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Padwal MK, Nazar AK, Parghane RV, Basu S, Basu B. Evaluating the prognostic significance of the pre-treatment neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratios in 177Lu-DOTATATE PRRT treated patients with advanced metastatic neuroendocrine tumors. Endocrine 2025:10.1007/s12020-025-04212-z. [PMID: 40131599 DOI: 10.1007/s12020-025-04212-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/13/2025] [Indexed: 03/27/2025]
Abstract
PURPOSE This study aimed to investigate the role of pre-treatment neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) in the prognosis assessment of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) treated patients with advanced metastatic neuroendocrine tumors (NETs). METHODS Eligible PRRT-treated patients (n = 247, 2010-2019) were included. Pre-PRRT NLR and MLR were calculated from complete blood count data. Data on tumor characteristics, response to PRRT, progression-free survival (PFS), and overall survival (OS) were evaluated using COXPH analyses. RESULTS In NET patients, median values of NLR and MLR were 2.21 (IQR = 1.66-3.00) and 0.14 (IQR = 0.06-0.24), respectively. NLR showed significant positive association with G3 tumors (median = 3.64, IQR = 2.1-4.26, p = 0.022) and high 18F-FDG avidity (SUVmax>5) (median = 2.5, IQR = 1.82-3.56, p = 0.003). MLR was significantly associated with high disease burden (median = 0.18, IQR = 0.08-0.29, p = 0.0083). MLR distinguished between the PRRT non-responders with progressive disease and responders with complete/partial response (median 0.19 versus 0.12, p = 0.043) or responders with stable disease (median 0.19 versus 0.14, p = 0.045). The ratios independently correlated with disease progression and OS. Patients in NLRhigh (>3.5) group displayed significantly shorter median PFS and OS (48 and 58 months) compared to NLRlow (≤3.5) group (108 and 96 months) (p < 0.01). Patients in MLRhigh (>0.25) group displayed significantly shorter median PFS and OS (40 and 52 months) compared to MLRlow (≤0.25) group (108 and 102 months) (p < 0.01). CONCLUSION Pre-treatment NLR and MLR had an independent prognostic impact on disease progression and OS in PRRT-treated NET patients. This routine, inexpensive CBC-based test in the standard pre-PRRT workup demonstrates the prognostic value and may aid clinicians in the risk stratification of NET patients.
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Affiliation(s)
- Mahesh K Padwal
- Molecular Biology Division, Bhabha Atomic Research Centre, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Amir K Nazar
- Homi Bhabha National Institute, Mumbai, India
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe, Mumbai, India
| | - Rahul V Parghane
- Homi Bhabha National Institute, Mumbai, India
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe, Mumbai, India
| | - Sandip Basu
- Homi Bhabha National Institute, Mumbai, India.
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe, Mumbai, India.
| | - Bhakti Basu
- Molecular Biology Division, Bhabha Atomic Research Centre, Mumbai, India.
- Homi Bhabha National Institute, Mumbai, India.
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Chen JS, Bai LY, Cheng HH, Chan SL, Zou JY, Shi X, Houchard A, Truong-Thanh XM, Chen MH. Real-World Study of Lanreotide Autogel in Routine Practice in Patients with Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) in Hong Kong and Taiwan. Oncol Ther 2025; 13:69-83. [PMID: 39215958 PMCID: PMC11880440 DOI: 10.1007/s40487-024-00302-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024] Open
Abstract
INTRODUCTION There is a lack of data on the efficacy, effectiveness, and safety of lanreotide autogel in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) of Chinese ethnicity. This noninterventional, retrospective study evaluated the effectiveness and safety of lanreotide autogel in patients of Chinese ethnicity with GEP-NETs in clinical practice. METHODS Patients' charts were abstracted from five hospitals in Hong Kong and Taiwan (July-September 2021), where lanreotide autogel is approved for treating GEP-NETs. Included patients were adults with unresectable, metastatic, or locally advanced GEP-NETs who received a first injection (index) of lanreotide autogel 120 mg between 01 January 2017 and 30 June 2020 (planned sample size: N = 30). Follow-up ran from index to a maximum of 48 (± 4) weeks or until disease progression, start of new antitumor treatment, or death. The primary endpoint was progression-free survival (PFS) rate at week 48 (±4), and secondary endpoints included PFS rate at week 24 (±4), estimated using Kaplan-Meier analyses. All analyses were descriptive. RESULTS Of 27 patients enrolled, 22 (81.5%) had 48 weeks of follow-up. Tumors of pancreatic origin were the most common (73.9%). PFS rate was 0.96 (95% confidence interval: 0.72 - 0.99) at 24 weeks and 0.82 (0.53-0.94) at 48 weeks. Overall, 74.1% patients experienced ≥ 1 treatment-emergent adverse event; none were serious. No deaths were reported. CONCLUSIONS Lanreotide autogel was well tolerated and showed good tumor control rate in a real-world setting. These findings align with results from previous studies in Caucasian, Japanese, and Korean patients, thus supporting lanreotide autogel for treating patients with GEP-NETs of Chinese ethnicity.
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Affiliation(s)
- Jen-Shi Chen
- Department of Hematology-Oncology, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan City, Taiwan
| | - Li-Yuan Bai
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | | | - Stephen Lam Chan
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | | | | | | | | | - Ming-Huang Chen
- Department of Oncology, Taipei Veterans General Hospital, Taipei City, 11217, Taiwan.
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Li S, Tang J, Wang J, Liu X, Zhou Y, Gu P. Metastasis of Mixed Adenoneuroendocrine Carcinoma of the Uterine Cervix to Thyroid Gland. EAR, NOSE & THROAT JOURNAL 2025; 104:55S-59S. [PMID: 35861212 DOI: 10.1177/01455613221113817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The thyroid metastasis from cervical cancer is extremely rare compared to other organs. It is sometimes difficult to distinguish primary tumors from metastases, as most metastatic thyroid nodules are asymptomatic. In this case, a 54-year-old woman had undergone radical hysterectomy due to cervical tumor of stage IB1 mixed adenoneuroendocrine carcinoma (MANEC) 5 years ago. After 3 years, ultrasound examination revealed a suspicious malignant nodule in the left lobe of thyroid gland at regular postoperative follow-up. This patient had no obvious clinical symptoms. The ultrasonography (US)-guided core needle biopsy (CNB) of the thyroid nodule was performed on the patient. The immunohistochemistry analyses revealed that it was poorly differentiated small-cell neuroendocrine carcinoma (SCNEC). Subsequently, the patient underwent left hemithyroidectomy plus isthmusectomy. The postoperative pathology and immunohistochemistry, combining with clinical history, confirmed that the thyroid nodule was a metastasis from cervical MANEC. Conventional chemotherapy and regular follow-up were carried out after the operation. The patient was readmitted 1 year later for pancreatic metastatic lesions and died 1 month after surgery. Early detection of metastatic cancer is potentially helpful, and when necessary, ultrasound-guided puncture biopsy can be utilized to further diagnose metastatic thyroid cancer.
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Affiliation(s)
- Shuai Li
- Department of Ultrasound and Sichuan Key Laboratory of Medical Imaging, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Jing Tang
- Department of Ultrasound and Sichuan Key Laboratory of Medical Imaging, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Juan Wang
- Department of Ultrasound and Sichuan Key Laboratory of Medical Imaging, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Xue Liu
- Department of Ultrasound and Sichuan Key Laboratory of Medical Imaging, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Yue Zhou
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Peng Gu
- Department of Ultrasound and Sichuan Key Laboratory of Medical Imaging, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
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Ozsoy MS, Erol CI, Aydemir MA, Baysal H, Buyuker F, Seneldir H, Ekinci O, Eren T, Alimoglu O. Gastroenteropancreatic Neuroendocrine Tumors: Does Tumor Location Affect Prognosis? ARCHIVES OF IRANIAN MEDICINE 2025; 28:29-39. [PMID: 40001327 PMCID: PMC11862391 DOI: 10.34172/aim.33366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 11/11/2024] [Indexed: 02/27/2025]
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare entities. Generally, they can be localized anywhere in the gastrointestinal or hepatobiliary tract. The purpose of our study is to evaluate the effect of tumor location on prognosis in patients with GEP-NET undergoing surgery. Our secondary objective is to examine other factors affecting the prognosis of patients with GEP-NET. METHODS We retrospectively analyzed data from 30 patients with GEP-NET who underwent surgery in the General Surgery Clinic between 2012 and 2022. The gNET group (n=18) included tumors located in the gastrointestinal tract, while the pNET group (n=12) included tumors located in the hepatopancreatobiliary system. Surgical, laboratory, radiological, and pathological findings of the patients, as well as follow-up outcomes were recorded and statistically analyzed. RESULTS In subgroup comparison, tumor size was found to be larger in the pNET group (P=0.002). The statistical analysis of recurrence (16.7% versus 33.3%) and mortality rates (16.7% versus 41.7%) between the subgroups (P=0.329 and P=0.210, respectively) did not reveal a significant difference. When all patients were evaluated, it was observed that advanced age, presence of carcinoma diagnosis, higher tumor grade, advanced TNM stage, larger tumor size, presence of lymphovascular or perineural invasion, elevated mitotic index, higher Ki-67 index, and having received adjuvant therapy increased the rates of recurrence and mortality. CONCLUSION There was no statistically significant difference in survival outcomes between the GEP-NET groups located in the gastrointestinal tract and the hepatopancreatobiliary system.
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Affiliation(s)
- Mehmet Sait Ozsoy
- Department of General Surgery, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Cem Ilgin Erol
- Department of General Surgery, Erzurum City Hospital, Erzurum, Turkey
| | - Muhammet Ali Aydemir
- Department of General Surgery, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Hakan Baysal
- Department of General Surgery, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Fatih Buyuker
- Department of General Surgery, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Hatice Seneldir
- Department of Pathology, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Ozgur Ekinci
- Department of General Surgery, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Tunc Eren
- Department of General Surgery, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Orhan Alimoglu
- Department of General Surgery, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
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Santhanam AP, Joel A, Paul A, Zachariah UG, Rebekah GJ, Kodiatte TA. Anti-phosphohistone H3 (PHH3) as a proliferation marker to assess mitotic activity and to grade neuroendocrine neoplasms of hepatopancreaticobiliary (HPB) system. INDIAN J PATHOL MICR 2025; 68:30-35. [PMID: 39133254 DOI: 10.4103/ijpm.ijpm_625_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 03/19/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND The world health organization (WHO) classification of neuroendocrine neoplasms (NENs, i.e. neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs)) of the gastrointestinal system involves grading of these tumors by mitotic count (i.e. H and E mitotic index or Haematoxylin and Eosin mitotic index [HE-MI] and Mindbomb E3 ubiquitin protein ligase 1 labelling index (MIB1-LI) into Grade 1 (G1), Grade 2 (G2), or Grade 3 (G3). However, the assessment of HE-MI and MIB1-LI is hindered by several factors that contribute to discordance between these two grading methods. Clinical data demonstrate the dependency of prognosis on grade. OBJECTIVES The objective of this study was to compare the grading of NENs of the hepatopancreatobiliary (HPB) system using Anti-phosphohistone H3 mitotic index (i.e. PHH3-MI), HE-MI and MIB1-LI. MATERIALS AND METHODS In a cohort of 140 NENs selected from January 2011 to August 2019, the concordance and correlation between HE-MI, MIB1-LI and PHH3-MI grading methods were analysed using Cohen's weighted kappa ( κ ) statistics and Spearman's correlation (ρ), respectively. Receiver operating characteristic (ROC) curve and cut-off analyses were done to determine optimal PHH3-MI cut-off values to grade NENs. RESULTS The rates of discordance between HE-MI vs. MIB1-LI, PHH3-MI vs. MIB1-LI and PHH3-MI vs. HE-MI were 52% ( κ =0.416), 29% ( κ =0.64) and 41% ( κ =0.508), respectively. There was a significant correlation between the grading methods. PHH3-MI had good overall sensitivity and specificity at cut-offs 2 and 17 in distinguishing between G1 vs. G2, and G2 vs. G3 tumors, respectively. CONCLUSION PHH3 immunolabeling allowed for quick and easy identification of mitotic figures (MF). It had the highest concordance with MIB1-LI. At cut-off values of 2 and 17, there was good overall sensitivity and specificity. The interobserver agreement was excellent.
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Affiliation(s)
- A Prisca Santhanam
- Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Anjana Joel
- Department of Medical Oncology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Anoop Paul
- Department of HPB Surgery, Christian Medical College, Vellore, Tamil Nadu, India
| | - Uday G Zachariah
- Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Grace J Rebekah
- Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
| | - Thomas A Kodiatte
- Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
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Martino F, Ilardi G, Varricchio S, Russo D, Di Crescenzo RM, Staibano S, Merolla F. A deep learning model to predict Ki-67 positivity in oral squamous cell carcinoma. J Pathol Inform 2024; 15:100354. [PMID: 38148967 PMCID: PMC10750186 DOI: 10.1016/j.jpi.2023.100354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 08/14/2023] [Accepted: 11/16/2023] [Indexed: 12/28/2023] Open
Abstract
Anatomical pathology is undergoing its third revolution, transitioning from analogical to digital pathology and incorporating new artificial intelligence technologies into clinical practice. Aside from classification, detection, and segmentation models, predictive models are gaining traction since they can impact diagnostic processes and laboratory activity, lowering consumable usage and turnaround time. Our research aimed to create a deep-learning model to generate synthetic Ki-67 immunohistochemistry from Haematoxylin and Eosin (H&E) stained images. We used 175 oral squamous cell carcinoma (OSCC) from the University Federico II's Pathology Unit's archives to train our model to generate 4 Tissue Micro Arrays (TMAs). We sectioned one slide from each TMA, first stained with H&E and then re-stained with anti-Ki-67 immunohistochemistry (IHC). In digitised slides, cores were disarrayed, and the matching cores of the 2 stained were aligned to construct a dataset to train a Pix2Pix algorithm to convert H&E images to IHC. Pathologists could recognise the synthetic images in only half of the cases in a specially designed likelihood test. Hence, our model produced realistic synthetic images. We next used QuPath to quantify IHC positivity, achieving remarkable levels of agreement between genuine and synthetic IHC. Furthermore, a categorical analysis employing 3 Ki-67 positivity cut-offs (5%, 10%, and 15%) revealed high positive-predictive values. Our model is a promising tool for collecting Ki-67 positivity information directly on H&E slides, reducing laboratory demand and improving patient management. It is also a valuable option for smaller laboratories to easily and quickly screen bioptic samples and prioritise them in a digital pathology workflow.
