A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms

Abstract BackgroundSignificant changes were made in the grading and staging systems for neuroendocrine neoplasms (NENs) in 2017. Therefore, a clinical report to comprehensively update the clinicopathological characteristics, therapeutic approaches, and prognosis of these patients should be drafted.MethodsWe retrospectively reviewed a database of 16 patients who developed NENs or mixed endocrine non-endocrine neoplasms (MiNENs) after curative resection. Among them, eight had ampulla of Vater (AoV) tumors, and eight had non-AoV tumors. One patient had NEN Grade 1, five had NEN Grade 2, and five had NEN Grade 3 (G3); all had poorly differentiated neuroendocrine carcinoma. Five patients had MiNEN or combined carcinoma.ResultsThe mean age was 57.88 years. The overall survival rates after curative surgery at 1, 3, and 5 years were 87.1, 80.4, and 71.4%, respectively. The 1-, 3-, and 5-year disease-free survival rates were 87.1%, 79.8%, and 71.8%, respectively. In univariate analysis, age >65 years, mitotic count (>20/10 high-power fields), Ki-67 index >20%, and presence of stones were significant prognosticators, whereas only the mitotic count was statistically significant in the multivariate analysis. Age >65 years (p=0.039), a Ki-67 index >20% (p=0.03), presence of stones (p=0.021), G3 stage disease, MiNEN (p=0.002), or perineural invasion (p<0.001) were more frequently observed in the non-AoV group than in the AoV group.ConclusionHigh mitosis count had a greater effect on extrahepatic biliary NEN than the tumor-node-metastasis staging system. Patients with AoV tumors had better prognostic predictor factors compared to those with non-AoV tumors.

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Clinical relevance of different WHO grade 3 pancreatic neuroendocrine neoplasms based on morphology

Endocrine Connections ◽

10.1530/ec-17-0388 ◽

2018 ◽

Vol 7 (2) ◽

pp. 355-363 ◽

Cited By ~ 9

Author(s):

Xu Han ◽

Xuefeng Xu ◽

Hongyun Ma ◽

Yuan Ji ◽

Dansong Wang ◽

...

Keyword(s):

Vascular Invasion ◽

Who Classification ◽

Univariate Analysis ◽

Tnm Staging ◽

Mitotic Count ◽

Biological Behavior ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Who Grade ◽

Pancreatic Neuroendocrine Neoplasms

Purpose Emerging evidence suggests G3 pancreatic neuroendocrine neoplasms (pNENs) present heterogeneous morphology and biology. The 2017 WHO classification has introduced a new category of well-differentiated pancreatic neuroendocrine tumors (WD-pNETs) G3, compared with poorly differentiated pancreatic neuroendocrine carcinomas (PD-pNECs) G3. We aim to analysis the demographics and outcomes of patients with resectable 2017 WHO G3 pNENs to facilitate the distinction between two entities. Methods The multi-institutional retrospective cohort involving 57 surgically treated patients affected by 2017 WHO G3 pNENs were morphologically identified and clinically analyzed. Patients having WD-pNETs G3 and those having PD-pNECs G3 were compared. Results Thirty patients had WD-pNETs and 27 patients had PD-pNECs. The distributions of Ki-67 and mitotic count in patients with PD-pNECs or WD-pNETs showed remarkable disparities. ROC indicated cut-off value of Ki-67 was 45. PD-pNECs were more common in patients with elevated Ki-67 and mitotic count, advanced AJCC TNM stage, vascular invasion, regional lymph-node metastases, elevated NSE and decreased CgA levels compared with WD-pNETs (P < 0.05). The association between 2017 WHO G3 grade and TTR was statistically significant (P < 0.05). Univariate analysis indicated OS rates were associated with morphologic differentiation (WD-pNETs vs PD-pNECs), Ki-67, TNM staging, synchronous distant metastases, initial treatments, vascular invasion, regional lymph nodes metastases, mitotic count and age (P < 0.05). Multivariate analyses illustrated Ki-67, differentiation, TNM staging and vascular invasion were independent predictors (P < 0.05). Conclusions PD-pNECs G3 presented malignant biological behavior and dismal outcome compared with WD-pNETs G3. These findings challenge 2010 WHO classification and suggest the categorization can be improved by refined tumor grading.

