scholarly journals INSM1 Is a Highly Specific Marker of Neuroendocrine Differentiation in Primary Neoplasms of the Gastrointestinal Tract, Appendix, and Pancreas

2020 ◽  
Vol 153 (6) ◽  
pp. 811-820 ◽  
Author(s):  
Kelsey E McHugh ◽  
Sanjay Mukhopadhyay ◽  
Erika E Doxtader ◽  
Christopher Lanigan ◽  
Daniela S Allende
Keyword(s):  
Goblet Cell ◽  
Neuroendocrine Differentiation ◽  
Neuroendocrine Neoplasms ◽  
Specific Marker ◽  
Low Grade ◽  
Ki 67 ◽  
Neuroendocrine Markers ◽  
Primary Neoplasms ◽  
Poorly Differentiated ◽  
Well Differentiated

Abstract Objectives INSM1 has been described as a sensitive and specific neuroendocrine marker. This study aims to compare INSM1 with traditional neuroendocrine markers in gastrointestinal neuroendocrine neoplasms. Methods Retrospective review (2008-2018) was used to retrieve paraffin-embedded tissue from 110 gastrointestinal neuroendocrine neoplasms and controls that was subsequently stained with INSM1, synaptophysin, chromogranin, CD56, and Ki-67. Results INSM1 was positive in 16 of 17 (94.1%) gastric, 17 of 18 (94.4%) pancreatic, 13 of 18 (72.2%) small bowel, 17 of 21 (81.0%) colonic, and 26 of 36 (72.2%) appendiceal tumors. INSM1 was positive in 58 of 70 (82.9%) well-differentiated neuroendocrine tumors, 17 of 20 (85.0%) poorly differentiated neuroendocrine carcinomas, 8 of 11 (72.7%) low-grade goblet cell adenocarcinomas (grade 1), and 6 of 9 (66.7%) high-grade goblet cell adenocarcinomas (grade 2/3). INSM1 sensitivity for neuroendocrine neoplasms (80.9%) was less than that of synaptophysin (99.1%), chromogranin (88%), and CD56 (95.3%); specificity was higher (95.7% vs 86.0%, 87.3%, and 86.0%, respectively). Conclusions INSM1 is a useful marker of neuroendocrine differentiation in gastrointestinal neuroendocrine and mixed neuroendocrine neoplasms. Compared with traditional neuroendocrine markers, INSM1 is less sensitive but more specific.

Temozolomide in grade III neuroendocrine neoplasms (G3 NENs): A multicenter retrospective review.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 321-321 ◽  
Author(s):  
David Chan ◽  
Emily K. Bergsland ◽  
Jennifer A. Chan ◽  
Rujuta Gadgil ◽  
Thorvardur Ragnar Halfdanarson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retrospective Review ◽  
Complete Response ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Poorly Differentiated ◽  
Well Differentiated ◽  
Pathology Reports ◽  
Multicenter Retrospective Review ◽  
Grade Iii

321 Background: G3 NENs are aggressive, and optimal systemic treatment is unclear. Temozolomide (TEM)-based regimens have been used to treat grade 1-2 NETs, but their efficacy in G3 NENs (Ki-67 > 20%) remains undetermined. Aims: To assess the clinical efficacy of TEM-containing regimens in advanced grade III gastroenteropancreatic NENs (GEPNENs). Methods: A multicentre retrospective review (2008-2017) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports without formal RECIST criteria. Results: 118 patients in six centers were included (median age 55, 65% male, 15% functional, 75% pancreatic NEN). 57% were well-differentiated, 35% poorly-differentiated, and 18% unknown based on local pathology reports. The regimen used was CAPTEM in 93% and TEM in 7%. Best radiological responses were: complete response (1%), partial response (39%), stable disease (22%), progressive disease (31%), unknown (7%) not by RECIST. Median TTF was 150 days and median overall survival (OS) 18.0 months. Fifteen patients (14%) required dose reductions/discontinuation due to adverse events. TTF was shorter for patients on TEM alone (p = 0.02, Table 1). Well-differentiated NENs had better response rate (52% vs 26%, p = 0.02) and overall survival (30.1 vs 12.0 mo, p = 0.008) compared to poorly-differentiated NEN. Conclusions: This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NET centers. 40% of patients showed some degree of response, and treatment was generally well-tolerated. TEM-based regimens should be considered a viable treatment option in this setting. Prospective confirmatory trials (such as EA2142) may face difficulties in accrual due to disease rarity. [Table: see text]