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Affiliation(s)
- Francesco Martino
- Dedalus HealthCare, Division of Diagnostic Imaging IT, Gertrude-Frohlich-Sandner-Straße 1, Wien 1100, Austria
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Gennaro Ilardi
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Silvia Varricchio
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Daniela Russo
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Rosa Maria Di Crescenzo
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Stefania Staibano
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Francesco Merolla
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Via De Sanctis, Campobasso 86100, Italy
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Guo S, Wu H, Gao S, Hu W, Jiang H, Bian Y, Zhang Y, Li B, Li G, Xu X, Wang M, Zhu C, Qu L, Huang Q, Qin R, Lou W, Jin G. Real-world effectiveness of adjuvant octreotide therapy in patients with pancreatic neuroendocrine tumors at high recurrence risk: A multicenter retrospective cohort study. J Neuroendocrinol 2024; 36:e13442. [PMID: 39255974 DOI: 10.1111/jne.13442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 08/19/2024] [Accepted: 08/23/2024] [Indexed: 09/12/2024]
Abstract
Adjuvant therapy for pancreatic neuroendocrine tumors (PanNETs) after radical resection lacks evidence-based data and remains controversial. This study aimed to validate whether long-acting octreotide is a potential candidate for adjuvant therapy in patients with G2 PanNETs at high recurrence risk by clustering real-world data. A retrospective review of patients with nonmetastatic grade 2 PanNETs who underwent radical resection at six research centers between 2008 and 2020 was conducted. Propensity score matching and inverse probability of treatment weight analysis were used to control confounding factors. Overall, 357 patients (octreotide group, n = 82; control group, n = 275) were analyzed. Kaplan-Meier survival analyses showed that the octreotide group had longer disease-free survival (DFS) compared with the control group (36 months: 93.3% vs. 79.0%, p = .0124; 60 months: 71% vs. 67.6%, p = .0596, respectively), as well as overall survival (OS) (60 months: 98% vs. 83.8%, p = .0117, respectively). Multivariate analyses indicated that octreotide long-acting repeatable (LAR) adjuvant therapy was associated with higher OS (p = .0270) at 60 months. Propensity score matching analysis showed that octreotide adjuvant therapy was associated with higher DFS (p = .0455) and OS (p = .0190) at 60 months. Similar results were obtained via inverse probability of treatment weight analysis. Subgroup analysis indicated that octreotide LAR was associated with a high DFS in patients with lymph node metastasis or Ki-67 <10% PanNETs. Adjuvant therapy with long-acting octreotide following radical resection of nonmetastatic G2 PanNETs may be associated with improved DFS and OS in a real-world setting.
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Affiliation(s)
- Shiwei Guo
- Department of Pancreatic Hepatobiliary Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tognji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Suizhi Gao
- Department of Pancreatic Hepatobiliary Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Weiyu Hu
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hui Jiang
- Department of Pathology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yun Bian
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yijie Zhang
- Department of Pancreatic Hepatobiliary Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Bo Li
- Department of Pancreatic Hepatobiliary Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Gang Li
- Department of Pancreatic Hepatobiliary Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xuefeng Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Min Wang
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenglin Zhu
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Linlin Qu
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qiang Huang
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Renyi Qin
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenhui Lou
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Gang Jin
- Department of Pancreatic Hepatobiliary Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
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Karim H, Winkelmann M, Grawe F, Völter F, Auernhammer C, Rübenthaler J, Ricke J, Ingenerf M, Schmid-Tannwald C. Quantitative SSTR-PET/CT: a potential tool for predicting everolimus response in neuroendoctine tumour patients. Radiol Oncol 2024; 58:348-356. [PMID: 38861687 PMCID: PMC11406901 DOI: 10.2478/raon-2024-0032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 05/10/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND This study aimed to assess 68Ga-DOTA-TATE (-TOC) PET/CT quantitative parameters in monitoring and predicting everolimus response in neuroendocrine tumor (NET) patients with hepatic metastases (NELM). PATIENTS AND METHODS This retrospective analysis included 29 patients with 62 target lesions undergoing everolimus treatment and pre-therapy, and follow-up 68Ga-DOTA-TATE (-TOC) PET/CT scans. Response evaluation utilized progression-free survival (PFS) categorized as responders (R; PFS > 6 months) and non-responders (NR; PFS ≤ 6 months). Lesion size and density, along with maximum and median standardize uptake value (SUV) in target lesions, liver, and spleen were assessed. Tumor-to-spleen (T/S) and tumor-to-liver (T/L) ratios were calculated, including the tumor-to-spleen (T/S) ratio and tumor-to-liver (T/L) ratio (using SUVmax/SUVmax, SUVmax/SUVmean, and SUVmean/SUVmean). RESULTS PET/CT scans were acquired 19 days (interquartile range [IQR] 69 days) pre-treatment and 127 days (IQR 74 days) post-starting everolimus. The overall median PFS was 264 days (95% CI: 134-394 days). R exhibited significant decreases in Tmax/Lmax and Tmean/Lmax ratios compared to NR (p = 0.01). In univariate Cox regression, Tmean/Lmax ratio was the sole prognostic parameter associated with PFS (HR 0.5, 95% CI 0.28-0.92, p = 0.03). Percentage changes in T/L and T/S ratios were significant predictors of PFS, with the highest area under curve (AUC) for the percentage change of Tmean/Lmax (AUC = 0.73). An optimal threshold of < 2.5% identified patients with longer PFS (p = 0.003). No other imaging or clinical parameters were predictive of PFS. CONCLUSIONS This study highlights the potential of quantitative SSTR-PET/CT in predicting and monitoring everolimus response in NET patients. Liver metastasis-to-liver parenchyma ratios outperformed size-based criteria, and Tmean/Lmax ratio may serve as a prognostic marker for PFS, warranting larger cohort investigation.
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Affiliation(s)
- Homeira Karim
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Michael Winkelmann
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Freba Grawe
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Friederike Völter
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Christoph Auernhammer
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
- Department of Internal Medicine 4, University Hospital, LMU Munich, Munich, Germany
| | - Johannes Rübenthaler
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
| | - Maria Ingenerf
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Christine Schmid-Tannwald
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
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Mandic A, Maksimovic T, Nadj GS, Maricic S, Celebic A. Neuroendocrine cervical cancer: Have we made any steps forward in its management? EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024:108570. [PMID: 39095302 DOI: 10.1016/j.ejso.2024.108570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/30/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024]
Abstract
INTRODUCTION Neuroendocrine tumors (NEC) were first described by Albores-Saavedra in 1972 and these tumors account for only 0.9% to 1.5% of all invasive cervical cancers.1,2 The most common type is small cell neuroendocrine carcinoma (SCNEC) of the cervix, which accounts for 80% of cases.2 The poor prognosis despite advances in treatment remains still a huge problem, so the aim of our review is to cover all current therapeutic options. METHOD We searched for all available interventional studies, reviews, case reports and meta-analyses published from 1995 to 2023. RESULTS In 2017 Castle et al.9 published a systematic review and meta-analysis and concluded that SCNC and large cell neuroendocrine carcinoma (LCNC) are, in most cases, caused by HPV, primarily HPV18 and HPV16. Comparative genomics data suggest that cervical NEC may be genetically more similar to common cervical cancer subtypes than to extra-cervical SCNEC of the lung and bladder.13 Surgery is recommended as the primary treatment in early stages of disease, with radical hysterectomy and nodal assessment followed by adjuvant pelvic radiotherapy and/or chemotherapy. However, simple hysterectomy may be adequate when followed by adjuvant radiotherapy with concurrent cisplatin and etoposide as additional chemotherapy.15 Considering that pathologic and clinical behavior is similar to small cell lung cancer, patients usually receive platinum and etoposide as part of their primary therapy.16 The recurrent disease remains a major clinical problem, because there is no standard treatment modality for these patients, and individualized therapy is recommeded. CONCLUSION Current therapeutic modalities are mainly based on experience in the treatment of SCNEC of the lung. Certainly, a multidisciplinary approach is very important inorder to design a personalized management plan.
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Affiliation(s)
- Aljosa Mandic
- Oncology Institute of Vojvodina, Serbia; University of Novi Sad, Medical Faculty, Serbia.
| | - Tamara Maksimovic
- Oncology Institute of Vojvodina, Serbia; University of Novi Sad, Medical Faculty, Serbia
| | - Gabrijel-Stefan Nadj
- Oncology Institute of Vojvodina, Serbia; University of Novi Sad, Medical Faculty, Serbia
| | - Slobodan Maricic
- Oncology Institute of Vojvodina, Serbia; University of Novi Sad, Medical Faculty, Serbia
| | - Aleksandar Celebic
- Institute of Oncology, Clinical Center of Montenegro, Podgorica, Montenegro
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Hu YF, Wang JK, Ma WJ, Hu HJ, Gu HF, Liu F, Lv TR, Yang SQ, Dai YS, Zou RQ, Jin YW, Li FY. Does the size of the neuroendocrine-carcinoma component determine the prognosis of gallbladder cancer? Front Endocrinol (Lausanne) 2024; 15:1217250. [PMID: 39104815 PMCID: PMC11298461 DOI: 10.3389/fendo.2024.1217250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 01/29/2024] [Indexed: 08/07/2024] Open
Abstract
Background Gallbladder mixed neuroendocrine-non-neuroendocrine neoplasm generally consists of a gallbladder neuroendocrine tumor and a non-neuroendocrine component. The World Health Organization (WHO) in 2019 established a guideline requiring each component, both neuroendocrine and non-neuroendocrine, to account for a minimum of 30% of the tumor mass. Methods Patients after surgery resection and diagnosed at microscopy evaluation with pure gallbladder neuroendocrine carcinoma (GBNEC), gallbladder mixed adeno-neuroendocrine carcinoma (GBMANEC, GBNEC≥30%), and gallbladder carcinoma mixed with a small fraction of GBNEC (GBNEC <30%) between 2010 and 2022 at West China Hospital of Sichuan University were collated for the analyses. Demographic features, surgical variables, and tumor characteristics were evaluated for association with patients' overall and recurrence-free survival (OS and RFS). Results The study included 26 GBNEC, 11 GBMANEC, 4 gallbladder squamous-cell carcinoma (GBSCC), and 7 gallbladder adenocarcinoma (GBADC) mixed with a small fraction of GBNEC. All patients had stage III or higher tumors (AJCC8th edition). The majority of included patients (79.17%) underwent curative surgical resection (R0), with only ten patients having tumoral resection margins. In the analysis comparing patients with GBNEC percentage (GBNEC≥30% vs. GBNEC<30%), the basic demographics and tumor characteristics of most patients were comparable. The prognosis of these patients was also comparable, with a median OS of 23.65 months versus 20.40 months (P=0.13) and a median RFS of 17.1 months versus 12.3 months (P=0.24). However, patients with GBADC or GBSCC mixed with GBNEC <30% had a statistically significant decreased OS and RFS (both P<0.0001)) compared with GBNEC and GBMANEC. Patients with GBNEC who exhibited advanced tumor stages and lymphovascular invasion had a higher risk of experiencing worse overall survival (OS) and recurrence-free survival (RFS). However, a 30% GBNEC component was not identified as an independent risk factor. Conclusion Patients with GBNEC were frequently diagnosed at advanced stages and their prognosis is poor. The 30% percentage of the GBNEC component is not related to the patient's survival.
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Affiliation(s)
- Ya-Fei Hu
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Jun-Ke Wang
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Wen-Jie Ma
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Hai-Jie Hu
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Han-Fei Gu
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Fei Liu
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Tian-Run Lv
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Si-Qi Yang
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yu-Shi Dai
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Rui-Qi Zou
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yan-Wen Jin
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Fu-Yu Li
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China
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Yıldırım ÜM, Koca D, Kebudi R. Gastroenteropancreatic neuroendocrine tumors in children and adolescents. Turk J Pediatr 2024; 66:332-339. [PMID: 39024601 DOI: 10.24953/turkjpediatr.2024.4526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 05/30/2024] [Indexed: 07/20/2024]
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare in children and adolescents. Standard management of these tumors has not been well established due to their rarity in this age group. We aimed to report the clinical and pathological characteristics of patients with this rare disease followed and treated between the years 1993-2022. MATERIALS AND METHODS The medical records of patients with GEP-NETs were reviewed. RESULTS Fourteen patients (11 girls, 3 boys) were diagnosed with GEP-NET. The median age was 13 (9-18) years. Tumor localization was the appendix in 12, stomach in one and pancreas in one patient. Mesoappendix invasion was detected in four patients two of whom underwent right hemicolectomy (RHC) and lymph node dissection (LND). Of those, one patient had lymph node involvement. The other two had not further operations. Somatostatin was used in one with pancreatic metastatic disease and the other with gastric disease after surgery. No additional treatment was given in other patients. All patients are under follow-up without evidence of disease at a median follow-up of 85 months (7-226 months). CONCLUSION GEP-NETs should be considered in the differential diagnosis of acute appendicitis and in cases with persistent abdominal pain. In children, there is invariably a favorable prognosis, and additional surgical interventions other than simple appendectomies generally do not provide benefits. Mesoappendix invasion may not necessitate RHC and LND.
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Affiliation(s)
- Ülkü Miray Yıldırım
- Division of Pediatric Hematology Oncology, Institute of Oncology, İstanbul University, İstanbul, Türkiye
| | - Dilşad Koca
- Division of Pediatric Hematology Oncology, Institute of Oncology, İstanbul University, İstanbul, Türkiye
| | - Rejin Kebudi
- Division of Pediatric Hematology Oncology, Institute of Oncology, İstanbul University, İstanbul, Türkiye
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12
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Sunny SS, Hephzibah J, Chacko RT, Kodiatte TA. Therapeutic Response to PRRNT in a Rare Case of Metastatic Renal Neuroendocrine Carcinoma. World J Nucl Med 2024; 23:141-146. [PMID: 38933067 PMCID: PMC11199026 DOI: 10.1055/s-0044-1785461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2024] Open
Abstract
Neuroendocrine tumors (NETs) are a rare spectrum of neoplasms that are characterized by neuroendocrine and neural differentiation. The treatment can be challenging in view of the heterogeneity in differentiation and behavior. Primary renal origin NETs are rare and only a few cases have been reported in the literature. There is limited knowledge on their presentation and response to various lines of treatment. We report a case of a patient with a metastatic renal NET from a rare histological subtype of large cell neuroendocrine carcinoma, known to cause aggressive disease with poor prognosis. A multimodality treatment approach was followed. In spite of surgical management and second-line chemotherapy, the disease progressed. The patient subsequently received peptide receptor radionuclide therapy (PRRNT) using lutetium-177 DOTATATE, following which the patient demonstrated a remarkable clinical and radiological response and is stable to date. In a rare tumor with poor prognosis, the relevance of theranostics and the efficacy of targeted therapies like PRRNT are noteworthy.
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Affiliation(s)
- Saumya Sara Sunny
- Department of Nuclear Medicine, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
| | - Julie Hephzibah
- Department of Medical Oncology, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
| | - Raju Titus Chacko
- Department of Medical Oncology, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
| | - Thomas Alex Kodiatte
- Department of Pathology, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
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Hooper J, Jervis N, Morgan L, Beckett V, Hand P, Higgs K, Munir A, Prinn J, Pritchard DM, Sarker D, Srirajaskanthan R, Ellis CB. Neuroendocrine neoplasms: Consensus on a patient care pathway. J Neuroendocrinol 2024; 36:e13380. [PMID: 38471798 DOI: 10.1111/jne.13380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 01/30/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024]
Abstract
People with neuroendocrine neoplasms (NENs) face a multitude of challenges, including delayed diagnosis, low awareness of the cancer among healthcare professionals and limited access to multidisciplinary care and expert centres. We have developed the first patient care pathway for people living with NENs in England to guide disease management and help overcome these barriers. The pathway was developed in two phases. First, a pragmatic review of the literature was conducted, which was used to develop a draft patient care pathway. Second, the draft pathway was then updated following semi-structured interviews with carefully selected expert stakeholders. After each phase, the pathway was discussed among a multidisciplinary, expert advisory group (which comprised the authors and the Deputy Chief Operating Officer, West Suffolk NHS Foundation Trust), who reached a consensus on the ideal care pathway. This article presents the outputs of this research. The pathway identified key barriers to care and highlighted how these may be addressed, with many of the findings relevant to the rest of the UK and international audiences. NENs are increasing in incidence and prevalence in England, compounding pre-existing inequities in diagnosis and disease management. Effective integration of this pathway within NHS England will help achieve optimal, equitable care provision for all people with NENs, and should be feasible within the existing expert multidisciplinary teams across the country.