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Mixed neuroendocrine–non-neuroendocrine neoplasms of the gallbladder: a case report

Surgical Case Reports ◽

10.1186/s40792-021-01152-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Tatsuki Ishikawa ◽

Katsunori Nakano ◽

Masafumi Osaka ◽

Kenichi Aratani ◽

Kadotani Yayoi ◽

...

Keyword(s):

System Analysis ◽

Cancer Control ◽

Staging System ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Regional Lymph Nodes ◽

Abdominal Ultrasonography ◽

Case Presentation ◽

History Of ◽

Lymph Nodes Dissection

Abstract Background Primary neuroendocrine tumors of the gallbladder (GB-NETs) are rare, accounting for 0.5% of all NETs and 2.1% of all gallbladder cancers. Among GB-NETs, mixed neuroendocrine–non-neuroendocrine neoplasms of the gallbladder (GB-MiNENs) are extremely rare. Case presentation We present the case of a 66-year-old woman who was referred to us for the management of a gallbladder tumor (incidentally found during abdominal ultrasonography indicated for gallbladder stones). The patient had no history of abdominal pain or fever, and the findings on a physical examination were unremarkable. Blood tests showed normal levels of tumor markers. Imaging studies revealed a mass of approximately 10 mm in diameter (with no invasion of the gallbladder bed) located at the fundus of the gallbladder. A gallbladder cancer was suspected. Therefore, an open whole-layer cholecystectomy with regional lymph nodes dissection was performed. The postoperative course was uneventful, and she was discharged on postoperative day 6. Pathological findings showed GB-MiNENs with invasion of the subserosal layer and no lymph node invasion (classified T2aN0M0 pStage IIA according to the Union for International Cancer Control, 8th edition staging system). Analysis of the neuroendocrine markers revealed positive chromogranin A and synaptophysin, and a Ki-67 index above 95%. Fourteen months after the operation, a local recurrence was detected, and she was referred to another hospital for chemotherapy. Conclusions GB-MiNENs are extremely aggressive tumors despite their tumor size. Optimal therapy should be chosen for each patient.

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Increase of Ki‐67 index and influence on mortality in patients with neuroendocrine neoplasms

Journal of Neuroendocrinology ◽

10.1111/jne.13018 ◽

2021 ◽

Author(s):

Pernille Holmager ◽

Seppo W. Langer ◽

Birgitte Federspiel ◽

Gro Linno Willemoe ◽

Rajendra Singh Garbyal ◽

...

Keyword(s):

Neuroendocrine Neoplasms ◽

Ki 67

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Multifocal Pancreatic Neuroendocrine Neoplasms In Tuberous Sclerosis: A Rare Case

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa161.168 ◽

2020 ◽

Vol 154 (Supplement_1) ◽

pp. S77-S77

Author(s):

N C Jadhav ◽

D L Gang

Keyword(s):

Tuberous Sclerosis ◽

Neurofibromatosis Type ◽

Abdominal Ultrasound ◽

Biologically Active ◽

Pancreatic Tumors ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Pancreatic Neuroendocrine Neoplasms ◽