scholarly journals Expression of Neuroendocrine Markers in Different Molecular Subtypes of Breast Carcinoma

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
David L. Wachter ◽  
Arndt Hartmann ◽  
Matthias W. Beckmann ◽  
Peter A. Fasching ◽  
Alexander Hein ◽  
...  
Keyword(s):  
Chromogranin A ◽  
Molecular Subtypes ◽  
Neuroendocrine Differentiation ◽  
World Health ◽  
Low Grade ◽  
Breast Carcinomas ◽  
Luminal A ◽  
Luminal B ◽  
Neuroendocrine Markers ◽  
Poorly Differentiated

Background. Carcinomas of the breast with neuroendocrine features are incorporated in the World Health Organization classification since 2003 and include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas/small cell carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. Neuroendocrine differentiation is known to be more common in certain low-grade histologic special types and has been shown to mainly cluster to the molecular (intrinsic) luminal A subtype.Methods. We analyzed the frequency of neuroendocrine differentiation in different molecular subtypes of breast carcinomas of no histologic special type using immunohistochemical stains with specific neuroendocrine markers (chromogranin A and synaptophysin).Results. We found neuroendocrine differentiation in 20% of luminal B-like carcinomas using current WHO criteria (at least 50% of tumor cells positive for synaptophysin or chromogranin A). In contrast, no neuroendocrine differentiation was seen in luminal A-like, HER2 amplified and triple-negative carcinomas. Breast carcinomas with neuroendocrine differentiation presented with advanced stage disease and showed aggressive behavior.Conclusions. We conclude that neuroendocrine differentiation is more common than assumed in poorly differentiated luminal B-like carcinomas. Use of specific neuroendocrine markers is thus encouraged in this subtype to enhance detection of neuroendocrine differentiation and hence characterize the biological and therapeutic relevance of this finding in future studies.

scholarly journals HIGH-GRADE GASTROENTEROPANCREATIC NEUROENDOCRINE NEOPLASMS. MODERN CLASSIFICATION, DIAGNOSTICS AND TREATMENT

2018 ◽  
Vol 8 (3) ◽  
pp. 13-20
Author(s):  
A. A. Kolomeytseva ◽  
V. A. Gorbunova ◽  
N. F. Orel ◽  
G. S. Emelianova ◽  
A. M. Ivanov ◽  
...  
Keyword(s):  
World Health ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
First Line Therapy ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Platinum Based Chemotherapy ◽  
Poorly Differentiated ◽  
Net G3 ◽  
Well Differentiated ◽  
Health Organization

Poorly differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare malignancies, most of which are characterized by aggressiveness, a tendency to rapid metastasis and an unfavorable prognosis even when localized. In 2017 World Health Organization (WHO) updated classification of GEP NENs and recognized the category of well-differentiated pancreatic NET G3, associated with Ki‑67 index usually over 20%. The upper level of Ki‑67 is not defined. Usually it is 55%. Highgrade poorly differentiated pancreatic NENs are defined as pancreatic neuroendocrine carcinomas (panNECs). Although the NET G3 category is recognized for pancreatic neuroendocrine neoplasms only, many specialists consider it reasonable to apply this term to all well-differentiated GEP NETs with Ki‑67 index in the 20 to 55 percent range. Clinical behavior and therapeutic approaches for advanced GEP NECs and NETs G3 are different. Standard palliative chemotherapy for GEP NECs consists of cisplatin or carboplatin combined with etoposide. The second-line regimens include irinotecan-, oxaliplatin, fluoropyrimidine- and temozolomide-based regimens. Temozolomide-based chemotherapy regimens, as well as targeted therapy are more preferable as first line therapy for patients with NETs G3. The platinum-based chemotherapy regimens are considered at the time of disease progression. Further clinical studies with the inclusion of much more patients will determine the optimal treatment strategy for this category of patients.

scholarly journals Molecular Pathology of Well-Differentiated Pulmonary and Thymic Neuroendocrine Tumors: What Do Pathologists Need to Know?

