽  
pp. 1-8
Author(s):  
Haruna Miyashita ◽  
Takuji Yamasaki ◽  
Yoshihiro Akita ◽  
Yoshitaka Ando ◽  
Yuki Maruyama ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Neuroendocrine Tumors ◽  
Tumor Size ◽  
Lymphovascular Invasion ◽  
Distant Metastases ◽  
High Rate ◽  
Ki 67 ◽  
Primary Endpoints ◽  
Invasion Impact ◽  
Prognostic Stratification

<b><i>Background and Aims:</i></b> In gastrointestinal neuroendocrine tumors (GI-NETs), tumor size and grading based on cellular proliferative ability indicate biological malignancy but not necessarily clinically efficient prognostic stratification. We analyzed tumor size- and grading-based prevalence of lymphovascular invasion in GI-NETs to establish whether these are true biological malignancy indicators. <b><i>Methods:</i></b> We included 155 cases (165 lesions), diagnosed histologically with GI-NETs, that had undergone endoscopic or surgical resection. Patient age, sex, method of treatment, tumor size, invasion depth, lymphovascular invasion positivity according to Ki-67 index-based neuroendocrine tumor grading, distant metastases, and outcome were evaluated. The primary endpoints were the prevalence of lymphovascular invasion according to tumor size and grading. <b><i>Results:</i></b> Overall, 24.8% were positive for lymphovascular invasion. There was a high rate of lymphovascular invasion positivity even among grade 1 cases (22.8%). The rate of lymphovascular invasion was 3.4% for grade 1 cases &#x3c;5 mm, with a lymphovascular invasion rate of 8.7% for those 5–10 mm. Lymphovascular invasion ≤10% required a tumor size ≤8 mm, and lymphovascular invasion ≤5% required a tumor size ≤6 mm. A cutoff of 6 mm was identified, which yielded a sensitivity of 79% and a specificity of 63%. Even small GI-NETs grade 1 of the whole GI tract also showed positive for lymphovascular invasion. <b><i>Conclusions:</i></b> GI-NETs ≤10 mm had a lymphovascular invasion prevalence exceeding 10%. The lymphovascular invasion impact in GI-NET development is incompletely understood, but careful follow-up, including consideration of additional surgical resection, is crucial in cases with lymphovascular invasion.

scholarly journals Predictive and Prognostic Impact of Blood-Based Inflammatory Biomarkers in Patients with Gastroenteropancreatic Neuroendocrine Tumors Commencing Peptide Receptor Radionuclide Therapy

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 504
Author(s):  
Fiona Ohlendorf ◽  
Rudolf Werner ◽  
Christoph Henkenberens ◽  
Tobias Ross ◽  
Hans Christiansen ◽  
...  
Keyword(s):  
Treatment Response ◽  
Neuroendocrine Tumors ◽  
Radionuclide Therapy ◽  
Somatostatin Receptor ◽  
Peptide Receptor Radionuclide Therapy ◽  
Tumor Burden ◽  
Inflammatory Biomarkers ◽  
Whole Body ◽  
Prognostic Impact ◽  
Peptide Receptor

Tumor microenvironment inflammation contributes to the proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, and reduced treatment response. We aimed to evaluate the early predictive and prognostic significance of markers of systemic inflammation in patients receiving somatostatin-receptor targeted peptide receptor radionuclide therapy (PRRT). This retrospective observational cohort study included 33 patients with advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) treated with PRRT. Pretreatment blood-based inflammatory biomarkers, e.g., Creactive protein levels (CRP), white blood cell count (WBC), and absolute neutrophil count (ANC), were documented and inflammation indexes, e.g., neutrophil-lymphocyte ratio (NLR) and Platelet × CRP multiplier (PCM), were calculated. Tumor burden was determined using [68Ga]GaDOTATATE PET/CT before enrollment and every 2 cycles thereafter until progression. Therapy response was assessed using RECIST 1.1, including its volumetric modification. Inflammatory biomarkers and inflammatory indexes demonstrated marked heterogeneity among patients, and were significantly higher in non-responders (e.g., CRP (P < 0.001), ANC (P = 0.002), and PCM (P < 0.001)). Change in whole-body tumor burden after two cycles of PRRT was significantly associated with CRP (P = 0.0157) and NLR (P = 0.0040) in multivariate regression analysis. A cut-off of 2.5 mg/L for CRP (AUC = 0.84, P = 0.001) revealed a significant outcome difference between patients with adversely high vs. low CRP (median PFS 508 days vs. not yet reached (HR = 4.52; 95% CI, 1.27 to 16.18; P = 0.02)). Tumor-driven systemic inflammatory networks may be associated with treatment response, change in tumor burden, and prognosis in patients with GEPNETs receiving PRRT.

scholarly journals Mixed adenoneuroendocrine carcinoma of the hepatic bile duct: a case report and review of the literature

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Sulai Liu ◽  
Zhendong Zhong ◽  
Meng Xiao ◽  
Yinghui Song ◽  
Youye Zhu ◽  
...  
Keyword(s):  
Bile Duct ◽  
Neuroendocrine Tumors ◽  
Radical Surgery ◽  
Malignant Tumors ◽  
World Health ◽  
Ki 67 ◽  
Mixed Adenoneuroendocrine Carcinoma ◽  
Hilar Bile Duct ◽  
Hilar Tumor

