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de Andrade FA, Bulzico D, Corbo R, Vaisman F. Is peptide receptor radionuclide therapy still a promising option for medullary thyroid carcinoma? Endocrine 2025; 87:943-950. [PMID: 39609369 DOI: 10.1007/s12020-024-04114-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 11/13/2024] [Indexed: 11/30/2024]
Abstract
Medullary thyroid carcinoma (MTC) is a rare cancer that originates from germline RET proto-oncogene mutations in all hereditary forms and from somatic RET mutations in most sporadic cases. Currently, highly selective RET inhibitors have been approved for clinical use in patients with RET mutations with persistent, recurrent or metastatic disease. This therapy has proven efficacy, low toxicity, and a limited impact on patients' quality of life. However, for recurrent or metastatic RET-negative disease, few systemic therapies are available. Multikinase inhibitors are used; however, tumour cells frequently develop resistance mechanisms, or treatment must be discontinued due to the high incidence of side effects. In this context, peptide receptor radionuclide therapy (PRRT) may be a treatment option, but its clinical utility remains under investigation. The aim of this review is to evaluate the evidence of PRRT in MTC and discuss its limitations in the RET inhibitor era.
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Affiliation(s)
| | - Daniel Bulzico
- Endocrine Oncology Unit, Brazilian National Cancer Institute, INCA, Rio de Janeiro, Brazil
- Nuclear Medicine Section, Brazilian National Cancer Institute, INCA, Rio de Janeiro, Brazil
| | - Rossana Corbo
- Endocrine Oncology Unit, Brazilian National Cancer Institute, INCA, Rio de Janeiro, Brazil
- Nuclear Medicine Section, Brazilian National Cancer Institute, INCA, Rio de Janeiro, Brazil
| | - Fernanda Vaisman
- Endocrine Oncology Unit, Brazilian National Cancer Institute, INCA, Rio de Janeiro, Brazil.
- Universidade Federal do Rio de Janeiro, UFRJ, Rio de Janeiro, Brazil.
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Xu Z, Wu X, Hu Y, Wu C, Wang X, Zhang X, Zhang Y, Huang Y. Clinical diagnosis and treatment of G2 laryngeal neuroendocrine tumors. Acta Otolaryngol 2025:1-7. [PMID: 39827402 DOI: 10.1080/00016489.2024.2437017] [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: 09/23/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Neuroendocrine tumors are rare malignancies of the head and neck, especially in the larynx. Variations in the location and morphology of laryngeal neuroendocrine tumors result in a lack of standardized clinical treatment. OBJECTIVE This study aimed to examine the treatment and prognosis of laryngeal neuroendocrine tumors in the G2 stage. MATERIAL AND METHODS Data from eight patients diagnosed with G2 stage laryngeal neuroendocrine tumors, this collection of common clinical cases was analyzed retrospectively to examine the disease's clinical characteristics, treatment, and prognosis affecting the larynx. RESULTS Seven cases were supraglottic type and one was a glottic type. These cases were treated with open surgery and CO2 laser resection with support laryngoscopy, respectively. After surgery, six patients survived, one passed away due to pulmonary metastasis, and one case was lost to follow-up. OS and DSF rates at 1, 3, 5 years were 87.50%, 65.63% and 65.60%, respectively. CONCLUSION AND SIGNIFICANCE The clinical manifestations of G2 stage laryngeal neuroendocrine tumors varied across different locations. Surgical resection of the lesion is the standard treatment. Selection between open neck surgery and support laryngoscope CO2 laser surgery depends on the tumor's size and location. Following radical surgery, the tumor demonstrates a favorable prognosis.