2021 ◽  
Vol 32 (1) ◽  
pp. 154-168 ◽  
Author(s):  
Marco Volante ◽  
Ozgur Mete ◽  
Giuseppe Pelosi ◽  
Anja C. Roden ◽  
Ernst Jan M. Speel ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Young Patients ◽  
Carcinoid Tumors ◽  
Neuroendocrine Neoplasms ◽  
Grey Zone ◽  
Cell Hyperplasia ◽  
Ki 67 ◽  
Familial Form ◽  
Well Differentiated ◽  
Neuroendocrine Carcinomas

AbstractThoracic (pulmonary and thymic) neuroendocrine tumors are well-differentiated epithelial neuroendocrine neoplasms that are classified into typical and atypical carcinoid tumors based on mitotic index cut offs and presence or absence of necrosis. This classification scheme is of great prognostic value but designed for surgical specimens, only. Deep molecular characterization of thoracic neuroendocrine tumors highlighted their difference with neuroendocrine carcinomas. Neuroendocrine tumors of the lung are characterized by a low mutational burden, and a high prevalence of mutations in chromatin remodeling and histone modification-related genes, whereas mutations in genes frequently altered in neuroendocrine carcinomas are rare. Molecular profiling divided thymic neuroendocrine tumors into three clusters with distinct clinical outcomes and characterized by a different average of copy number instability. Moreover, integrated histopathological, molecular and clinical evidence supports the existence of a grey zone category between neuroendocrine tumors (carcinoid tumors) and neuroendocrine carcinomas. Indeed, cases with well differentiated morphology but mitotic/Ki-67 indexes close to neuroendocrine carcinomas have been increasingly recognized. These are characterized by specific molecular profiles and have an aggressive clinical behavior. Finally, thoracic neuroendocrine tumors may arise in the background of genetic susceptibility, being MEN1 syndrome the well-defined familial form. However, pathologists should be aware of rarer germline variants that are associated with the concurrence of neuroendocrine tumors of the lung or their precursors (such as DIPNECH) with other neoplasms, including but not limited to breast carcinomas. Therefore, genetic counseling for all young patients with thoracic neuroendocrine neoplasia and/or any patient with pathological evidence of neuroendocrine cell hyperplasia-to-neoplasia progression sequence or multifocal disease should be considered.

Prognostic Signicance of Cellular Iron Metabolism in Breast Cancer

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Rizwan Ullah Khan ◽  
Amber Hassan ◽  
Imrana Tanvir ◽  
Kashifa Ehsan
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Ki 67 ◽  
Luminal B ◽  
Cellular Iron ◽  
Menopausal Women ◽  
New Strategy ◽  
Poorly Differentiated ◽  
Well Differentiated ◽  
Post Menopausal

Breast carcinoma is among the most common malignancy in women. Abstract:Original ArticleAim of the present study was to evaluate the prognostic signicance of iron expression in the biopsies of patients with breast cancer Objective:24 breast biopsies were studied. 19 cases were poorly differentiated, 5 cases were moderately differentiated and there was no well differentiated case. Iron, Estrogen receptor (ER), Progesterone receptor (PR), HER2 and Ki-67 immunohistochemical staining was performed for all these cases. Methods: Among the 5 moderately differentiated cases, 3 (60%) were positive for iron staining and among 19 poorly differentiated cases, 11 cases (57.89%) were positive. More iron positive cases (7 out of 14) were triple positive belonging to Luminal B class. Out of 14 iron positive cases, 11 were positive for HER2, 10 for ER, 9 for PR and all positive for Ki-67. Results: Iron deciency in premenopausal and overload in post-menopausal women can contribute to the development of breast carcinoma. So, iron can be considered as a cheap and effective marker for the prognosis of breast cancer. Association between a rise in iron levels and HER2 expression may provide new strategy for breast cancer treatment.