Abstract Background The World Health Organization's updated classification of digestive system neuroendocrine tumors in 2010 first proposed the classification of mixed adenoneuroendocrine carcinoma (MANEC). The incidence of biliary malignant tumors with neuroendocrine tumors accounts for less than 1% of all neuroendocrine tumors. Moreover, the incidence of hilar bile duct with MANEC is very rare. Case presentation A 65-year-old female patient came to our hospital for repeated abdominal pain for more than 4 months and skin sclera yellow staining for 1 week. Contrast-enhanced computed tomography imaging and magnetic resonance results suggested a hilar tumor for Bismuth-Corlette Type II. The patient underwent radical surgery for hilar cholangiocarcinoma. Finally, the patient was diagnosed with hilar bile duct MANEC, staged 1 (pT1N0M0) based on the eighth edition of the AJCC. Histopathology showed that the tumor was a biliary tumor with both adenocarcinoma and neuroendocrine carcinoma. No evidence of recurrence and metastasis after 20 months of follow-up. Conclusions We first reported a MANEC that originated in the hilar bile duct. As far as we known, there were few reports of biliary MANEC, and the overall prognosis was poor. We also found that the higher the Ki-67 index, the worse the prognosis of this type of patient. Radical surgery is the most effective treatment.

scholarly journals Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma

2018 ◽  
Vol 25 (2) ◽  
pp. 145-162 ◽  
Author(s):  
Sara Molatore ◽  
Andrea Kügler ◽  
Martin Irmler ◽  
Tobias Wiedemann ◽  
Frauke Neff ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Early Stage ◽  
Pituitary Tumors ◽  
Transcriptome Profiling ◽  
Thyroid Neoplasms ◽  
Recessive Trait ◽  
Wild Type ◽  
Incurable Cancer ◽  
Medullary Thyroid ◽  
Adrenal Pheochromocytoma

Rats affected by the MENX syndrome spontaneously develop multiple neuroendocrine tumors (NETs) including adrenal, pituitary and thyroid gland neoplasms. MENX was initially reported to be inherited as a recessive trait and affected rats were found to be homozygous for the predisposingCdkn1bmutation encoding p27. We here report that heterozygous MENX-mutant rats (p27+/mut) develop the same spectrum of NETs seen in the homozygous (p27mut/mut) animals but with slower progression. Consequently, p27+/mut rats have a significantly shorter lifespan compared with their wild-type (p27+/+) littermates. In the tumors of p27+/mut rats, the wild-typeCdkn1ballele is neither lost nor silenced, implying that p27 is haploinsufficient for tumor suppression in this model. Transcriptome profiling of rat adrenal (pheochromocytoma) and pituitary tumors having different p27 dosages revealed a tissue-specific, dose-dependent effect of p27 on gene expression. In p27+/mut rats, thyroid neoplasms progress to invasive and metastatic medullary thyroid carcinomas (MTCs) accompanied by increased calcitonin levels, as in humans. Comparison of expression signatures of late-stage vs early-stage MTCs from p27+/mut rats identified genes potentially involved in tumor aggressiveness. The expression of a subset of these genes was evaluated in human MTCs and found to be associated with aggressive RET-M918T-positive tumors. Altogether, p27 haploinsufficiency in MENX rats uncovered a novel, representative model of invasive and metastatic MTC exploitable for translational studies of this often aggressive and incurable cancer.

scholarly journals Recent Updates on Neuroendocrine Tumors From the Gastrointestinal and Pancreatobiliary Tracts

2016 ◽  
Vol 140 (5) ◽  
pp. 437-448 ◽  
Author(s):  
Joo Young Kim ◽  
Seung-Mo Hong
Keyword(s):  
World Health Organization ◽  
Neuroendocrine Tumors ◽  
Classification Scheme ◽  
Neuroendocrine Cells ◽  
Labeling Index ◽  
World Health ◽  
World Health Organization Classification ◽  
Clinicopathologic Characteristics ◽  
Ki 67 ◽  
Health Organization

Context.—Gastrointestinal (GI) and pancreatobiliary tracts contain a variety of neuroendocrine cells that constitute a diffuse endocrine system. Neuroendocrine tumors (NETs) from these organs are heterogeneous tumors with diverse clinical behaviors. Recent improvements in the understanding of NETs from the GI and pancreatobiliary tracts have led to more-refined definitions of the clinicopathologic characteristics of these tumors. Under the 2010 World Health Organization classification scheme, NETs are classified as grade (G) 1 NETs, G2 NETs, neuroendocrine carcinomas, and mixed adenoneuroendocrine carcinomas. Histologic grades are dependent on mitotic counts and the Ki-67 labeling index. Several new issues arose after implementation of the 2010 World Health Organization classification scheme, such as issues with well-differentiated NETs with G3 Ki-67 labeling index and the evaluation of mitotic counts and Ki-67 labeling. Hereditary syndromes, including multiple endocrine neoplasia type 1 syndrome, von Hippel-Lindau syndrome, neurofibromatosis 1, and tuberous sclerosis, are related to NETs of the GI and pancreatobiliary tracts. Several prognostic markers of GI and pancreatobiliary tract NETs have been introduced, but many of them require further validation. Objective.—To understand clinicopathologic characteristics of NETs from the GI and pancreatobiliary tracts. Data Sources.—PubMed (US National Library of Medicine) reports were reviewed. Conclusions.—In this review, we briefly summarize recent developments and issues related to NETs of the GI and pancreatobiliary tracts.

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