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Affiliation(s)
- Zhen Xu
- Deparment of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao City, China
| | - Xiuyun Wu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao City, China
| | - Yanjiao Hu
- Deparment of Pathology, The Affiliated Hospital of Qingdao University, Qingdao City, China
| | - Ce Wu
- Deparment of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao City, China
| | - Xin Wang
- Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao City, China
| | - Xiaojuan Zhang
- Department of Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao City, China
| | - Yong Zhang
- Department of Stomatology, The Huangdao District Central Hospital, Qingdao City, China
| | - Yichuan Huang
- Deparment of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao City, China
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Tsoy U, Pogosian K, Ryzhkova D, Yudina O, Yakovenko K, Ryazanov P, Matsueva I, Sokolnikova P, Salov M, Karonova T, Grineva E. Somatostatin Receptor Imaging in the Diagnosis and Management of Parathyroid Neuroendocrine Neoplasia. Diagnostics (Basel) 2024; 14:2718. [PMID: 39682626 DOI: 10.3390/diagnostics14232718] [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: 11/16/2024] [Revised: 11/28/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND Parathyroid tumors are classified as parathyroid neuroendocrine neoplasia (NEN) by the IARC-WHO classification. These tumors can occur with NENs from other sites, which often require total-body [68Ga]-DOTA-peptides PET/CT. This study aimed to assess the utility of [68Ga]-DOTA-peptide PET/CT in imaging parathyroid NENs and to evaluate the underlying mechanisms. METHODS Fifty patients with primary hyperparathyroidism (PHPT) and parathyroid NENs histologically confirmed as parathyroid adenomas (PAs) were included. PET/CT with [68Ga]-DOTA-peptide was performed in 16 patients with localized PAs, including 10 with MEN1 syndrome. Somatostatin receptor types 2 and 5 (SST2 and SST5) staining was performed on PAs from 48 patients. Somatostatin analogs (SSA) were prescribed in four patients with MEN 1 syndrome and 1 with persistent acromegaly, all with PAs and PHPT. The therapy effects on calcium and parathyroid hormone (iPTH) were evaluated. RESULTS [68Ga]-DOTA-peptide PET/CT detected 20 PAs with high radiopharmaceutical uptake. SST2 expression was negative on PA cell membranes in all cases and positive on endothelium in 39 (81%) PAs. Membrane SST5 expression was positive in 25 (52%) PAs and endothelial was positive in 40 (83%). Serum calcium levels decreased in patients on SSA therapy, while iPTH did not. CONCLUSIONS PET/CT with [68Ga]-DOTA-peptides can detect parathyroid NENs. The incidental detection of high [68Ga]-DOTA-peptide uptake in the parathyroid region during whole-body PET/CT may prompt biochemical evaluation for PHPT. We suggest that endothelial SST expression mediates high radiopharmaceutical uptake by PAs and that SSA treatment can reduce hypercalcemia in PHPT patients.
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Affiliation(s)
- Uliana Tsoy
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
| | - Karina Pogosian
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
| | - Daria Ryzhkova
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
| | - Olga Yudina
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
| | - Ksenia Yakovenko
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
| | - Pavel Ryazanov
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
| | - Irina Matsueva
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
| | - Polina Sokolnikova
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
| | - Maksim Salov
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
| | - Tatiana Karonova
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
| | - Elena Grineva
- Almazov National Medical Research Centre, 2 Akkuratova Street, Saint Petersburg 197341, Russia
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Tsoy UA, Sokolnikova PS, Kravchuk EN, Ryazanov PA, Kozyreva AA, Fomicheva YV, Aramisova LS, Karonova TL, Kostareva AA, Grineva E. A Comprehensive Target Panel Allows to Extend the Genetic Spectrum of Neuroendocrine Tumors. Neuroendocrinology 2024:1-21. [PMID: 39536727 DOI: 10.1159/000542223] [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: 04/09/2024] [Accepted: 09/17/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION Neuroendocrine tumors (NETs) frequently have a genetic basis, and the range of genes implicated in NET development continues to expand. Application of targeted gene panels (TGPs) in next-generation sequencing is a central strategy for elucidating novel variants associated with NET development. METHODS In this study, we conducted comprehensive molecular genetic analyses using TGP on a cohort of 93 patients diagnosed with various NETs subtypes, mainly accompanied by various endocrine syndromes: insulinoma (n = 26), pheochromocytoma and paraganglioma (PPGL) (n = 38), parathyroid adenoma (n = 18, including three with insulinoma), and NETs of other locations (n = 14). The TGP encompassed genes linked to diverse NETs and other hereditary endocrine disorders, with subsequent variant classification according to the American College of Medical Genetics and Genomics guidelines. RESULTS Among the identified variants, 20 were found in genes previously linked to specific tumor types, and 10 were found in genes with a limited likelihood and unclear molecular mecanisms of association with observed NETs. Remarkably, 13 variants were discovered in genes not previously associated with the NETs observed in our patients. These genes, such as ABCC8, KCNJ11, KLF11, HABP2, and APC, were implicated in insulinoma; ZNRF3, GNAS, and KCNJ5 were linked with PPGL; parathyroid adenomas were related to variants in SDHB and TP53; while NETs of other locations displayed variants in APC and ABCC8. CONCLUSION Our study demonstrates that utilizing broad TGP in examining patients with various functioning NETs facilitates the identification of new germinal variants in genes that may contribute to the diseases. The verification of revealed findings requires research in vaster sample.