Von Hippel Lindau ◽

Multifocal Disease

Abstract Casestudy: Pancreatic neuroendocrine neoplasms (PanNEN) are rare accounting for 2-5% of pancreatic tumors. Although mostly sporadic, 10-20% are associated with inherited syndromes, notably MEN-1, Von Hippel- Lindau disease, neurofibromatosis type 1, and tuberous sclerosis (TS). When compared to sporadic cases, PanNEN in hereditary syndromes occur at a younger age, are often multifocal, cystic, and may show characteristic microscopic patterns. TS is an autosomal dominant multi-system disorder with mutations involving TSC1 or TSC2 genes which function as tumor suppressors by inhibiting mTORC1 kinase. PanNEN is observed in 1.5-1.8% of patients with TS and no surveillance guidelines for the assessment of pancreatic lesions are established. Compared to other syndromes, PanNEN associated with TS are solitary. To our knowledge, only two cases of multifocal PanNEN in TS patients have been reported. We present a case of a 67-year-old gentleman with a history of TS also affecting two daughters. He presented to the emergency department with severe abdominal pain. Abdominal ultrasound suggested acute appendicitis and an incidental 2.0 cm solid lesion was noted in the head of the pancreas. Follow-up MRI revealed two additional non-cystic masses in the pancreatic tail. Endoscopic ultrasound-guided biopsy of a tail lesion revealed monomorphic tumor cells with stippled chromatin without cytologic atypia. Immunohistochemical staining was positive for synaptophysin and chromogranin. Ki-67 labelling index was under 1%. Diagnosis of a well-differentiated neuroendocrine tumor (G1) was made. The patient denied symptoms of the carcinoid syndrome and no biologically active hormones were detected. Gallium PET scan revealed multiple foci of radiotracer uptake throughout the pancreas in addition to those described on MRI. Although PanNEN are rare in TS, malignant behavior has been reported. This case reinforces the importance of early detection through active surveillance, especially as surgical options may be limited in multifocal disease.

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Leptomeningeal Carcinomatosis: A Clinical Dilemma in Neuroendocrine Neoplasms

Biology ◽

10.3390/biology10040277 ◽

2021 ◽

Vol 10 (4) ◽

pp. 277

Author(s):

Leonidas Apostolidis ◽

Jörg Schrader ◽

Henning Jann ◽

Anja Rinke ◽

Sebastian Krug

Keyword(s):

Brain Metastases ◽

Median Overall Survival ◽

Case Reports ◽

Individual Case ◽

Leptomeningeal Carcinomatosis ◽

Neuroendocrine Neoplasms ◽

Cns Involvement ◽

Ki 67 ◽

Sensory Deficits ◽

Clinical Dilemma

Central nervous system (CNS) involvement by paraneoplastic syndromes, brain metastases, or leptomeningeal carcinomatosis (LC) in patients with neuroendocrine neoplasms (NEN) has only been described in individual case reports. We evaluated patients with LC in four neuroendocrine tumor (NET) centers (Halle/Saale, Hamburg, Heidelberg, and Marburg) and characterized them clinically. In the study, 17 patients with a LC were defined with respect to diagnosis, clinic, and therapy. The prognosis of a LC is very poor, with 10 months in median overall survival (mOS). This is reflected by an even worse course in neuroendocrine carcinoma (NEC) G3 Ki-67 >55%, with a mOS of 2 months. Motor and sensory deficits together with vigilance abnormalities were common symptoms. In most cases, targeted radiation or temozolomide therapy was used against the LC. LC appears to be similarly devastating to brain metastases in NEN patients. Therefore, the indication for CNS imaging should be discussed in certain cases.

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Grading pancreatic neuroendocrine neoplasms by Ki-67 staining on cytology cell blocks: manual count and digital image analysis of 58 cases

Journal of the American Society of Cytopathology ◽

10.1016/j.jasc.2016.03.002 ◽

2016 ◽

Vol 5 (5) ◽

pp. 286-295 ◽

Cited By ~ 5

Author(s):

Ming Jin ◽

Rachel Roth ◽

Vera Gayetsky ◽

Nicholas Niederberger ◽

Amy Lehman ◽

...

Keyword(s):

Image Analysis ◽

Digital Image ◽

Digital Image Analysis ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Pancreatic Neuroendocrine Neoplasms ◽

Manual Count

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

Endocrine Pathology ◽

10.1007/s12022-021-09668-z ◽

2021 ◽

Vol 32 (1) ◽

pp. 154-168 ◽

Cited By ~ 1

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.

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