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Affiliation(s)
| | | | | | - Vivienne Beckett
- Advanced Accelerators Applications (UK & Ireland) Ltd, a Novartis Company, London, UK
| | - Philippa Hand
- London North West University Healthcare NHS Trust, London, UK
| | | | - Alia Munir
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield Teaching Hospitals European Neuroendocrine Tumor Society Center of Excellence, Sheffield, UK
| | | | - D Mark Pritchard
- University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool Regional NET Service (European Neuroendocrine Tumor Society Center of Excellence), Liverpool, UK
| | - Debashis Sarker
- Guy's, St Thomas' and King's College Hospitals, King's Health Partners NET Centre (European Neuroendocrine Tumor Society Center of Excellence), London, UK
| | - Raj Srirajaskanthan
- King's College Hospital NHS Foundation Trust, King's Health Partners NET Centre (European Neuroendocrine Tumor Society Center of Excellence), London, UK
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14
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Singh S, Ferone D, Capdevila J, Chan JA, de Herder WW, Halperin D, Mailman J, Hellström L, Liedman H, Svedberg A, Tiberg F. Methodology of the SORENTO clinical trial: a prospective, randomised, active-controlled phase 3 trial assessing the efficacy and safety of high exposure octreotide subcutaneous depot (CAM2029) in patients with GEP-NET. Trials 2024; 25:58. [PMID: 38229199 PMCID: PMC10790497 DOI: 10.1186/s13063-023-07834-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 11/24/2023] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND The current standard of care (SoC) for the initial treatment of unresectable or metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NET) requires initiation of first-generation somatostatin receptor ligand (SRL) therapy, octreotide and lanreotide, which provide safe and efficacious tumour/symptom control in most patients. However, disease progression can occur with SoC SRL treatment and the optimal dose response of SRL remains unknown. Octreotide subcutaneous depot (CAM2029) is a novel, long-acting, high-exposure formulation that has shown greater bioavailability and improved administration than octreotide long-acting release (LAR) with a well-tolerated safety profile. Retrospective data have highlighted a potential benefit of high-exposure SRL for improved disease control in patients who did not adequately respond to the current SoC SRL treatment. This trial will investigate the efficacy and tolerability of CAM2029 compared to the current SoC, including octreotide LAR and lanreotide autogel (ATG). METHODS SORENTO is a prospective, multicentre, randomised, active-controlled, open-label phase 3 trial aiming to demonstrate superiority of treatment with 20 mg octreotide subcutaneous depot (CAM2029) every 2 weeks (Q2W) compared to treatment with the Investigator's choice of SRL therapy at standard doses for tumour control (octreotide LAR 30 mg or lanreotide ATG 120 mg every 4 weeks [Q4W]) as assessed by progression-free survival (PFS) in approximately 300 patients with unresectable/metastatic and well-differentiated GEP-NET. Upon confirmation of disease progression (determined by a Blinded Independent Review Committee [BIRC] and defined as per RECIST 1.1), patients may enter an open-label extension treatment period with once weekly dosing, to investigate the effects of higher frequency dosing. Overall survival follow-up will end a maximum of 2 years after primary analysis. The primary endpoint will be analysed after 194 confirmed PFS events. DISCUSSION This is the first trial investigating the efficacy of CAM2029 versus SoC SRL therapy using a head-to-head, superiority trial design. It is expected to be the first trial to investigate the efficacy of increased dosing frequency of a high-exposure SRL. A BIRC will limit bias and measurement variability and ensure high-quality efficacy data. Additionally, inclusion of patients with well-differentiated Grade 3 NET may elucidate treatment strategies for this rarely investigated patient population. TRIAL REGISTRATION ClinicalTrials.gov NCT05050942. Registered on 21st September 2021.
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Affiliation(s)
- Simron Singh
- Sunnybrook Health Sciences Center, Toronto, Canada
| | - Diego Ferone
- Endocrinology, Department of Internal Medicine & Medical Specialties, University of Genova, Endocrinology Clinic IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | | | | | | | - Daniel Halperin
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Josh Mailman
- Northern California CarciNET Community, Oakland, CA, USA
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15
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Guo X, Zhao X, Huang G, Yu Y. Advances in Endoscopic Diagnosis and Treatment of Gastric Neuroendocrine Neoplasms. Dig Dis Sci 2024; 69:27-35. [PMID: 37971578 DOI: 10.1007/s10620-023-08180-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 11/01/2023] [Indexed: 11/19/2023]
Abstract
Gastric neuroendocrine neoplasms refer to a group of diseases that are relatively rare. They can be classified into three subtypes based on their clinical and histopathological features, and there are significant differences in diagnosis, treatment, and prognosis among the different subtypes. The incidence of gastric neuroendocrine neoplasms has been increasing globally in recent years with the localized disease being particularly evident. Gastrointestinal endoscopy is of irreplaceable importance for the diagnosis and management of g-NENs. Endoscopy with biopsy is the gold standard for the diagnosis of g-NENs. Ultrasound endoscopy can assess the depth of tumor invasion and the presence of lymphatic metastases, which is important for the development of treatment strategies. Meanwhile, for some small and low-risk lesions, endoscopic surveillance or endoscopic resection has satisfactory therapeutic results and prognosis. This means that even though the incidence has increased, advances in endoscopic techniques have allowed more patients to adopt a relatively conservative treatment strategy. However, the criteria for patients suitable for endoscopic surveillance or endoscopic resection remain controversial.
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Affiliation(s)
- Xinrui Guo
- Department of Gastroenterology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China
- Shandong Provincial Clinical Research Center for Digestive Disease, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China
| | - Xiaohan Zhao
- Department of Gastroenterology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China
- Shandong Provincial Clinical Research Center for Digestive Disease, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China
| | - Gang Huang
- Department of Gastroenterology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China
- Shandong Provincial Clinical Research Center for Digestive Disease, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China
| | - Yanbo Yu
- Department of Gastroenterology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China.
- Shandong Provincial Clinical Research Center for Digestive Disease, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
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Ingenerf M, Grawe F, Winkelmann M, Karim H, Ruebenthaler J, Fabritius MP, Ricke J, Seidensticker R, Auernhammer CJ, Zacherl MJ, Seidensticker M, Schmid-Tannwald C. Neuroendocrine liver metastases treated using transarterial radioembolization: Identification of prognostic parameters at 68Ga-DOTATATE PET/CT. Diagn Interv Imaging 2024; 105:15-25. [PMID: 37453859 DOI: 10.1016/j.diii.2023.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 07/18/2023]
Abstract
PURPOSE To identify prognostic clinical and imaging parameters for patients with neuroendocrine liver metastases (NELMs) undergoing transarterial radioembolization (TARE). MATERIALS AND METHODS Forty-seven patients (27 men; mean age, 64 years) with NELMs who received TARE, along with pre-procedure liver MRI and 68Ga-DOTATATE positron emission tomography/computed tomography were included. Apparent diffusion coefficient and standardized uptake value (SUV) of three liver metastases, normal spleen and liver were measured. SUVmax or SUVmean were used for the calculation of tumor-to-organ ratios (tumor-to-spleen and tumor-to-liver ratios) using all possible combinations (including SUVmax/SUVmax, SUVmax/SUVmean, and SUVmean/SUVmean). Clinical parameters (hepatic tumor-burden, presence of extra-hepatic metastases, chromograninA, Ki-67 and bilirubin levels) were assessed. Overall survival, progression-free survival (PFS) and hepatic progression-free survival (HPFS) were calculated using Kaplan-Meier curves. RESULTS Median overall survival, PFS and HPFS were 49.6, 13.1 and 28.3 months, respectively. In multivariable Cox regression analysis, low Ki-67 (≤ 5%), low hepatic tumor-burden (< 10%), absence of extrahepatic metastases, and increased Tmean/Lmax ratio were significant prognostic factors of longer overall survival and HPFS. High baseline chromograninA (> 1330 ng/mL) was associated with shorter HPFS. Tmean/Lmax > 1.9 yielded a median overall survival of 69 vs. 33 months (P < 0.04), and a median HPFS of 30 vs. 19 months (P = 0.09). For PFS, high baseline SUVmax of NELMs was the single significant parameter in the multivariable model. SUVmax > 28 resulted in a median PFS of 16.9 vs. 6.5 months, respectively (P = 0.001). CONCLUSION High preinterventional Tmean/Lmax ratios, and high SUVmax on 68Ga-DOTATATE positron emission tomography/computed tomography seem to have prognostic value in patients with NELMs undergoing TARE, potentially aiding patient selection and management alongside conventional variables.
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Affiliation(s)
- Maria Ingenerf
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany.
| | - Freba Grawe
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; Department of Nuclear Medicine, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Michael Winkelmann
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Homeira Karim
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Johannes Ruebenthaler
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; Interdisciplinary Centre of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), University Hospital, LMU Munich, 81377 Munich, Germany
| | | | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; Interdisciplinary Centre of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), University Hospital, LMU Munich, 81377 Munich, Germany
| | | | - Christoph Josef Auernhammer
- Department of Internal Medicine 4, University Hospital, LMU Munich, 81377 Munich, Germany; Interdisciplinary Centre of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), University Hospital, LMU Munich, 81377 Munich, Germany
| | | | - Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; Interdisciplinary Centre of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), University Hospital, LMU Munich, 81377 Munich, Germany
| | - Christine Schmid-Tannwald
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; Interdisciplinary Centre of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), University Hospital, LMU Munich, 81377 Munich, Germany
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Singh A, Kushwaha R, Chauhan P, Kumar G. Primary neuroendocrine carcinoma of cervical lymph node masquerading as non-Hodgkin lymphoma: A diagnostic challenge. J Cancer Res Ther 2023:01363817-990000000-00031. [PMID: 38102915 DOI: 10.4103/jcrt.jcrt_2572_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/02/2023] [Indexed: 12/17/2023]
Abstract
ABSTRACT A large extended family of tumors classified as neuroendocrine tumors most commonly occurs in the gastrointestinal tract and bronchus pulmonary tree. It is extremely unusual for a primary neuroendocrine tumor to present as a cervical lymph node mass at initial presentation. We discuss the rare case of a 55-year-old man who initially complained of a right neck mass that was misinterpreted as non-Hodgkin lymphoma on fine needle aspiration cytology. By integrating clinical findings, radiography, fine-needle aspiration cytology, histomorphology, and immunohistochemistry analysis, a definitive diagnosis of primary neuroendocrine carcinoma of the cervical lymph node was made. He received chemotherapy and decompressive radiation as treatment. Regarding the course of disease in the present case, the patients underwent a distant subcutaneous metastasis over the right anterior chest wall 10 months after the initial manifestation. The patient is still alive, albeit his general condition has gotten deteriorated, and he is getting regular follow-ups.
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Affiliation(s)
- Anurag Singh
- Department of Pathology, King George Medical University, Lucknow, Uttar Pradesh, India
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18
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Song C, Lee JJ, Lee SH, Park JY, Kim DY, Suh DS, Kim JH, Kim YM, Kim JH. Application of preoperative fluorodeoxyglucose-PET/CT parameters for predicting prognosis of high-grade neuroendocrine cervical cancer. Nucl Med Commun 2023; 44:1005-1010. [PMID: 37578339 PMCID: PMC10566590 DOI: 10.1097/mnm.0000000000001741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 07/31/2023] [Indexed: 08/15/2023]
Abstract
OBJECTIVE High-grade neuroendocrine cervical cancer (HGNECC) is a rare and aggressive cervical cancer subtype. In this study, we aimed to evaluate the prognostic value of fluorodeoxyglucose-PET/computed tomography (CT) parameters for HGNECC. MATERIALS AND METHODS This single-center retrospective study included 29 patients with HGNECC who underwent fluorodeoxyglucose-PET/CT scan followed by surgery between 2006 and 2016. RESULTS The median follow-up period was 40 (range, 4-184) months. After surgery, the resection margins were tumor-negative in 28 patients (96.6%), 8 (27.6%) patients had parametrial tumor invasion, and 7 patients (24.1%) tested positive for lymph node metastasis. The tumor recurred in 20 patients (69%) and 18 patients (62.1%) died during the observation period. In the univariate analyses, age and total lesion glycolysis (TLG) were associated with worse disease-free survival (DFS) (age, hazard ratio 1.056, 95% CI 1.014-1.100, P = 0.009; TLG2.5, hazard ratio 1.003, 95% CI 1-1.006, P = 0.033; and TLG3.0, hazard ratio 1.003, 95% CI 1-1.006, P = 0.034). In the multivariate analyses, older age and higher TLG3.0 were identified as independent poor prognostic factors for DFS (age, hazard ratio 1.058, 95% CI 1.014-1.104, P = 0.009; TLG3.0, hazard ratio 1.004, 95% CI 1-1.007, P = 0.033), while resection margin involvement was identified as an independent factor to predict poor overall survival (hazard ratio 20.717, 95% CI 1.289-332.964, P = 0.032). CONCLUSION Among the preoperative fluorodeoxyglucose-PET/CT parameters, TLG3.0 may be useful for predicting DFS in patients with HGNECC.
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Affiliation(s)
- Changho Song
- Department of Obstetrics and Gynecology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan
| | - Jong Jin Lee
- Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul
| | - Shin-Hwa Lee
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong-Yeol Park
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dae-Yeon Kim
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dae-Shik Suh
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jong-Hyeok Kim
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yong-Man Kim
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju-Hyun Kim
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Wang W, Zhang F, Li Y, Chen B, Gu Y, Shan Y, Li Y, Chen W, Jin Y, Pan L. Whole exome sequencing identifies common mutational landscape of cervix and endometrium small cell neuroendocrine carcinoma. Front Oncol 2023; 13:1182029. [PMID: 37920164 PMCID: PMC10618670 DOI: 10.3389/fonc.2023.1182029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 10/05/2023] [Indexed: 11/04/2023] Open
Abstract
Background Primary small cell neuroendocrine carcinomas of the cervix and endometrium are rare gynecological malignancies with limited treatment options. This study aimed to improve the understanding of the carcinogenesis process and identify potential therapeutic targets for these two tumor types by constructing the mutational landscape at the whole exome level. Methods Primary tumor tissues and their matched blood samples were obtained from 10 patients with small cell cervical neuroendocrine carcinoma (NECC) and five patients with small cell endometrial neuroendocrine carcinoma (NECE). Whole exome sequencing was performed to construct the somatic mutation profiles. Mutational signature and recurrent mutated gene analysis were used to identify tumor subtypes and common carcinogenesis processes. Results Based on the burden of different mutational signatures, the NECCs in this work can be divided into two subtypes, including the mismatch repair deficiency like (dMMR-like) type (4/10) and the high spontaneous deamination type (6/10). Components of the PI3K/AKT signaling and RAS signaling were exclusively mutated in these two subtypes, respectively. The integration of human papillomavirus made a limited contribution to tumorigenesis in NECC (20%). The dysfunction of the mismatch repair system and microsatellite instability are the major features of NECE. PI3K/AKT, JAK/STAT signaling, and chromatin remodeling activity were the common mutated pathways in NECE. PIK3CA, WNK2, and KMT2B underwent mutations in both the dMMR-like subtype of NECC (50% - 75%) and in NECE (60% - 80%) specimens, while exhibiting infrequent mutational occurrences in publicly available data pertaining to neuroendocrine carcinomas of the lung or bladder (< 10%). Conclusion We identified the two subtypes of NECC with distinct mutated pathways and potential therapy targets. The dMMR-like type NECC and NECE may share a similar carcinogenesis process that include dysfunction of PI3K/AKT signaling, cell cycle, antiapoptotic processes, and chromatin remodeling activity.