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Affiliation(s)
- Uliana A Tsoy
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Polina S Sokolnikova
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Ekaterina N Kravchuk
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Pavel A Ryazanov
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Alexandra A Kozyreva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Yulia V Fomicheva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Liana S Aramisova
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Tatiana L Karonova
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Anna A Kostareva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
- Department of Women's and Children's Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Elena Grineva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
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Zhou H, Zhu Y, Qin B, Liu Y, Wang Z, Guo C, Wang J, Chen X. The association between non-HDL cholesterol and high-grade pancreatic neuroendocrine neoplasms. Endocrine 2024; 86:584-591. [PMID: 38844608 DOI: 10.1007/s12020-024-03910-4] [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: 04/25/2024] [Accepted: 06/01/2024] [Indexed: 10/19/2024]
Abstract
PURPOSE High-density lipoprotein cholesterol (HDL-c) plays an important role in tumorigenesis in several endocrine-related cancers. Few studies have shown the effect of non-HDL-c in malignant tumors. The present study aimed to identify the association between non-HDL-c and high-grade pancreatic neuroendocrine neoplasms (PNENs). METHODS A total of 197 PNEN patients who underwent surgery were analyzed retrospectively. Clinical and histopathological features, such as patients' age and sex, tumor location and size, tumor grade, the level of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and fasting plasma-glucose levels were obtained. Non-HDL-c was calculated as total cholesterol - HDL-c. The relationships between those features and high-grade PNENs were identified using logistic regression analysis. RESULTS Among the 197 patients with PNENs, a lower HDL-c level was more common seen in patients with poorly differentiated PNENs than in those with well-differentiated PNENs (P < 0.05). The non-HDL-c/HDL-c ratio was greater in patients with poorly differentiated PNENs than in those with well-differentiated PNENs (P < 0.01). Similarly, a greater proportion of patients with a non-HDL-c/HDL-c ratio larger than 5 was found in patients with poorly differentiated PNENs than in those with well-differentiation PNENs (P < 0.01). Multivariate logistic analysis showed that the non-HDL-c/HDL-c ratio was positively associated with poorly differentiated PNENs (odds ratio (OR) = 1.45, 95% conference interval (CI):1.13-1.87). Similarly, the risk of poorly differentiated PNENs increased significantly in patients with a non-HDL-c/HDL-c greater than 5 (OR = 14.13, 95%CI: 2.98-66.89). The risk of high-grade PNENs increased in patients with a high non-HDL-c/HDL-c ratio (OR = 1.27, 95% CI: 1.04-1.55), and the risk also increased markedly when the ratio was greater than 5 (OR = 5.00, 95%CI: 1.28-19.49). CONCLUSIONS A high ratio of non-HDL-c/HDL-c was associated with high-grade PNENs or poorly differentiated PNENs.
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Affiliation(s)
- Hao Zhou
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Yong Zhu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Bin Qin
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Yongkang Liu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Zhongqiu Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Chuangen Guo
- Department of Radiology, the First Affiliated Hospital of Zhejiang University School of Medicine, Haznghozu, 310003, China
| | - Jianhua Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
| | - Xiao Chen
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
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Li C, Bian L, Fan G, Huang Y, Li J, He B. Case report: Recurrence of primary hepatic neuroendocrine tumors after resection of liver segments IV in 8 years follow-up. Front Med (Lausanne) 2024; 11:1437650. [PMID: 39351005 PMCID: PMC11439660 DOI: 10.3389/fmed.2024.1437650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 09/02/2024] [Indexed: 10/04/2024] Open
Abstract
Background Primary hepatic neuroendocrine tumors (PHNETs) are an utterly rare entity. The diagnosis of PHNETs could legitimize when an extrahepatic primary NET must always be excluded. PHNETs can achieve a high survival rate after complete surgical resection, however, most patients still have an 18% risk of recurrence within 5 years after surgery. In our case, the recurrence occurred 8 years after the first hepatectomy, which is relatively rare in the current literature. Therefore, rigorous postoperative follow-up is necessary for early detection and timely treatment of recurrent PHNETs. Case information We report a case of PHNET in a 24-year-old previously healthy female patient who relapsed 8 years after hepatectomy. This case focuses on the importance of diagnosis of primary and recurrent PHNETS in young patients, rare pathological types, and post-operative follow-up. Conclusion This case report detailed the rare pathological morphology and characteristic immunohistochemical markers in our case for PHNETS, which enhanced the new understanding of the diagnosis of this entity. In addition, we also highlighted the variable duration of recurrence after treatment of PHNETs. The 8-year recurrent period in our case suggests the importance of regular examination in patients with PHNETs by following the doctor's instructions.