Dedifferentiated Liposarcoma With a Paraganglioma-like Histologic Pattern: A Case Report and Review of the Literature

2004 ◽  
Vol 128 (7) ◽  
pp. 788-791
Author(s):  
Dating Liu ◽  
Guillermo Quinonez ◽  
Steven Latosinsky
Keyword(s):  
Neuron Specific Enolase ◽  
Malignant Neoplasm ◽  
Neuroendocrine Differentiation ◽  
Growth Patterns ◽  
Dedifferentiated Liposarcoma ◽  
Tissue Mass ◽  
Histologic Pattern ◽  
History Of ◽  
Poorly Differentiated ◽  
Well Differentiated

Abstract A 53-year-old man presented with a 4-month history of increasing abdominal discomfort and distension. A large retroperitoneal mass was found on imaging. Image-guided needle core biopsy demonstrated a poorly differentiated malignant neoplasm. A 30 × 32 × 33-cm soft tissue mass was removed. Microscopically, the tumor consisted of predominantly epithelioid malignant cells arranged in a paraganglioma-like growth pattern. Immunohistochemically, these cells were strongly positive for neuron-specific enolase. Stains for synaptophysin and chromogranin, however, were negative. There was no ultrastructural evidence of neuroendocrine differentiation. Adjacent sarcomatous areas were composed of spindled cells arranged in storiform and fibrosarcoma-like growth patterns. A small area of well-differentiated liposarcoma was identified, and a diagnosis of dedifferentiated liposarcoma was established. To the best of our knowledge, this represents the first reported case of dedifferentiated liposarcoma with a paraganglioma-like histologic pattern. A brief review focusing on the morphologic variations of dedifferentiated liposarcoma is also presented.

scholarly journals Clinical Routine Application of the Second-generation Neuroendocrine Markers ISL1, INSM1, and Secretagogin in Neuroendocrine Neoplasia: Staining Outcomes and Potential Clues for Determining Tumor Origin

2020 ◽  
Vol 31 (4) ◽  
pp. 401-410
Author(s):  
Carl Christofer Juhlin ◽  
Jan Zedenius ◽  
Anders Höög
Keyword(s):  
Second Generation ◽  
Neuroendocrine Differentiation ◽  
Diagnostic Process ◽  
Neuroendocrine Neoplasms ◽  
Clinical Routine ◽  
Who Grade ◽  
Primary Tumors ◽  
Tissue Specific ◽  
Neuroendocrine Markers ◽  
Immunohistochemical Markers

AbstractNeuroendocrine neoplasms (NENs) have traditionally been identified via expression of proteins associated to the regulation of secretory vesicles and granules. We report the clinical usage of the “second-generation” proteins ISL LIM homeobox 1 (ISL1), INSM transcriptional repressor 1 (INSM1), and secretagogin (SECG) as immunohistochemical markers of neuroendocrine differentiation since their introduction in clinical routine and compare the results with the established proteins chromogranin A (CGA) and synaptophysin (SYP). In total, 161 tumors, including 139 NENs and 22 “non-NENs” (unrelated tumors with an initial suspicion of NEN), were informatively stained for ISL1, and subsets were also interrogated for INSM1 and/or SECG. Diffuse or focal positive immunoreactivity was noted for ISL1 in 91/139 NENs (65%) and in 6/22 (27%) non-NENs, for INSM1 in 76/85 NENs (89%) and in 2/5 (40%) non-NENs, and for SECG in 49 out of 64 NENs (77%) and in 0/5 non-NENs (0%). Generally, ISL1, INSM1, and SECG exhibited sensitivities in line with or slightly below that of CGA and SYP—largely attributable to tissue-specific patterns regarding tumoral origin. Moreover, for pancreatic and small intestinal NENs, the two largest subgroups, ISL1 staining results were consistent irrespectively of tumor source and WHO grade. We verify previously suggested immunohistochemical schemes of neuroendocrine markers of first- and second-generations to facilitate the diagnostic process for NENs and confirm that the second-generation neuroendocrine markers display tissue-specific patterns. We therefore recommend their implementation in tertiary endocrine pathology centers, not least to aid in the identification of primary tumors when analyzing metastases.

Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms

2011 ◽  
Vol 18 (S1) ◽  
pp. S1-S16 ◽  
Author(s):  
Günter Klöppel
Keyword(s):  
Gastrointestinal Tract ◽  
Neuroendocrine Tumours ◽  
Neuroendocrine Tumour ◽  
Tnm Stage ◽  
Neuroendocrine Neoplasms ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Poorly Differentiated ◽  
Well Differentiated ◽  
Neuroendocrine Carcinomas

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are composed of cells with a neuroendocrine phenotype. The old and the new WHO classifications distinguish between well-differentiated and poorly differentiated neoplasms. All well-differentiated neoplasms, regardless of whether they behave benignly or develop metastases, will be called neuroendocrine tumours (NETs), and graded G1 (Ki67 <2%) or G2 (Ki67 2–20%). All poorly differentiated neoplasms will be termed neuroendocrine carcinomas (NECs) and graded G3 (Ki67 >20%). To stratify the GEP-NETs and GEP-NECs regarding their prognosis, they are now further classified according to TNM-stage systems that were recently proposed by the European Neuroendocrine Tumour Society (ENETS) and the AJCC/UICC. In the light of these criteria the pathology and biology of the various NETs and NECs of the gastrointestinal tract (including the oesophagus) and the pancreas are reviewed.

scholarly journals Paranasal Sinus Neuroendocrine Carcinoma: A Case Report and Review of the Literature

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Nagesh T. Sirsath ◽  
K. Govind Babu ◽  
Umesh Das ◽  
C. S. Premlatha
Keyword(s):  
Paranasal Sinus ◽  
Neuroendocrine Carcinoma ◽  
Neuroendocrine Tumour ◽  
Neuroendocrine Differentiation ◽  
Complete Response ◽  
The Body ◽  
Intracranial Extension ◽  
Neuroendocrine Neoplasms ◽  
Rare Site ◽  
Poorly Differentiated

Neuroendocrine neoplasms are defined as epithelial neoplasms with predominant neuroendocrine differentiation. They can arise in almost every organ of the body although they are most commonly found in the gastrointestinal tract and respiratory system. Nasal cavity and paranasal sinuses are a rare site for neuroendocrine carcinoma. In contrast to the other regions, neuroendocrine tumours of the sinuses have been reported to be recurrent and locally destructive. Very few cases of paranasal sinus neuroendocrine carcinoma have been reported till date. Difficulty in pathologic diagnosis and rarity of this malignancy have hindered the progress in understanding the clinical course and improving outcomes. We herein report a case of poorly differentiated neuroendocrine tumour of ethmoid and sphenoid sinus with invasion of orbit and intracranial extension. The patient had complete response at the end of chemoradiation and he was disease-free for 9 months duration after which he developed bone metastasis without regional recurrence.

scholarly journals Chloroquine induces apoptosis in pancreatic neuroendocrine neoplasms via endoplasmic reticulum stress

2020 ◽  
Vol 27 (7) ◽  
pp. 431-439
Author(s):  
Kenzo Nakano ◽  
Toshihiko Masui ◽  
Akitada Yogo ◽  
Yuichiro Uchida ◽  
Asahi Sato ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Tumour Size ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
Pancreatic Neuroendocrine Neoplasms ◽  
Dismal Prognosis ◽  
Well Differentiated

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.

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