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Affiliation(s)
- Wei Wang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
- Department of Obstetrics and Gynecology, The Fifth People’s Hospital of Ningxia, Shizuishan, China
| | - Fan Zhang
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Engineering Medicine, Beihang University, Beijing, China
| | - Yan Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Bo Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Gu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Ying Shan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Yaping Li
- Department of Obstetrics and Gynecology, The Fifth People’s Hospital of Ningxia, Shizuishan, China
| | - Wei Chen
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Engineering Medicine, Beihang University, Beijing, China
| | - Ying Jin
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Lingya Pan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
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20
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Nakazawa K, Hirata Y, Kakimoto K, Miyazaki T, Ota S, Hamamoto H, Ishida M, Nakamura S, Nishikawa H. Neuroendocrine carcinoma of the small intestine diagnosed as a result of paraneoplastic neurological syndrome. Clin J Gastroenterol 2023; 16:663-667. [PMID: 37434043 DOI: 10.1007/s12328-023-01822-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 06/06/2023] [Indexed: 07/13/2023]
Abstract
Paraneoplastic neurological syndromes, a diverse group of neurological syndromes, are associated with small cell lung, testicular, ovarian, and breast cancers; however, their association with neuroendocrine carcinoma of the small intestine remains unreported. In this report, we present the case of a 78-year-old man diagnosed with neuroendocrine carcinoma of the small intestine and experienced symptoms such as subacute progressive numbness of the extremities and impaired gait. These symptoms were diagnosed as tumor-associated neurological syndrome. The patient had also undergone pyloric gastrectomy for early-stage gastric cancer several years prior to the appearance of the neurological symptoms. Therefore, we could not determine whether the tumor-related neurologic syndrome was owing to gastric cancer or neuroendocrine carcinoma of the small intestine; however, one of these conditions was the cause of the neuropathy. The gait disturbance and numbness relatively improved after surgery for the neuroendocrine carcinoma of the small intestine, suggesting that the neuroendocrine carcinoma of the small intestine likely caused the paraneoplastic neurological syndrome. Collectively, we present a unique report highlighting the putative relationship between small bowel neuroendocrine carcinoma and tumor-associated neurologic syndromes.
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Affiliation(s)
- Kei Nakazawa
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, Japan
| | - Yuki Hirata
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, Japan.
| | - Kazuki Kakimoto
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, Japan
| | - Takako Miyazaki
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, Japan
| | - Shin Ota
- 4th Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Hiroki Hamamoto
- Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Mitsuaki Ishida
- Pathology Division, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Shiro Nakamura
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, Japan
| | - Hiroki Nishikawa
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, Japan
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21
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Sultana Q, Kar J, Verma A, Sanghvi S, Kaka N, Patel N, Sethi Y, Chopra H, Kamal MA, Greig NH. A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management. J Clin Med 2023; 12:5138. [PMID: 37568540 PMCID: PMC10420169 DOI: 10.3390/jcm12155138] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/13/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors with neuroendocrine differentiation that can arise from any organ. They account for 2% of all malignancies in the United States. A significant proportion of NEN patients experience endocrine imbalances consequent to increased amine or peptide hormone secretion, impacting their quality of life and prognosis. Over the last decade, pathologic categorization, diagnostic techniques and therapeutic choices for NENs-both well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs)-have appreciably evolved. Diagnosis of NEN mostly follows a suspicion from clinical features or incidental imaging findings. Hormonal or non-hormonal biomarkers (like serum serotonin, urine 5-HIAA, gastrin and VIP) and histology of a suspected NEN is, therefore, critical for both confirmation of the diagnosis and classification as an NET or NEC. Therapy for NENs has progressed recently based on a better molecular understanding, including the involvement of mTOR, VEGF and peptide receptor radionuclide therapy (PRRT), which add to the growing evidence supporting the possibility of treatment beyond complete resection. As the incidence of NENs is on the rise in the United States and several other countries, physicians are more likely to see these cases, and their better understanding may support earlier diagnosis and tailoring treatment to the patient. We have compiled clinically significant evidence for NENs, including relevant changes to clinical practice that have greatly updated our diagnostic and therapeutic approach for NEN patients.
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Affiliation(s)
- Qamar Sultana
- Department of Medicine, Deccan College of Medical Sciences, Hyderabad 500058, India;
- PearResearch, Dehradun 248001, India; (J.K.); (A.V.); (S.S.); (N.K.); (N.P.)
| | - Jill Kar
- PearResearch, Dehradun 248001, India; (J.K.); (A.V.); (S.S.); (N.K.); (N.P.)
- Department of Medicine, Lady Hardinge Medical College, New Delhi 110001, India
| | - Amogh Verma
- PearResearch, Dehradun 248001, India; (J.K.); (A.V.); (S.S.); (N.K.); (N.P.)
- Rama Medical College Hospital and Research Centre, Hapur 245304, India
| | - Shreya Sanghvi
- PearResearch, Dehradun 248001, India; (J.K.); (A.V.); (S.S.); (N.K.); (N.P.)
- Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai 400022, India
| | - Nirja Kaka
- PearResearch, Dehradun 248001, India; (J.K.); (A.V.); (S.S.); (N.K.); (N.P.)
- Department of Medicine, GMERS Medical College, Himmatnagar 390021, India
| | - Neil Patel
- PearResearch, Dehradun 248001, India; (J.K.); (A.V.); (S.S.); (N.K.); (N.P.)
- Department of Medicine, GMERS Medical College, Himmatnagar 390021, India
| | - Yashendra Sethi
- PearResearch, Dehradun 248001, India; (J.K.); (A.V.); (S.S.); (N.K.); (N.P.)
- Government Doon Medical College, HNB Uttarakhand Medical Education University, Dehradun 248001, India
| | - Hitesh Chopra
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, India;
| | - Mohammad Amjad Kamal
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610017, China;
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1216, Bangladesh
- Enzymoics, Hebersham, NSW 2770, Australia
- Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia
| | - Nigel H. Greig
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
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Hautefeuille V, Walter T, Do Cao C, Coriat R, Dominguez S, Mineur L, Cadiot G, Terrebonne E, Sobhani I, Gueguen D, Houchard A, Mouawad C, Anota A, Hammel P. OPERA: perception of information in patients with gastroenteropancreatic neuroendocrine tumors on lanreotide autogel. Eur J Endocrinol 2023; 189:281-289. [PMID: 37542470 DOI: 10.1093/ejendo/lvad094] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/02/2023] [Accepted: 06/12/2023] [Indexed: 08/07/2023]
Abstract
IMPORTANCE Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can affect patient health-related quality of life (HRQoL). Appropriate information may improve their adherence to treatment and quality of life. OBJECTIVE To evaluate the change in patient's perceptions of the level of information at lanreotide (LAN) treatment initiation for GEP-NETs vs after 6 months. DESIGN OPERA (NCT03562091) was a prospective, longitudinal, noninterventional study. SETTING Thirty-one centers in France specialized in the management of patients with NETs. INTERVENTION Planned clinical visits at enrollment and end-of-study visits at month 6, with completion of the European Organisation for Research and Treatment of Cancer 25-item Quality of Life Questionnaire-Information Module (QLQ-INFO25) and 30-item Quality of Life Questionnaire-Core. MAIN OUTCOME Absolute change in the patient's perception of the information between baseline and month 6, using the relevant domains of the QLQ-INFO25. Endpoints measured at baseline and month 6 for at least 1 of the 3 targeted QLQ-INFO25 dimensions of the primary endpoint. RESULTS Ninety-three of the 115 patients enrolled completed ≥1 primary endpoint information dimension. Mean (SD) scores for the primary endpoint information dimensions were high at baseline (disease, 63.41 [20.71]; treatment, 58.85 [19.00]; supportive care, 26.53 [24.69]; maximum 100). There were no significant changes between baseline (98.34% CI) and 6 months (disease, -2.84 [-8.69, 3.01; P = .24]; treatment, -4.37 [-11.26, 2.52; P = .13]; supportive care, 0.46 [-6.78, 7.70; P = .88]), and in HRQoL between baseline and 6 months. CONCLUSIONS AND RELEVANCE The lack of change in patient's perceptions of the disease, treatment, and supportive care information provided over the first 6 months of LAN treatment may suggest that physicians provided adequate information at the treatment initiation.
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Affiliation(s)
| | | | | | - Romain Coriat
- Hôpital Cochin, GH AP-HP Centre-University Paris Cite, Paris, France
| | - Sophie Dominguez
- Hemato-Oncology Department, Lille Catholic Hospitals, Lille Catholic University, Lille, France
| | | | | | | | | | | | | | | | | | - Pascal Hammel
- Paul Brousse Hospital APHP, University Paris-Saclay, Villejuif, France
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Aubreville M, Wilm F, Stathonikos N, Breininger K, Donovan TA, Jabari S, Veta M, Ganz J, Ammeling J, van Diest PJ, Klopfleisch R, Bertram CA. A comprehensive multi-domain dataset for mitotic figure detection. Sci Data 2023; 10:484. [PMID: 37491536 PMCID: PMC10368709 DOI: 10.1038/s41597-023-02327-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/22/2023] [Indexed: 07/27/2023] Open
Abstract
The prognostic value of mitotic figures in tumor tissue is well-established for many tumor types and automating this task is of high research interest. However, especially deep learning-based methods face performance deterioration in the presence of domain shifts, which may arise from different tumor types, slide preparation and digitization devices. We introduce the MIDOG++ dataset, an extension of the MIDOG 2021 and 2022 challenge datasets. We provide region of interest images from 503 histological specimens of seven different tumor types with variable morphology with in total labels for 11,937 mitotic figures: breast carcinoma, lung carcinoma, lymphosarcoma, neuroendocrine tumor, cutaneous mast cell tumor, cutaneous melanoma, and (sub)cutaneous soft tissue sarcoma. The specimens were processed in several laboratories utilizing diverse scanners. We evaluated the extent of the domain shift by using state-of-the-art approaches, observing notable differences in single-domain training. In a leave-one-domain-out setting, generalizability improved considerably. This mitotic figure dataset is the first that incorporates a wide domain shift based on different tumor types, laboratories, whole slide image scanners, and species.
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Affiliation(s)
| | - Frauke Wilm
- Pattern Recognition Lab, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Department Artificial Intelligence in Biomedical Engineering, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Nikolas Stathonikos
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Katharina Breininger
- Department Artificial Intelligence in Biomedical Engineering, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | | | - Samir Jabari
- Department of Neuropathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Mitko Veta
- Medical Image Analysis Group, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Jonathan Ganz
- Technische Hochschule Ingolstadt, Ingolstadt, Germany
| | | | - Paul J van Diest
- Department Artificial Intelligence in Biomedical Engineering, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Robert Klopfleisch
- Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany
| | - Christof A Bertram
- Institute of Pathology, University of Veterinary Medicine Vienna, Vienna, Austria
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Drozdov ES, Grishchenko MY, Kharitonkin VI, Lyan NI, Borodin OY, Fesik EA, Korotkevich AG. A rare clinical case of a patient with mixed neuroendocrine-non-neuroendocrine neoplasms of the ampulla of vater. SIBERIAN JOURNAL OF ONCOLOGY 2023; 22:168-174. [DOI: 10.21294/1814-4861-2023-22-2-168-174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Background. Neuroendocrine tumors are rare neoplasias accounting for 1 % of all digestive malignancies. In 2010, mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) were classified by the World Health Organization This type of tumor is extremely rare and most commonly occurs in the appendix, colon, and rectum. To date, only 30 clinical cases of MINEN of the major duodenal papilla (MDP) have been described in the available world literature, while we have not found a description of this pathology in the domestic literature.Description of the clinical case. We present a case of a 64-year-old male patient with MiNEN MDP. The first clinical manifestation of the disease was obstructive jaundice. To eliminate the jaundice, papillosphincterotomy, transpapillary stenting of the choledochus with a plastic stent was performed. MDP tumor was verifed as adenocarcinoma by histological examination. The patient underwent gastropancreatoduodenal resection. Postoperative immunohistochemical examination showed the expression of antibodies in tumor cells: Synaptophysin (clone 27G12) +++, Chromogranin A (5H7) +, CD 57 (NK-1) ++, Ki 67 (Mib 1) 80 %.Conclusion: mixed neuroendocrine (G3) non-neuroendocrine carcinoma (G2) of the major duodenal papilla with growth within the wall of the duodenum; metastases of the neuroendocrine component in three lymph nodes, adenocarcinoma metastasis in 1 out of 15 lymph nodes examined; pT2N2M0, MiNEN high grade (classified by S. La Rosa). Conclusion. Mixed neuroendocrine-non-neuroendocrine tumors of MDP are an extremely rare pathology. The accuracy of preoperative morphological diagnostics is not high, therefore, this diagnosis can be easily missed at the preoperative stage. In the morphological study of malignant tumors of MDP, a pathologist should take into account the feasibility of a combination of a neuroendocrine tumor with adenocarcinoma.
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Affiliation(s)
- E. S. Drozdov
- Tomsk Regional Oncology Hospital;
Siberian State Medical University of the Ministry of Health of Russia
| | | | | | | | - O. Yu. Borodin
- Tomsk Regional Oncology Hospital;
Research Institute of Cardiology, Тomsk National Research Medical Center, Russian Academy of Sciences
| | | | - A. G. Korotkevich
- Novokuznetsk State Institute for Advanced Training of Doctors – branch of the Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russia
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25
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Prado PHT, Paula RVD, de Faria ATR, Silva BL, Ardengh JC. A gastric neuroendocrine tumor after prolonged use of proton pump inhibitors. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2023; 115:209-210. [PMID: 36148661 DOI: 10.17235/reed.2022.9126/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
We describe a case of a gastric neuroendocrine tumor (NET) in a patient with a history of long- term proton pump inhibitor (PPI) use. A 29- year- old man using PPI for the last 10 years due to gastroesophageal reflux disease developed progressive bouts of heartburn. Upper gastrointestinal endoscopy localized an elevated lesion with central depression in the greater curvature of gastric body. Lesion biopsies revealed a well- differentiated neuroendocrine tumor. Despite PPIs have a well- established safety profile, concerns have been raised about a potential relationship between PPI- induced hypergastrinemia and the development of neuroendocrine tumors.
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26
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Verma S, Dubey H, Gupta S, Ranjan A, Goel H, Sharma A. Neuroendocrine carcinoma of cervix and review literature. Int J Surg Case Rep 2023; 105:107982. [PMID: 36948055 PMCID: PMC10040689 DOI: 10.1016/j.ijscr.2023.107982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/01/2023] [Accepted: 03/11/2023] [Indexed: 03/24/2023] Open
Abstract
INTRODUCTION Neuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer with poor prognosis and high mortality. Recurrence is seen with multi-organ metastasis including liver. CASE PRESENTATION A 65 year old female presented with vaginal bleeding for the past one year. Cervical cancer screening and biopsy demonstrated poorly differentiated squamous carcinoma. Immunohistochemistry showed positive expression of chromogranin, synaptophysin, pancytokeratin, TTP1, and CEA and negative expression of p40 and estrogen receptors. An adenocarcinoma with neuroendocrine tumor was suggested. Hysterectomy with bilateral salpingo-oophrectomy was performed. This was followed by carboplatin and etoposide therapy to have clinical remission for a year. Then recurrence was observed to start same drugs again resulting in to partial improvement. It was followed by radiotherapy. The patient succumbed to death approximately after three months. CONCLUSION A metastatic lesion in liver may be a case of Neuroendocrine tumor of cervix, a rare condition that can be easily missed on histopathological examination. More studies are required to establish a standard therapeutic protocol.
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Affiliation(s)
- Saransh Verma
- All India Institute of Medical Sciences, Delhi, India.
| | - Harshita Dubey
- Dr. B.R.A. Institute - Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
| | - Swati Gupta
- Dr. B.R.A. Institute - Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
| | - Amar Ranjan
- Dr. B.R.A. Institute - Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
| | - Harsh Goel
- Dr. B.R.A. Institute - Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
| | - Anil Sharma
- All India Institute of Medical Sciences, Delhi, India.