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Affiliation(s)
- Chunli Li
- Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Li Bian
- Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Guangtao Fan
- Medical Imaging Department, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, China
| | - Yilong Huang
- Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jiang Li
- Hepatobiliary Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Bo He
- Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China
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Shen Z, Zhang X, Li Q, Wang R. Comparison of 18F-FDG PET/CT and 18F-DOTATATE PET/CT in the diagnosis of multiple metastases in rectal neuroendocrine neoplasms. Radiol Case Rep 2024; 19:3757-3762. [PMID: 38983281 PMCID: PMC11231501 DOI: 10.1016/j.radcr.2024.03.051] [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: 12/15/2023] [Revised: 03/18/2024] [Accepted: 03/20/2024] [Indexed: 07/11/2024] Open
Abstract
This case report describes a 62-year-old male with a notable medical history, including surgically treated bladder cancer and the suspicion of metastatic disease. He underwent 18F-FDG PET/CT imaging as part of the initial diagnostic workup, which identified several marginally hypodense hepatic lesions. These lesions exhibited metabolic activity that was slightly lower than the surrounding hepatic parenchyma, raising concerns for metastatic involvement. Subsequent 18F-DOTATATE PET/CT imaging significantly expanded the diagnostic perspective by identifying multiple somatostatin receptor (SSTR)-positive lesions, not only in the liver but also in lymph nodes and bones. This marked an important diagnostic advancement over the initial FDG PET/CT findings, showcasing the superior sensitivity of 18F-DOTATATE PET/CT in detecting SSTR-expressing tumors. Pathological evaluation after these imaging studies confirmed the diagnosis of a rectal neuroendocrine tumor (NET) with extensive hepatic metastasis, altering the clinical management and therapeutic approach for the patient. This case underscores the pivotal role of integrating 18F-DOTATATE and FDG PET/CT in the diagnostic and therapeutic management of neuroendocrine tumors, highlighting the complementary nature of these imaging modalities. The findings advocate for the use of 18F-DOTATATE PET/CT in cases where NETs are suspected, particularly for its enhanced sensitivity in detecting SSTR-positive lesions across various sites, thereby facilitating a more comprehensive disease assessment and informed therapeutic planning.
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Affiliation(s)
- Zhihui Shen
- Department of Nuclear Medicine, the First Medical Centre, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Xiaojun Zhang
- Department of Nuclear Medicine, the First Medical Centre, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Qingxiao Li
- Department of Nuclear Medicine, the First Medical Centre, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Ruimin Wang
- Department of Nuclear Medicine, the First Medical Centre, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China
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Buchstab O, Knösel T. [Current WHO classification (2022) of neuroendocrine neoplasms]. RADIOLOGIE (HEIDELBERG, GERMANY) 2024; 64:531-535. [PMID: 38622292 DOI: 10.1007/s00117-024-01295-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/12/2024] [Indexed: 04/17/2024]
Abstract
CLINICAL ISSUE After the first description of the "carcinoid tumors" by the pathologist Siegfried Oberndorfer in Munich, the classification system of neuroendocrine neoplasms (NENs) is still a challenge and an evolving concept. METHODICAL INNOVATIONS The new WHO classification system proposed a framework for universal classification. ACHIEVEMENTS The new WHO classification system recognizes two distinct families distinguished by genetic, morphology and clinical behaviour: Well differentiated NENs are defined as neuroendocrine tumor (NET G1, G2, G3), while poorly differentiated ones are defined as neuroendocrine carcinoma (NEC, G3) and further subdivided into small and large cell carcinoma. All NENs are characterized by the expression of synaptophysin and chromogranin A, Ki-67 and morphology. MOLECULAR PATHOLOGY The morphological NEN dichotomy is supported by genetic alterations. NECs show TP53 and RB1 alterations that are absent in NETs and are therefore useful for differentiating between NETs and NECs. PRACTICAL RECOMMENDATIONS All NENs are divided into well-differentiated neuroendocrine tumor (NET G1, G2, G3) or poorly differentiated neuroendocrine carcinoma (NEC, G3). They are categorized by morphology, mitotic count and immunohistochemistry with synaptophysin, chromogranin and Ki-67.