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27
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Xu P, Wu D, Liu X. A proposed grading scheme for predicting recurrence in medullary thyroid cancer based on the Ki67 index and metastatic lymph node ratio. Endocrine 2023:10.1007/s12020-023-03328-4. [PMID: 36823341 DOI: 10.1007/s12020-023-03328-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 02/10/2023] [Indexed: 02/25/2023]
Abstract
PURPOSE The Ki67 index and lymph node ratio (LNR) have been proposed as components of alternative pathological classification schemes, but the most appropriate classification for patients with medullary thyroid cancer (MTC) remains unknown. The aim of the present study was to examine the usefulness of a new grading system combining the Ki67 index and LNR as a predictor of prognostic and disease-free survival (DFS) in MTC. METHODS We conducted a retrospective study of patients with MTC who were registered at Sun Yat-sen University Cancer Center, Guangzhou, P. R. China from June 2003 to October 2021. The DFS rates were assessed using risk-adjusted Cox proportional hazard regression modeling to explore the relationship among pathological features, nutritional status and DFS. The Ki67 index (cutoff value: 5% and 10%) and LNR (cutoff value: 0.2 and 0.3) were combined to create a new grading system. RESULTS In total, 101 matched patients were assessed. The integrated grading system showed better separation of Kaplan Meier (KM) curves for DFS. As the grading stage progressed, there was a significant stepwise decrease in DFS, which was better than Ki67, LNR and N staging alone. According to the grading system, the high-risk group had a worse prognosis. CONCLUSION The proposed grading scheme demonstrated a better prognostic performance in MTC patients than the Ki67, LNR and N staging alone. However, larger scale studies are needed to further verify our findings.
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Affiliation(s)
- Pengfei Xu
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, PR China
- State Key Laboratory of Oncology in South China, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, PR China
- Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, PR China
| | - Di Wu
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, PR China
- State Key Laboratory of Oncology in South China, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, PR China
- Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, PR China
| | - Xuekui Liu
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, PR China.
- State Key Laboratory of Oncology in South China, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, PR China.
- Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, PR China.
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28
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Stiefel R, Lehmann K, Winder T, Siebenhüner AR. What have we learnt from the past - would treatment decisions for GEP-NET patients differ between 2012 to 2016 by the new recommendations in 2022? BMC Cancer 2023; 23:148. [PMID: 36782152 PMCID: PMC9926660 DOI: 10.1186/s12885-023-10567-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 01/19/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors with a broad range of local and systemic treatment options. Still a lack of data regarding treatment sequences exists. The aim of this study was to analyse outcomes in GEP-NETs depending on stage and treatment steps and compare our treatment decisions to the latest treatment recommendations of European Society of Medical Oncology (ESMO) 2020 for GEP-NETs. METHODS Patients were included in this retrospective single-center analysis from 2012-2016. All patients suffering from a GEP-NET, who were screened, treated or evaluated at ENETS Center in Zurich, Switzerland were included in analysis. Patients with any other diagnosis of NET were not included. We used Kaplan Meier estimator as well as Cox regression to compare survival rates between different sites of localization, grades or stages and treatment sequences. RESULTS Overall, we identified 256 GEP-NETs, most in advanced stage (62%) and located in small intestine tract or pancreatic gland. Survival depended on stage, grade, primary site and duration of response for the early systemic treatment. On average patients underwent 2.6 different treatment modalities, mostly depending on stage and higher tumor grade. Surgery was performed early but also in advanced stages, usually followed by Somatostatine-Agonist modalities. In distant disease (Stage IV), we investigated a positive effect of PFS after treatment with Somatostatine Analogues (SSA) (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.21 - 0.97; p = 0.04) and systemic treatment (HR, 0.51; 95% CI, 0.26 - 0.99; p = 0.047) if patients underwent prior surgery or endoscopic resection. Kaplan Meier distributions predict shorter OS in distant disease (Stage IV), (Figure. 1; HR, 2.06; 95% CI, 1.46 - 2.89; log-rank test, p < 0.001). CONCLUSION This retrospective analysis presents a great overview of all patients', disease and treatment characteristics of GEP-NETs at ENETS Center in Zurich, Switzerland. We illustrated survival (PFS) depending on implemented therapies. According to these findings, we formed a suggested treatment algorithm for advanced GEP-NETs, which does not differ from the latest treatment recommendation by ESMO guidelines for GEP-NETs. The results of this project may define GEP-NET patients' selection for upcoming clinical prospective studies.
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Affiliation(s)
- Rahel Stiefel
- grid.414526.00000 0004 0518 665XMedical Oncology and Hematology, Triemli Hospital Zurich, Zurich, Switzerland
| | - Kuno Lehmann
- grid.7400.30000 0004 1937 0650Department of Surgery and Transplantation, University Hospital and University of Zurich, Zurich, Switzerland
| | - Thomas Winder
- grid.413250.10000 0000 9585 4754Internal Medicine II, Hematology, Oncology and Gastroenterology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria ,grid.7400.30000 0004 1937 0650University of Zurich, Zurich, Switzerland
| | - Alexander R. Siebenhüner
- grid.7400.30000 0004 1937 0650Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland ,Clinic of Internal Medicine and Oncology, Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland
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Gheorghișan-Gălățeanu AA, Ilieșiu A, Lambrescu IM, Țăpoi DA. The Complex Histopathological and Immunohistochemical Spectrum of Neuroendocrine Tumors-An Overview of the Latest Classifications. Int J Mol Sci 2023; 24:1418. [PMID: 36674939 PMCID: PMC9863618 DOI: 10.3390/ijms24021418] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/05/2023] [Accepted: 01/08/2023] [Indexed: 01/12/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) originate from the neuroendocrine cell system, which may either take the shape of organoid cell aggregations or be composed of dispersed cells across various organs. Therefore, these tumors are heterogenous regarding the site of origin, functional status, degree of aggressiveness, and prognosis. When treating patients with neuroendocrine tumors, one of the most significant challenges for physicians is determining the correct tumor grade and thus classifying patients into risk categories. Over the years, the classification of these tumors has changed significantly, often causing confusion due to clinical, molecular, and immunohistochemical variability. This review aims to outline the latest NENs classifications regardless of their site of origin. Thus, an overview of the key histopathological and immunohistochemical characteristics of NENs could pave the way to validate possible predictive and prognostic markers and also guide the therapeutic conduct.
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Affiliation(s)
- Ancuța-Augustina Gheorghișan-Gălățeanu
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- C.I. Parhon National Institute of Endocrinology, 011863 Bucharest, Romania
| | - Andreea Ilieșiu
- Department of Pathology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Pathology, University Emergency Hospital, 050098 Bucharest, Romania
| | - Ioana Maria Lambrescu
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania
| | - Dana Antonia Țăpoi
- Department of Pathology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Pathology, University Emergency Hospital, 050098 Bucharest, Romania
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Kahraman S, Bardakci M, Aykan MB, Yasar S, Erol C, Hizal M, Akinci MB, Kos FT, Kos T, Dede DS, Karadurmus N, Yalcin S, Sendur MAN, Yalcin B. Clinicopathological and survival features of neuroendocrine tumors: A retrospective analysis of 153 cases, our current remarks on a heterogeneous tumor group, and still unmet future expectations. J Cancer Res Ther 2023; 19:347-354. [PMID: 37006071 DOI: 10.4103/jcrt.jcrt_353_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023]
Abstract
Objective Neuroendocrine neoplasms (NENs) originate from the diffuse neuroendocrine cell system and constitute a heterogeneous group of tumors exhibiting diverse clinical and biological characteristics. NENs include well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). In the present study, we performed a retrospective analysis of patients diagnosed with NET to evaluate clinicopathological characteristics, treatment and outcomes. Material and Methods Data from 153 patients diagnosed with NET who were treated and followed up at three tertiary care centers from November 2002 to June 2021 were retrospectively evaluated. Clinicopathological and prognostic factors, treatment modalities and survival data were analyzed. Kaplan-Meier analysis was used to assess survival data and comparisons were performed using the logrank test. Results Median age (IQR) was 53 (18-80) years. 85.6% of the patients had gastro-entero-pancreatic (GEP)-NET. The primary tumor was resected in 95 patients (62.1%) and metastasectomy were performed in 22 patients (14.4%). Seventy-eight patients received systemic therapy for metastatic disease. Patients were followed up for a median of 22 (IQR = 33.8) months. The estimated one-year and three-year survival rate was 89.8% and 74.4%, respectively. Median progression-free survival (PFS) were 10.1, 8.5, and 4.2 months after first-, second- and third-line therapy, respectively. Conclusion The number of systemic treatment options and diagnostic tools for NETs has significantly improved in the last few years. NET classification, which treatment will be more appropriate for which group of patients, the molecular basis of this disease and the development of treatment strategies are open-ended questions that still need to be investigated.
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Affiliation(s)
- Seda Kahraman
- Department of Medical Oncology, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey
| | - Murat Bardakci
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Musa B Aykan
- Gülhane Training and Research Hospital, Ankara, Turkey
| | - Serkan Yasar
- Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Cihan Erol
- Department of Medical Oncology, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey
| | - Mutlu Hizal
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - M Bulent Akinci
- Department of Medical Oncology, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey
| | - Fahriye Tugba Kos
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Tugba Kos
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Didem S Dede
- Department of Medical Oncology, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey
| | - Nuri Karadurmus
- Department of Medical Oncology, Gulhane Education and Research Hospital, Ankara, Turkey
| | - Suayib Yalcin
- Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Mehmet Ali Nahit Sendur
- Department of Medical Oncology, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey
| | - Bulent Yalcin
- Department of Medical Oncology, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey
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Veenstra EB, Noordzij W, Erba PA. Neuroendocrine Neoplasm Imaging and Image-Guided Therapies. MULTIMODALITY IMAGING AND INTERVENTION IN ONCOLOGY 2023:419-439. [DOI: 10.1007/978-3-031-28524-0_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Mori M, Palumbo D, Muffatti F, Partelli S, Mushtaq J, Andreasi V, Prato F, Ubeira MG, Palazzo G, Falconi M, Fiorino C, De Cobelli F. Prediction of the characteristics of aggressiveness of pancreatic neuroendocrine neoplasms (PanNENs) based on CT radiomic features. Eur Radiol 2022; 33:4412-4421. [PMID: 36547673 DOI: 10.1007/s00330-022-09351-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/13/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES To predict tumor grade (G1 vs. G2/3), presence of distant metastasis (M+), metastatic lymph nodes (N+), and microvascular invasion (VI) of pancreatic neuroendocrine neoplasms (PanNEN) based on preoperative CT radiomic features (RFs), by applying a machine learning approach aimed to limit overfit. METHODS This retrospective study included 101 patients who underwent surgery for PanNEN; the entire population was split into training (n = 70) and validation cohort (n = 31). Based on a previously validated methodology, after tumor segmentation on contrast-enhanced CT, RFs were extracted from unenhanced CT images. In addition, conventional radiological and clinical features were combined with RFs into multivariate logistic regression models using minimum redundancy and a bootstrap-based machine learning approach. For each endpoint, models were trained and validated including only RFs (RF_model), and both (radiomic and clinicoradiological) features (COMB_model). RESULTS Twenty-five patients had G2/G3 tumor, 37 N+, and 14 M+ and 38 were shown to have VI. From a total of 182 RFs initially extracted, few independent radiomic and clinicoradiological features were identified. For M+ and G, the resulting models showed moderate to high performances: areas under the curve (AUC) for training/validation cohorts were 0.85/0.77 (RF_model) and 0.81/0.81 (COMB_model) for M+ and 0.67/0.72 and 0.68/0.70 for G. Concerning N+ and VI, only the COMB_model could be built, with poorer performance for N+ (AUC = 0.72/0.61) compared to VI (0.82/0.75). For all endpoints, the negative predictive value was good (≥ 0.75). CONCLUSIONS Combining few radiomic and clinicoradiological features resulted in presurgical prediction of histological characteristics of PanNENs. Despite the limited risk of overfit, external validations are warranted. KEY POINTS • Histology is the only tool currently available allowing characterization of PanNEN biological characteristics important for prognostic assessment; significant limitations to this approach exist. • Based upon preoperative contrast-enhanced CT images, a machine learning approach optimized to favor models' generalizability was successfully applied to train predictive models for tumor grading (G1 vs. G2/3), microvascular invasion, metastatic lymph nodes, and distant metastatic spread. • Moderate to high discriminative models (AUC: 0.67-0.85) based on few parameters (≤ 3) showing high negative predictive value (0.75-0.98) were generated and then successfully validated.
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Veenstra EB, Brouwers AH, de Groot DJA, Hofland J, Walenkamp AME, Brabander T, Zandee WT, Noordzij W. Comparison of [18F]DOPA and [68Ga]DOTA-TOC as a PET imaging tracer before peptide receptor radionuclide therapy. Eur J Hybrid Imaging 2022; 6:12. [PMID: 35701566 PMCID: PMC9198185 DOI: 10.1186/s41824-022-00133-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 03/23/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
In treatment of neuroendocrine neoplasms (NENs), confirmation of somatostatin receptor expression with 68Ga-DOTA somatostatin analogues is mandatory to determine eligibility for peptide receptor radionuclide therapy (PRRT). [18F]DOPA can detect additional lesions compared to [68Ga]DOTA-TOC. The aim of this study was to explore differences in tumour detection of both tracers and their relevance for selecting patients for PRRT. We retrospectively studied eight patients with NENs who underwent both [68Ga]DOTA-TOC and carbidopa-enhanced [18F]DOPA PET/CT, before first-time PRRT with [177Lu]DOTA-TATE. Tracer order was influenced due to stock availability or to detect suspected metastases with a second tracer. On CT, disease control was defined as a lesion showing complete response, partial response, or stable disease, according to RECIST 1.1. criteria.
Results
Seven patients with in total 89 lesions completed four infusions of 7.4 GBq [177Lu]DOTA-TATE, one patient received only two cycles. Before treatment, [18F]DOPA PET/CT detected significantly more lesions than [68Ga]DOTA-TOC PET/CT (79 vs. 62, p < .001). After treatment, no difference in number of lesions with disease control was found for [18F]DOPA-only (5/27) and [68Ga]DOTA-TOC-only lesions (4/10, p = .25). [18F]DOPA detected more liver metastases (24/27) compared to [68Ga]DOTA-TOC (7/10, p = .006). Six patients showed inpatient heterogeneity in treatment response between [18F]DOPA-only and [68Ga]DOTA-TOC-only lesions.
Conclusions
Response to PRRT with [177Lu]DOTA-TATE was comparable for both [68Ga]DOTA-TOC- and [18F]DOPA-only NEN lesions. [18F]DOPA may be capable of predicting response to PRRT while finding more lesions compared to [68Ga]DOTA-TOC, although these additional lesions are often small of size and undetected by diagnostic CT.
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Urso L, Nieri A, Rambaldi I, Castello A, Uccelli L, Cittanti C, Panareo S, Gagliardi I, Ambrosio MR, Zatelli MC, Bartolomei M. Radioligand therapy (RLT) as neoadjuvant treatment for inoperable pancreatic neuroendocrine tumors: a literature review. Endocrine 2022; 78:255-261. [PMID: 36018539 PMCID: PMC9585010 DOI: 10.1007/s12020-022-03170-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/08/2022] [Indexed: 01/09/2023]
Abstract
In the last 10 years, several literature reports supported radioligand therapy (RLT) in neoadjuvant settings for pancreatic neuroendocrine tumors (PanNETs). Indeed, primary tumor shrinkage has been frequently reported following RLT in unresectable or borderline resectable PanNETs. Moreover, RLT-induced intratumoral modifications facilitate surgery, both on primary tumor and metastasis, having a great impact on progression free survival (PFS), overall survival (OS) and quality of life (QoL). However, prospective controlled investigations are necessary to confirm preliminary data and to define the best RLT scheme and the ideal patient that, in a multidisciplinary approach, should be referred to neoadjuvant RLT.
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Affiliation(s)
- Luca Urso
- Nuclear Medicine Unit, Department of Oncology and Specialist Medicines, University Hospital of Ferrara, Ferrara, Italy
- Translational Medicine Department, Ferrara University, Via L. Borsari, 46, 44121, Ferrara, Italy
| | - Alberto Nieri
- Nuclear Medicine Unit, Department of Oncology and Specialist Medicines, University Hospital of Ferrara, Ferrara, Italy
| | - Ilaria Rambaldi
- Nuclear Medicine Unit, Department of Oncology and Specialist Medicines, University Hospital of Ferrara, Ferrara, Italy
| | - Angelo Castello
- Department of Nuclear Medicine, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Licia Uccelli
- Nuclear Medicine Unit, Department of Oncology and Specialist Medicines, University Hospital of Ferrara, Ferrara, Italy
- Translational Medicine Department, Ferrara University, Via L. Borsari, 46, 44121, Ferrara, Italy
| | - Corrado Cittanti
- Nuclear Medicine Unit, Department of Oncology and Specialist Medicines, University Hospital of Ferrara, Ferrara, Italy
- Translational Medicine Department, Ferrara University, Via L. Borsari, 46, 44121, Ferrara, Italy
| | - Stefano Panareo
- Nuclear Medicine Unit, Oncology and Haematology Department, University Hospital of Modena, Modena, Italy
| | - Irene Gagliardi
- Section of Endocrinology, Geriatric and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Maria Rosaria Ambrosio
- Section of Endocrinology, Geriatric and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Maria Chiara Zatelli
- Section of Endocrinology, Geriatric and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
| | - Mirco Bartolomei
- Nuclear Medicine Unit, Department of Oncology and Specialist Medicines, University Hospital of Ferrara, Ferrara, Italy
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Surgery, Liver Directed Therapy and Peptide Receptor Radionuclide Therapy for Pancreatic Neuroendocrine Tumor Liver Metastases. Cancers (Basel) 2022; 14:cancers14205103. [PMID: 36291892 PMCID: PMC9599940 DOI: 10.3390/cancers14205103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/19/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are described by the World Health Organization (WHO) classification by grade (1–3) and degree of differentiation. Grade 1 and 2; well differentiated PNETs are often characterized as relatively “indolent” tumors for which locoregional therapies have been shown to be effective for palliation of symptom control and prolongation of survival even in the setting of advanced disease. The treatment of liver metastases includes surgical and non-surgical modalities with varying degrees of invasiveness; efficacy; and risk. Most of these modalities have not been prospectively compared. This paper reviews literature that has been published on treatment of pancreatic neuroendocrine liver metastases using surgery; liver directed embolization and peptide receptor radionuclide therapy (PRRT). Surgery is associated with the longest survival in patients with resectable disease burden. Liver-directed (hepatic artery) therapies can sometimes convert patients with borderline disease into candidates for surgery. Among the three embolization modalities; the preponderance of data suggests chemoembolization offers superior radiographic response compared to bland embolization and radioembolization; but all have similar survival. PRRT was initially approved as salvage therapy in patients with advanced disease that was not amenable to resection or embolization; though the role of PRRT is evolving rapidly
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Treatment Assessment of pNET and NELM after Everolimus by Quantitative MRI Parameters. Biomedicines 2022; 10:biomedicines10102618. [PMID: 36289880 PMCID: PMC9599819 DOI: 10.3390/biomedicines10102618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/01/2022] [Accepted: 10/11/2022] [Indexed: 11/17/2022] Open
Abstract
Assessment of treatment response to targeted therapies such as everolimus is difficult, especially in slow-growing tumors such as NETs. In this retrospective study, 17 patients with pancreatic neuroendocrine tumors (pNETs) and hepatic metastases (NELMs) (42 target lesions) who received everolimus were analyzed. Intralesional signal intensities (SI) of non-contrast T1w, T2w and DCE imaging, and apparent diffusion coefficients (ADCmean and ADCmin) of DWI, were measured on baseline and first follow-up MRI after everolimus initiation. Response assessment was categorized according to progression-free survival (PFS), with responders (R) showing a PFS of ≥11 months. ADCmin of NELMs decreased in Rs whereas it increased in non-responders (NR). Percentual changes of ADCmin and ADCmean differed significantly between response groups (p < 0.03). By contrast, ADC of the pNETs tended to increase in Rs, while there was no change in NRs. Tumor-to-liver (T/L) ratio of T1 SI of NELMs increased in Rs and decreased in NRs, and percentual changes differed significantly between response groups (p < 0.02). T1 SI of the pNETs tended to decrease in Rs and increase in Ns. The quotient of pretherapeutic and posttherapeutic ADCmin values (DADCmin) and length of everolimus treatment showed significant association with PFS in univariable Cox analysis. In conclusion, quantitative MRI, especially DWI, seems to allow treatment assessment of pNETs with NELMs under everolimus. Interestingly, the responding NELMs showed decreasing ADC values, and there might be an opposite effect on ADC and T1 SI between NELMs and pNETs.
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La Salvia A, Carletti R, Verrico M, Feola T, Puliani G, Bassi M, Sesti F, Pernazza A, Mazzilli R, Lamberti G, Siciliani A, Mancini M, Manai C, Venuta F, Ibrahim M, Tomao S, D’Amati G, Di Gioia C, Giannetta E, Cappuzzo F, Faggiano A. Angioside: The role of Angiogenesis and Hypoxia in Lung Neuroendocrine Tumours According to Primary Tumour Location in Left or Right Parenchyma. J Clin Med 2022; 11:5958. [PMID: 36233825 PMCID: PMC9570740 DOI: 10.3390/jcm11195958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 11/05/2022] Open
Abstract
Well-differentiated lung neuroendocrine tumours (Lu-NETs), classified as typical (TC) and atypical (AC) carcinoids, represent 30% of NETs. Angiogenesis plays an essential role in NET development and progression. A higher vascular network is a marker of differentiation, with positive prognostic implications. Materials and Methods: We retrospectively evaluated microvessel density (MVD) by CD34 immunohistochemical (IHC) staining and hypoxia by IHC staining for Hypoxia-inducible factor 1α (HIF-1α), comparing right- and left-lung parenchyma in 53 lung NETs. Results: The median age was 66 years (39−81), 56.6% males, 24.5% AC, 40.5% left-sided tumours and 69.8% TNM stage I. The mitotic count was <2/10 per 10 HPF in 79.2%, and the absence of necrosis in 81.1%, 39.6% with Ki67, was ≤2%. The MVD, the number of vessels and the average vessel area median values were significantly higher in the right than the left parenchyma (p: 0.025, p: 0.019, p: 0.016, respectively). Hypoxia resulted present in 14/19 (73.6%) left tumours and in 10/20 (50%) right tumours in the parenchyma (p: 0.129). Conclusions: This study suggests a biological rationale for a different angiogenesis and hypoxia according to the Lu-NETs’ location. In our study, left primary tumours were less vascularized and most likely to present hypoxia than right primary tumours. This finding could have potentially useful prognostic and predictive implications for Lu-NETs.
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Affiliation(s)
- Anna La Salvia
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Raffaella Carletti
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Monica Verrico
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Tiziana Feola
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
- Neuroendocrinology, Neuromed Institute, IRCCS, 86077 Pozzilli, Italy
| | - Giulia Puliani
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
- Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Massimiliano Bassi
- Department of Thoracic Surgery, Policlinico Umberto I, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Franz Sesti
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Angelina Pernazza
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Rossella Mazzilli
- Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, 00185 Rome, Italy
| | - Giuseppe Lamberti
- Department of Specialized, Experimental and Diagnostic Medicine, S. Orsola-Malpighi Hospital, University of Bologna, 40126 Bologna, Italy
| | - Alessandra Siciliani
- Department of Thoracic Surgery, Sant’Andrea Hospital, Sapienza University of Rome, 00185 Rome, Italy
| | - Massimiliano Mancini
- Division of Morphologic and Molecular Sant’Andrea Hospital, Sapienza University of Rome, 00185 Rome, Italy
| | - Chiara Manai
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Federico Venuta
- Department of Thoracic Surgery, Policlinico Umberto I, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Mohsen Ibrahim
- Department of Thoracic Surgery, Sant’Andrea Hospital, Sapienza University of Rome, 00185 Rome, Italy
| | - Silverio Tomao
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Giulia D’Amati
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Cira Di Gioia
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Elisa Giannetta
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Federico Cappuzzo
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Antongiulio Faggiano
- Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, 00185 Rome, Italy
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Wu Z, Qiu X, Zhi Y, Shi X, Lv G. The risk and prognostic factors for G1 pancreatic neuroendocrine tumors: A retrospective analysis of the SEER database. Front Oncol 2022; 12:993524. [PMID: 36276109 PMCID: PMC9582835 DOI: 10.3389/fonc.2022.993524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 09/16/2022] [Indexed: 11/13/2022] Open
Abstract
Background Pancreatic neuroendocrine tumors (pNETs) are rare neuroendocrine neoplasms (NENs) for which little is known about their clinical features, treatment options, and survival prognosis. The purpose of this study is to evaluate the risk factors affecting the overall survival (OS) and cancer-specific survival (CSS) in patients with grade 1 pNETs (G1 pNETs) and to provide a new theoretical basis for clinical diagnosis and treatment. Methods A retrospective analysis of individuals with G1 pNETs registered in the Surveillance, Epidemiology, End Results (SEER) database was performed. Risk factors affecting OS and CSS were analyzed using Kaplan-Meier analysis, Cox proportional hazards model, and Fine-Gray competing-risk model. Results A total of 751 patients were included, most of whom were white (77.2%) women (53.9%) under the age of 60 years (54.9%), of whom 66 died of pNETs (8.78%) and 34 died of other causes (4.52%). Patients who were older than 60 years at diagnosis (hazard ratio [HR] = 1.866, 95% confidence interval [CI]: 1.242-2.805) had worse OS. And stage in the regional extent (HR = 1.777, 95% CI: 1.006-3.137) or distance extent (HR = 4.540, 95% CI: 2.439-8.453) had worse OS. Patients who delayed treatment after diagnosis had shorter CSS (delayed treatment < 1 month: HR = 1.933, 95% CI: 0.863-4.333; delayed treatment ≥ 1 month: HR = 2.208; 95% CI:1.047-4.654). Patients with lymph node metastasis (HR = 1.989, 95% CI: 1.137-3.479) or distant metastasis (HR = 5.625, 95% CI: 1.892-16.726) had worse CSS. Acceptance of surgery can significantly improve the patient’s OS and CSS. OS (partial pancreatectomy [PP]: HR = 0.350, 95% CI: 0.182-0.672; pancreatectomy and duodenectomy [PD]: HR = 0.426, 95% CI: 0.222-0.815; total pancreatectomy [TP]: HR = 0.495, 95% CI: 0.193-1.267). CSS(PP: HR = 0.148, 95% CI: 0.0054-0.401; PD: HR = 0.332, 95% CI: 0.150-0.730; TP: HR = 0.69, 95% CI: 0.254-1.872). Conclusion Age and stage were identified as independent risk factors for OS. Delayed treatment, N stage and M stage were independent risk factors for CSS. Only surgery was identified as independent protective factors for OS and CSS.
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Pang S, Zong Y, Zhang K, Zhao H, Wang Y, Wang J, Liu C, Wu Y, Li P. Multiple rectal neuroendocrine tumors: An analysis of 15 cases and literature review. Front Oncol 2022; 12:996306. [PMID: 36185313 PMCID: PMC9515498 DOI: 10.3389/fonc.2022.996306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 08/24/2022] [Indexed: 12/07/2022] Open
Abstract
Multiple neuroendocrine tumors (M-NETs) are rare in the rectum and there is no consensus on their characteristics and treatments. Here, we report 15 cases of rectal M-NETs and review the previous literature. We discuss the clinical characteristics, endoscopic features and pathological features of rectal M-NETs, aiming to analyze the treatments and follow-up strategies in combination with these characteristics. We retrospectively reviewed and analyzed the data of 15 patients with rectal M-NETs who were diagnosed and treated at Beijing Friendship Hospital, Capital Medical University. Their clinical data, endoscopic findings, pathological features and treatments were analyzed. Follow-up evaluations and literature review were performed. In all, 14 male (93.3%) and 1 female (6.7%) were recruited. The average age at diagnosis was 55.7 years. The clinical manifestations include asymptomatic in 9 patients (60.0%), defecation habits changes in 2 patients (13.3%), anal distension in 2 patients (13.3%), and abdominal distension in 2 patient (13.3%). The largest tumor diameter ≤10mm was found in 13 patients (86.7%) and >10mm in 2 patients (13.3%). All of the lesions originated from the mucous or submucosa layer. WHO grades were all NET G1. The number of tumors diagnosed by pathology in 13 patients was consistent with that observed by endoscopy, while more lesions were observed by pathology than endoscopy in two patients. Lymph node metastasis occurred in 1 patient (6.7%), and vascular or lymphatic invasion occurred in 9 patients (60.0%). Among the 13 patients with the largest tumor diameter being ≤10mm, lymphovascular invasion occurred in 8 patients (61.5%). And among the 2 patients with the largest tumor diameter of >10mm, lymphovascular invasion occurred in 1 patient (50.0%). 14 patients underwent endoscopic resection and 1 underwent surgical excision. Postoperative follow-up was achieved in 13 patients and no recurrence or metastasis was found. The true number of rectal M-NETs may be more than seen under endoscopy. Rectal M-NETs is associated with a high risk of metastasis; therefore, treatment and surveillance strategies should be more radical than single lesion.
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Affiliation(s)
- Shu Pang
- Department of General Practice, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ye Zong
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Kun Zhang
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Haiying Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yongjun Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Junxiong Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Chuntao Liu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yongdong Wu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- *Correspondence: Yongdong Wu, ; Peng Li,
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- *Correspondence: Yongdong Wu, ; Peng Li,
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Clinicopathological Features and Postoperative Survival Analysis of Gastric Carcinoma with Neuroendocrine Differentiation. JOURNAL OF ONCOLOGY 2022; 2022:4440098. [PMID: 36035314 PMCID: PMC9402359 DOI: 10.1155/2022/4440098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 07/05/2022] [Indexed: 11/17/2022]
Abstract
Objectives This study aims at investigating the differences of clinicopathological features and postoperative prognosis in three different types of neuroendocrine differentiation-related gastric cancers. Methods From January 1, 2015 to September 30, 2016, 47 patients diagnosed with neuroendocrine differentiation-related gastric cancers were collected from 1095 patients with gastric cancer who underwent surgical treatment in the Department of Gastrointestinal Surgery, Jiangsu Cancer Hospital. Patients were followed up regularly, and the last follow-up time was October 25, 2021. A total of 38 cases met the inclusion criteria and completed follow-up. The clinicopathological characters and immunohistochemical results of these three special pathological types of gastric cancer (adenocarcinoma with neuroendocrine differentiation, mixed adenoneuroendocrine carcinoma, and neuroendocrine carcinoma of the stomach) patients were compared. Tissues from these patients were tested with immunohistochemical markers synaptophysin (Syn), chromogranin A (CgA), and Ki-67. The Kaplan–Meier method and log-rank test were used to analyze the effect of different histological types of gastric cancer on overall survival (OS). The differences in positive rates of chromogranin A (CgA) and Ki-67 were analyzed by univariate Cox regression analysis as independent risk factors that may affect the survival of gastric cancer patients. Results Ki-67 and N staging were significantly correlated with OS in gastric cancer patients and were independent prognostic factors affecting the survival of gastric cancer patients. There was no statistical difference in OS between the two histopathological types (adenocarcinoma with neuroendocrine differentiation and mixed adenoneuroendocrine carcinoma) of gastric cancer patients. There were no significant differences in the positive rates of immunohistochemical markers Syn, CgA, and Ki-67 in gastric cancer patients with different histological types. Conclusion The combined detection of Syn and CgA is of great value for the diagnosis of neuroendocrine differentiation-related gastric cancers, Ki-67 is of significance for the prognosis prediction of neuroendocrine differentiation-related gastric cancers, regional lymph node metastasis has a great impact on tumor prognosis, and the N staging determines the necessity of postoperative adjuvant chemotherapy for patients with neuroendocrine differentiation-related gastric cancer.
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Wei D, Xin Y, Rong Y, Hao Y. Correlation between the Expression of VEGF and Ki67 and Lymph Node Metastasis in Non-small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:9693746. [PMID: 35800006 PMCID: PMC9256412 DOI: 10.1155/2022/9693746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 05/27/2022] [Accepted: 05/30/2022] [Indexed: 11/18/2022]
Abstract
Background Lymph node metastasis is the most common and important way of metastasis in NSCLC and is also the most important factor affecting lung cancer stage and prognosis. It is very important to analyze the relationship between the expression of vascular endothelial growth factor (VEGF) and Ki67 and lymph node metastasis (LNM) in non-small-cell lung cancer (NSCLC). Methods We searched the PubMed, EMBASE, and Cochrane Library and conducted meta-analyses using the R meta-package. Relative risk (RR) with a 95% confidence interval (95% CI) was the main indicator. Results Totally, 18 studies were considered eligible, with 4521 patients, including 1518 LNM-positive patients and 3033 LNM-negative patients. The incidence of LNM in Ki67-negative patients was lower than that in Ki67-positive patients (RR = 0.66, 95% CI: 0.44, 0.98). The incidence of LNM in VEGF-A-negative patients was lower than that in VEGF-A-positive patients (RR = 0.64, 95% CI: 0.49, 0.83). The incidence of LNM in VEGF-C negative patients was lower than that in VEGF-C positive patients (RR = 0.68, 95% CI: 0.53, 0.88). The incidence of LNM in VEGF-D negative and positive patients were of no significant differences (RR = 0.84, 95% CI: 0.61, 1.14). Conclusion The high expression of Ki67, VEGF-A, and VEGF-C significantly increases the risk of lymph node metastasis in NSCLC, while the VEGF-D expression has no correlation with lymph node metastasis. The expression levels of Ki67, VEGF-A, and VEGF-C show a good potential for lymph node metastasis prediction.
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Affiliation(s)
- Dong Wei
- Department of Thoracic Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei, China
| | - Yunchao Xin
- Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei, China
| | - Yu Rong
- Department of Thoracic Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei, China
| | - Yanbing Hao
- Department of Thoracic Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei, China
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Chen HY, Pan Y, Chen JY, Liu LL, Yang YB, Li K, Yu RS, Shao GL. Quantitative analysis of enhanced CT in differentiating well-differentiated pancreatic neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Eur Radiol 2022; 32:8317-8325. [PMID: 35759016 DOI: 10.1007/s00330-022-08891-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/02/2022] [Accepted: 05/18/2022] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To identify quantitative CT features for distinguishing well-differentiated pancreatic neuroendocrine tumors (PNETs) from poorly differentiated pancreatic neuroendocrine carcinomas (PNECs). MATERIALS AND METHODS Seventeen patients with PNECs and 131 patients with PNETs confirmed by biopsy or surgery were retrospectively included. General demographic (sex, age) and CT quantitative parameters (arterial/portal absolute enhancement, arterial/portal relative enhancement ratio, arterial/portal enhancement ratio) were collected. Univariate and multivariate logistic regression analyses were performed to confirm independent variables for differentiating PNECs from PNETs. Receiver operating characteristic (ROC) curves for each quantitative parameter were generated to determine their diagnostic ability. RESULTS PNECs had a much lower mean arterial/portal absolute enhancement value (19.5 ± 11.0 vs. 78.8 ± 47.2; 28.1 ± 15.8 vs. 77.0 ± 39.4), arterial/portal relative enhancement ratio (0.57 ± 0.36 vs. 2.03 ± 1.31; 0.80 ± 0.52 vs. 1.99 ± 1.13), and arterial/portal enhancement ratio (0.62 ± 0.27 vs. 1.22 ± 0.49; 0.74 ± 0.19 vs. 1.21 ± 0.36) than PNETs (all p < 0.001). After multivariable analysis, arterial absolute enhancement (odds ratio [OR]: 0.96, 95% confidence interval [CI]: 0.93, 0.99) and portal absolute enhancement (OR: 0.96, 95% CI: 0.92, 0.99) were independent factors for differentiating PNECs from PNETs. For each quantitative parameter, arterial lesion enhancement yielded the highest diagnostic performance, with an area under the curve (AUC) of 0.922 (95% CI: 0.867-0.960), followed by portal absolute enhancement. CONCLUSIONS Arterial/portal absolute enhancements were independent predictors with good diagnostic accuracy for differentiating between PNETs and PNECs. Quantitative parameters of enhanced CT can distinguish PNECs from PNETs. KEY POINTS • PNECs were hypovascular and had a much lower enhanced CT attenuation in both arterial and portal phases than well-differentiated PNETs. • Quantitative parameters derived from enhanced CT can be used to distinguish PNECs from PNETs. • Arterial absolute enhancement and portal absolute enhancement were independent predictive factors for differentiating between PNETs and PNECs.
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Affiliation(s)
- Hai-Yan Chen
- Department of Radiology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China.,Institue of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, 310018, China
| | - Yao Pan
- Department of Radiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88#, Hangzhou, 310009, China
| | - Jie-Yu Chen
- Department of Radiology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China.,Institue of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, 310018, China
| | - Lu-Lu Liu
- Department of Radiology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China.,Institue of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, 310018, China
| | - Yong-Bo Yang
- Department of Radiology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China.,Institue of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, 310018, China
| | - Kai Li
- Department of Radiology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China.,Institue of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, 310018, China
| | - Ri-Sheng Yu
- Department of Radiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88#, Hangzhou, 310009, China.
| | - Guo-Liang Shao
- Institue of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, 310018, China. .,Department of Interventional Radiology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China. .,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Qingchun Road 79#, Hangzhou, 310006, China.
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Surgical Outcomes and Prognostic Factors of G3 Pancreatic Neuroendocrine Carcinomas: A Consecutive Analysis Based on Previous Study Results. J Clin Med 2022; 11:jcm11113176. [PMID: 35683561 PMCID: PMC9181221 DOI: 10.3390/jcm11113176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/16/2022] [Accepted: 05/25/2022] [Indexed: 02/05/2023] Open
Abstract
In 2017, the World Health Organization (WHO) officially defined pancreatic neuroendocrine neoplasms into well-differentiated tumors, namely G1/G2/G3 pancreatic neuroendocrine tumors, and poorly differentiated carcinomas referring to G3 pancreatic neuroendocrine carcinomas (p-NECs). However, the surgical outcomes and prognostic factors of G3 p-NECs are still unclear. Methods: We retrospectively collected and analyzed the data of eligible patients with G3 p-NECs defined by the WHO 2017 grading classification. Results: We eventually identified 120 patients with G3 p-NECs, including 72 females and 48 males, with a median age of 53 y. The 3-year overall survival (OS) of G3 p-NECs by Kaplan−Meier method was 37.3%. The 3-year OS for functional G3 p-NECs was 57.4%, which was statistically longer than 23.0% of non-functional ones (p = 0.002). Patients with surgical resection presented a significantly better 3-year OS than those with palliative operation (43.3% vs. 13.1%; p < 0.001). The 3-year OS for Stage Ⅰ, Stage Ⅱ, Stage Ⅲ, and Stage Ⅳ was 87.1%, 56.5%, 12.9%, and not applicable, respectively (p < 0.001). We demonstrated in a Cox regression model that palliative operation (p = 0.013), vascular infiltration (p = 0.039), lymph node involvement (p = 0.024), and distant metastasis (p = 0.016) were independent predictors of poor outcome for patients with surgically treated G3 p-NECs. Conclusion: Our data in the present analysis indicated that patients with G3 p-NECs could significantly benefit from surgical resection. Meanwhile, vascular infiltration, lymph node involvement, and distant metastasis were independent predictors of poor outcome for these patients.
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Alkhatib HH, Maroun CA, Amin N, Zhu G, Guller M, Herberg ME, Wu ES, Seiwert TY, Rooper LM, Eisele DW, Fakhry C, Pardoll D, Mandal R. Tumor Histological Grade and Immunotherapy Response in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. JAMA Otolaryngol Head Neck Surg 2022; 148:540-546. [PMID: 35482301 PMCID: PMC9052109 DOI: 10.1001/jamaoto.2022.0640] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 03/12/2022] [Indexed: 11/14/2022]
Abstract
Importance Tumor histological factors that predict immunotherapy response in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are not well defined. Objective To investigate the association between tumor grade and immunotherapy response in patients with recurrent or metastatic mucosal HNSCC. Design, Setting, and Participants In this retrospective cohort study, the medical records of 60 patients with recurrent or metastatic mucosal HNSCC treated with immune checkpoint inhibitors at Johns Hopkins Hospital between July 1, 2015, and January 22, 2020, were reviewed. Exposures High-grade tumors (HGTs) vs low-grade tumors (LGTs) in recurrent or metastatic HNSCC. Main Outcomes and Measures Patients were divided into 2 groups: those with LGTs (well differentiated and moderately differentiated) and those with HGTs (poorly differentiated). The main outcome was a clinically beneficial immunotherapy response, defined as complete response or partial response. Univariable and multivariable logistic regressions were conducted to calculate odds ratios for each variable's association with immunotherapy response. Survival differences were evaluated using Kaplan-Meier survival curves with multivariable Cox proportional hazards regression models. Results The 60 patients (35 with HGTs and 25 with LGTs) had a mean (SD) age of 64.6 (8.88) years; 51 were male (85%); and 38 were current or former smokers (63%). The oropharynx was the most common primary tumor site both in patients with HGTs (22 of 35; 63%) and those with LGTs (12 of 25; 48%). Bivariate analysis showed the proportion of patients having a beneficial response to immunotherapy was greater for patients with HGTs (12 of 35; 34.3%) than those with LGTs (2 of 25, 8.0%) (difference, 26.3%; 95% CI, 7.3%-45.3%). Upon multivariable analysis, patients with HGTs had 5.35-fold increased odds (95% CI, 1.04-27.37) of having a clinically beneficial response to immunotherapy. Among patients with available tumor genomic profiling data, the mean tumor mutational burden was greater for patients with HGTs (mean [SD], 8.6 [5.4] mut/Mb; n = 8) than patients with LGTs (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference = 5.0 mut/Mb; 95% CI -1.4 to 11.4 mut/Mb; Cohen d = 1.2). Conclusions and Relevance In this cohort study, tumor grade was independently associated with immunotherapy response in patients with recurrent or metastatic mucosal HNSCC. These findings highlight the potential role of tumor grade in predicting immunotherapy response in mucosal HNSCC.
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Affiliation(s)
- Hosam H. Alkhatib
- Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Christopher A. Maroun
- Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Neha Amin
- Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Gangcai Zhu
- Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Meytal Guller
- Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Matthew E. Herberg
- Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Evan S. Wu
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Tanguy Y. Seiwert
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lisa M. Rooper
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - David W. Eisele
- Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Carole Fakhry
- Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Drew Pardoll
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Rajarsi Mandal
- Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medical Institutions, Baltimore, Maryland
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La Salvia A, Persano I, Siciliani A, Verrico M, Bassi M, Modica R, Audisio A, Zanata I, Trabalza Marinucci B, Trevisi E, Puliani G, Rinzivillo M, Parlagreco E, Baldelli R, Feola T, Sesti F, Razzore P, Mazzilli R, Mancini M, Panzuto F, Volante M, Giannetta E, Romero C, Appetecchia M, Isidori A, Venuta F, Ambrosio MR, Zatelli MC, Ibrahim M, Colao A, Brizzi MP, García-Carbonero R, Faggiano A. Prognostic significance of laterality in lung neuroendocrine tumors. Endocrine 2022; 76:733-746. [PMID: 35301675 PMCID: PMC9156515 DOI: 10.1007/s12020-022-03015-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 02/06/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE Well-differentiated lung neuroendocrine tumors (Lu-NET) are classified as typical (TC) and atypical (AC) carcinoids, based on mitotic counts and necrosis. However, prognostic factors, other than tumor node metastasis (TNM) stage and the histopathological diagnosis, are still lacking. The current study is aimed to identify potential prognostic factors to better stratify lung NET, thus, improving patients' treatment strategy and follow-up. METHODS A multicentric retrospective study, including 300 Lung NET, all surgically removed, from Italian and Spanish Institutions. RESULTS Median age 61 years (13-86), 37.7% were males, 25.0% were AC, 42.0% were located in the lung left parenchyma, 80.3% presented a TNM stage I-II. Mitotic count was ≥2 per 10 high-power field (HPF) in 24.7%, necrosis in 13.0%. Median overall survival (OS) was 46.1 months (0.6-323), median progression-free survival (PFS) was 36.0 months (0.3-323). Female sex correlated with a more indolent disease (T1; N0; lower Ki67; lower mitotic count and the absence of necrosis). Left-sided primary tumors were associated with higher mitotic count and necrosis. At Cox-multivariate regression model, age, left-sided tumors, nodal (N) positive status and the diagnosis of AC resulted independent negative prognostic factors for PFS and OS. CONCLUSIONS This study highlights that laterality is an independent prognostic factors in Lu-NETs, with left tumors being less frequent but showing a worse prognosis than right ones. A wider spectrum of clinical and pathological prognostic factors, including TNM stage, age and laterality is suggested. These parameters could help clinicians to personalize the management of Lu-NET.
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Affiliation(s)
- Anna La Salvia
- Department of Oncology, 12 de Octubre University Hospital, Madrid, Spain
| | - Irene Persano
- Department of Oncology, San Luigi Gonzaga Hospital, Orbassano, Italy
| | | | - Monica Verrico
- Department of Radiological, Oncological, and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Massimiliano Bassi
- Department of Thoracic Surgery, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy
| | - Roberta Modica
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | | | - Isabella Zanata
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy
| | | | - Elena Trevisi
- Department of Oncology, San Luigi Gonzaga Hospital, Orbassano, Italy
| | - Giulia Puliani
- Oncological Endocrinology Unit, Regina Elena National Cancer Institute, Rome, Italy
- Department of Experimental Medicine, "Sapienza" University of Roma, Rome, Italy
| | - Maria Rinzivillo
- Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy
| | - Elena Parlagreco
- Department of Oncology, San Luigi Gonzaga Hospital, Orbassano, Italy
| | - Roberto Baldelli
- Endocrinology Unit, Department of Oncology and Medical Specialities, A.O. San Camillo-Forlanini, Rome, Italy
| | - Tiziana Feola
- Department of Experimental Medicine, "Sapienza" University of Roma, Rome, Italy
- Neuroendocrinology, Neuromed Institute, IRCCS, Pozzilli, Italy
| | - Franz Sesti
- Department of Experimental Medicine, "Sapienza" University of Roma, Rome, Italy
| | - Paola Razzore
- Endocrinology Unit, Mauriziano Hospital, Turin, Italy
| | - Rossella Mazzilli
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, ENETS Center of Excellence, Rome, Italy
| | | | - Francesco Panzuto
- Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy
| | - Marco Volante
- Department of Oncology, Pathology Unit of San Luigi Hospital, University of Turin, Orbassano, Turin, Italy
| | - Elisa Giannetta
- Department of Experimental Medicine, "Sapienza" University of Roma, Rome, Italy
| | - Carmen Romero
- Scientific Support, 12 de Octubre University Hospital, Madrid, Spain
| | | | - Andrea Isidori
- Department of Experimental Medicine, "Sapienza" University of Roma, Rome, Italy
| | - Federico Venuta
- Department of Thoracic Surgery, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy
| | - Maria Rosaria Ambrosio
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy
| | - Maria Chiara Zatelli
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy
| | - Mohsen Ibrahim
- Department of Thoracic Surgery, Sant'Andrea University Hospital, Rome, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Maria Pia Brizzi
- Department of Oncology, San Luigi Gonzaga Hospital, Orbassano, Italy
| | | | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, ENETS Center of Excellence, Rome, Italy.
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Papaefthymiou A, Laskaratos FM, Koffas A, Manolakis A, Gkolfakis P, Coda S, Sodergren M, Suzuki N, Toumpanakis C. State of the Art in Endoscopic Therapy for the Management of Gastroenteropancreatic Neuroendocrine Tumors. Curr Treat Options Oncol 2022; 23:1014-1034. [PMID: 35511346 DOI: 10.1007/s11864-022-00986-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2022] [Indexed: 12/13/2022]
Abstract
OPINION STATEMENT Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) comprise a heterogeneous group of slow growing tumors arising from the neuroendocrine cells of the gastrointestinal (GI) tract. Although they are considered relatively rare, their incidence is rising and it is believed that the more frequent use of endoscopy and imaging studies have at least in part contributed to the increased diagnosis especially of localized neoplasms. The management of these neoplasms should be guided by a multidisciplinary NEN team following appropriate staging investigations. Localized neoplasms of the GI tract may be suitable for endoscopic therapy, while patients with pancreatic NENs, unsuitable for surgery, should be considered for endoscopic ultrasound (EUS)-guided ablation. In this review, we discuss the evidence regarding endoscopic resection of luminal NENs and EUS-guided therapy of pancreatic NENs. The efficacy, safety, and other longer-term outcomes of these techniques are summarized. In conclusion, this review of endoscopic therapies for localized NENs may be a useful guide for NEN clinicians and endoscopists who are considering these therapeutic options for the management of focal GEP NENs.
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Affiliation(s)
- Apostolis Papaefthymiou
- Department of Gastroenterology, General University Hospital of Larisa, Mezourlo, 41110, Larisa, Greece.,First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece
| | | | - Apostolos Koffas
- Department of Gastroenterology, General University Hospital of Larisa, Mezourlo, 41110, Larisa, Greece
| | - Anastasios Manolakis
- Department of Gastroenterology, General University Hospital of Larisa, Mezourlo, 41110, Larisa, Greece
| | - Paraskevas Gkolfakis
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, 1070, Brussels, Belgium
| | - Sergio Coda
- Digestive Diseases Centre, Barking Havering and Redbridge University Hospitals NHS Trust, London, UK
| | - Mikael Sodergren
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Noriko Suzuki
- Wolfson Unit for Endoscopy, St Mark's Hospital and Academic Institute, London, UK
| | - Christos Toumpanakis
- Neuroendocrine Tumour Unit (ENETS Centre of Excellence) Centre for Gastroenterology, Royal Free Hospital, London, UK
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Tsunokake J, Fujishima F, Watanabe H, Sato I, Miura K, Sakamoto K, Suzuki H, Sawai T, Itakura Y, Hoshi T, Kunimitsu A, Yamauchi T, Akaishi R, Ozawa Y, Fukutomi T, Okamoto H, Sato C, Taniyama Y, Kamei T, Sasano H. Tumor Microenvironment in Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: Interaction between Tumors and Immune Cells, and Potential Effects of Neuroendocrine Differentiation on the Tumor Microenvironment. Cancers (Basel) 2022; 14:2152. [DOI: doi.org/10.3390/cancers14092152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/03/2023] Open
Abstract
The tumor microenvironment is considered to play a pivotal role in various human malignancies. Neuroendocrine and non-neuroendocrine neoplasms are considered to have different tumor microenvironments. However, owing to differences in the systemic and/or local immune statuses, tumor microenvironments in different patients may be difficult to compare. Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs), although rare, could be useful for exploring the effects of neuroendocrine differentiation on the tumor microenvironment, because both neuroendocrine and non-neuroendocrine components are present in the same tumor. Here, we examined 33 cases of histologically confirmed MiNENs and evaluated the influence of neuroendocrine differentiation on the tumor microenvironment by comparing tumor-infiltrating lymphocytes, tumor-associated macrophages, and other relevant factors in the two components the same tumor. The immunoreactivity of those examined above was evaluated quantitatively. The values of vasohibin-1-positive density (p < 0.0001) and immunoreactivity (p < 0.0001) (representing the neoangiogenesis status) were significantly higher in neuroendocrine as compared to non-neuroendocrine areas of the same tumors. In addition, the Foxp3/CD8 (p = 0.0717) and the PD-1/CD8 ratios (p = 0.0176) (representing tumor immunity suppression) tend to increase in neuroendocrine carcinomas. Immunoreactivity of CD163, a marker of M2-like macrophages, was also higher in the neuroendocrine areas. Our findings indicate that neuroendocrine and non-neuroendocrine tumors differ from each other with respect to the characteristics of both tumor cells and the tumor microenvironment.
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Tsunokake J, Fujishima F, Watanabe H, Sato I, Miura K, Sakamoto K, Suzuki H, Sawai T, Itakura Y, Hoshi T, Kunimitsu A, Yamauchi T, Akaishi R, Ozawa Y, Fukutomi T, Okamoto H, Sato C, Taniyama Y, Kamei T, Sasano H. Tumor Microenvironment in Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: Interaction between Tumors and Immune Cells, and Potential Effects of Neuroendocrine Differentiation on the Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14092152. [PMID: 35565281 PMCID: PMC9100554 DOI: 10.3390/cancers14092152] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/16/2022] [Accepted: 04/23/2022] [Indexed: 11/16/2022] Open
Abstract
The tumor microenvironment is considered to play a pivotal role in various human malignancies. Neuroendocrine and non-neuroendocrine neoplasms are considered to have different tumor microenvironments. However, owing to differences in the systemic and/or local immune statuses, tumor microenvironments in different patients may be difficult to compare. Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs), although rare, could be useful for exploring the effects of neuroendocrine differentiation on the tumor microenvironment, because both neuroendocrine and non-neuroendocrine components are present in the same tumor. Here, we examined 33 cases of histologically confirmed MiNENs and evaluated the influence of neuroendocrine differentiation on the tumor microenvironment by comparing tumor-infiltrating lymphocytes, tumor-associated macrophages, and other relevant factors in the two components the same tumor. The immunoreactivity of those examined above was evaluated quantitatively. The values of vasohibin-1-positive density (p < 0.0001) and immunoreactivity (p < 0.0001) (representing the neoangiogenesis status) were significantly higher in neuroendocrine as compared to non-neuroendocrine areas of the same tumors. In addition, the Foxp3/CD8 (p = 0.0717) and the PD-1/CD8 ratios (p = 0.0176) (representing tumor immunity suppression) tend to increase in neuroendocrine carcinomas. Immunoreactivity of CD163, a marker of M2-like macrophages, was also higher in the neuroendocrine areas. Our findings indicate that neuroendocrine and non-neuroendocrine tumors differ from each other with respect to the characteristics of both tumor cells and the tumor microenvironment.
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Affiliation(s)
- Junichi Tsunokake
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (A.K.); (T.Y.); (R.A.); (Y.O.); (T.F.); (H.O.); (C.S.); (Y.T.); (T.K.)
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (F.F.); (H.W.); (H.S.)
- Correspondence: ; Tel.: +81-22-717-7440
| | - Fumiyoshi Fujishima
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (F.F.); (H.W.); (H.S.)
| | - Hirofumi Watanabe
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (F.F.); (H.W.); (H.S.)
| | - Ikuro Sato
- Department of Pathology, Miyagi Cancer Center, Natori 981-1293, Japan;
| | - Koh Miura
- Department of Surgery, Miyagi Cancer Center, Natori 981-1293, Japan;
| | - Kazuhiro Sakamoto
- Department of Pathology, Osaki Citizen Hospital, Osaki 989-6183, Japan;
| | - Hiroyoshi Suzuki
- Department of Pathology, Sendai Medical Center, Sendai 983-8520, Japan;
| | - Takashi Sawai
- Department of Pathology, Sendai Open Hospital, Sendai 983-0824, Japan;
| | - Yuko Itakura
- Department of Pathology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki 986-8522, Japan;
| | - Tatsuya Hoshi
- Department of Internal Medicine, Kesennuma Citizen Hospital, Kesennuma 988-0181, Japan;
| | - Atsushi Kunimitsu
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (A.K.); (T.Y.); (R.A.); (Y.O.); (T.F.); (H.O.); (C.S.); (Y.T.); (T.K.)
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (F.F.); (H.W.); (H.S.)
| | - Takuro Yamauchi
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (A.K.); (T.Y.); (R.A.); (Y.O.); (T.F.); (H.O.); (C.S.); (Y.T.); (T.K.)
| | - Ryujiro Akaishi
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (A.K.); (T.Y.); (R.A.); (Y.O.); (T.F.); (H.O.); (C.S.); (Y.T.); (T.K.)
| | - Yohei Ozawa
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (A.K.); (T.Y.); (R.A.); (Y.O.); (T.F.); (H.O.); (C.S.); (Y.T.); (T.K.)
| | - Toshiaki Fukutomi
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (A.K.); (T.Y.); (R.A.); (Y.O.); (T.F.); (H.O.); (C.S.); (Y.T.); (T.K.)
| | - Hiroshi Okamoto
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (A.K.); (T.Y.); (R.A.); (Y.O.); (T.F.); (H.O.); (C.S.); (Y.T.); (T.K.)
| | - Chiaki Sato
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (A.K.); (T.Y.); (R.A.); (Y.O.); (T.F.); (H.O.); (C.S.); (Y.T.); (T.K.)
| | - Yusuke Taniyama
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (A.K.); (T.Y.); (R.A.); (Y.O.); (T.F.); (H.O.); (C.S.); (Y.T.); (T.K.)
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (A.K.); (T.Y.); (R.A.); (Y.O.); (T.F.); (H.O.); (C.S.); (Y.T.); (T.K.)
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (F.F.); (H.W.); (H.S.)
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Management of adrenocorticotropic hormone-secreting neuroendocrine tumors and the role of bilateral adrenalectomy in ectopic Cushing syndrome. Surgery 2022; 172:559-566. [PMID: 35437162 PMCID: PMC9681028 DOI: 10.1016/j.surg.2022.03.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 02/11/2022] [Accepted: 03/14/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Neuroendocrine tumors can cause ectopic Cushing syndrome, and most patients have metastatic disease at diagnosis. We identified risk factors for outcome, evaluated ectopic Cushing syndrome management, and explored the role of bilateral adrenalectomy in this population. METHODS This was a retrospective study including patients with diagnosis of ectopic Cushing Syndrome secondary to neuroendocrine tumors with adrenocorticotropic hormone secretion treated at our quaternary referral center over a 40-year period (1980-2020). RESULTS Seventy-six patients were included. Mean age at diagnosis was 46.3 ± 15.8 years. Most patients (N = 61, 80%) had metastases at ectopic Cushing syndrome diagnosis. Average follow-up was 2.9 ± 3.7 years (range, 4 months-17.2 years). Patients with neuroendocrine tumors before ectopic Cushing syndrome had more frequent metastatic disease and resistant ectopic Cushing syndrome. Patients with de novo hyperglycemia, poor neuroendocrine tumor differentiation, and metastatic disease had worse survival. Of those with nonmetastatic disease, 8 (53%) had ectopic Cushing syndrome resolution after neuroendocrine tumor resection, 3 (20%) were medically controlled, and 4 (27%) underwent bilateral adrenalectomy. In patients with metastatic neuroendocrine tumors, hypercortisolism was initially medically managed in 92%, 3% underwent immediate bilateral adrenalectomy, 2% had control after primary neuroendocrine tumor debulking, and 2% were lost to follow-up. Medical treatment resulted in hormonal control in 7 (13%) patients. Of the 49 patients with metastatic disease and medically resistant ectopic Cushing syndrome, 23 ultimately had bilateral adrenalectomy with ectopic Cushing syndrome cure in all. CONCLUSION Patients with neuroendocrine tumors before ectopic Cushing syndrome development were more likely metastatic and had worse survival. De novo hyperglycemia and poor neuroendocrine tumor differentiation were predictive of worse prognosis. Medical control of hypercortisolism is difficult to achieve in patients with neuroendocrine tumors-ectopic Cushing syndrome. Well-selected patients may benefit from bilateral adrenalectomy early in the treatment algorithm, and multidisciplinary management is essential in this complex disease.
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Bostan H, Duger H, Akhanli P, Calapkulu M, Turkmenoglu TT, Erdol AK, Duru SA, Sencar ME, Kizilgul M, Ucan B, Ozbek M, Cakal E. Cushing's syndrome due to adrenocorticotropic hormone-secreting metastatic neuroendocrine tumor of unknown primary origin: a case report and literature review. Hormones (Athens) 2022; 21:147-154. [PMID: 34478059 PMCID: PMC8414022 DOI: 10.1007/s42000-021-00316-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 08/24/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND In this article, we present a case of neuroendocrine neoplasm of unknown primary origin (UPO NEN), which is a rare cause of ectopic Cushing's syndrome (ECS) presenting numerous challenges, together with a literature review. CASE REPORT A 43-year-old male patient presented with clinical features consistent with Cushing's syndrome (CS) and adrenocorticotropic hormone (ACTH)-dependent hypercortisolemia. Despite a suspicious lesion on pituitary MRI, the high-dose dexamethasone suppression test and bilateral inferior petrosal sinus sampling results were not compatible with Cushing's disease. Bilateral non-homogeneous opacities were observed in the thorax CT of the patient, who also had a history of COVID-19 infection, but no tumoral lesion was detected. When 68Ga-SSTR PET/CT and 18FDG-PET/CT were performed, multiple metastatic foci were detected in mediastinal and hilar lymph nodes and the axial skeleton. Paratracheal-subcarinal lymph nodes were excised mediastinoscopically, and the diagnosis of NEN was made. Histopathological findings indicated that the possible origin was an atypical pulmonary carcinoid with a low Ki-67 labeling index. After controlling hypercortisolemia, a regimen of somatostatin analogs and capecitabine plus temozolomide was decided upon as treatment by a multidisciplinary council. CONCLUSION This is a challenging case of UPO NEN presenting with ECS and confounding factors, such as previous infection and incidental lesions, during the diagnosis process. The case in question highlighted the fact that atypical pulmonary carcinoid with a low proliferation index may cause visible metastases even when radiologically undetectable.
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Affiliation(s)
- Hayri Bostan
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ziraat Mahallesi, Şht. Ömer Halisdemir Blv. No. 1, 6110, Ankara, Turkey.
| | - Hakan Duger
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ziraat Mahallesi, Şht. Ömer Halisdemir Blv. No. 1, 6110, Ankara, Turkey
| | - Pinar Akhanli
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ziraat Mahallesi, Şht. Ömer Halisdemir Blv. No. 1, 6110, Ankara, Turkey
| | - Murat Calapkulu
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ziraat Mahallesi, Şht. Ömer Halisdemir Blv. No. 1, 6110, Ankara, Turkey
| | - Tugba Taskin Turkmenoglu
- Department of Pathology, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
| | - Ayse Kevser Erdol
- Department of Chest Diseases, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
| | - Serap Akcali Duru
- Department of Chest Diseases, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
| | - Muhammed Erkam Sencar
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ziraat Mahallesi, Şht. Ömer Halisdemir Blv. No. 1, 6110, Ankara, Turkey
| | - Muhammed Kizilgul
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ziraat Mahallesi, Şht. Ömer Halisdemir Blv. No. 1, 6110, Ankara, Turkey
| | - Bekir Ucan
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ziraat Mahallesi, Şht. Ömer Halisdemir Blv. No. 1, 6110, Ankara, Turkey
| | - Mustafa Ozbek
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ziraat Mahallesi, Şht. Ömer Halisdemir Blv. No. 1, 6110, Ankara, Turkey
| | - Erman Cakal
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ziraat Mahallesi, Şht. Ömer Halisdemir Blv. No. 1, 6110, Ankara, Turkey
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