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Affiliation(s)
- Oliver Buchstab
- Pathologisches Institut, Ludwig-Maximilians-Universität (LMU), Thalkirchnerstr. 36, 80337, München, Deutschland
| | - Thomas Knösel
- Pathologisches Institut, Ludwig-Maximilians-Universität (LMU), Thalkirchnerstr. 36, 80337, München, Deutschland.
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Munekane M, Fuchigami T, Ogawa K. Recent advances in the development of 225Ac- and 211At-labeled radioligands for radiotheranostics. ANAL SCI 2024; 40:803-826. [PMID: 38564087 PMCID: PMC11035452 DOI: 10.1007/s44211-024-00514-w] [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: 11/28/2023] [Accepted: 01/16/2024] [Indexed: 04/04/2024]
Abstract
Radiotheranostics utilizes a set of radioligands incorporating diagnostic or therapeutic radionuclides to achieve both diagnosis and therapy. Imaging probes using diagnostic radionuclides have been used for systemic cancer imaging. Integration of therapeutic radionuclides into the imaging probes serves as potent agents for radionuclide therapy. Among them, targeted alpha therapy (TAT) is a promising next-generation cancer therapy. The α-particles emitted by the radioligands used in TAT result in a high linear energy transfer over a short range, inducing substantial damage to nearby cells surrounding the binding site. Therefore, the key to successful cancer treatment with minimal side effects by TAT depends on the selective delivery of radioligands to their targets. Recently, TAT agents targeting biomolecules highly expressed in various cancer cells, such as sodium/iodide symporter, norepinephrine transporter, somatostatin receptor, αvβ3 integrin, prostate-specific membrane antigen, fibroblast-activation protein, and human epidermal growth factor receptor 2 have been developed and have made remarkable progress toward clinical application. In this review, we focus on two radionuclides, 225Ac and 211At, which are expected to have a wide range of applications in TAT. We also introduce recent fundamental and clinical studies of radiopharmaceuticals labeled with these radionuclides.
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Affiliation(s)
- Masayuki Munekane
- Graduate School of Medical Sciences, Kanazawa University, Kakuma-Machi, Kanazawa, Ishikawa, 920-1192, Japan
| | - Takeshi Fuchigami
- Graduate School of Medical Sciences, Kanazawa University, Kakuma-Machi, Kanazawa, Ishikawa, 920-1192, Japan.
| | - Kazuma Ogawa
- Graduate School of Medical Sciences, Kanazawa University, Kakuma-Machi, Kanazawa, Ishikawa, 920-1192, Japan.
- Institute for Frontier Science Initiative, Kanazawa University, Kakuma-Machi, Kanazawa, Ishikawa, 920-1192, Japan.
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Nogareda Seoane Z, Mallón Araújo MC, Calatayud Cubes A, Barberán Corral C, Domínguez Novoa Y, Cousillas Castiñeira A, Martínez Lago N, de Matías Leralta JM, Pubul Nuñez V. Functional imaging in neuroendocrine tumors: assessment of molecular heterogeneity using [ 68Ga]Ga-DOTA-TOC and [ 18F]FDG PET/CT. Rev Esp Med Nucl Imagen Mol 2024; 43:500011. [PMID: 38643835 DOI: 10.1016/j.remnie.2024.500011] [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: 02/07/2024] [Accepted: 04/08/2024] [Indexed: 04/23/2024]
Abstract
OBJECTIVE The aim of the study was evaluate the diagnostic performance of [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT in patients with histologically proven neuroendocrine tumors (NETs), as well as the correlation of the visualized findings with the tumor grade. MATERIAL AND METHODS We included 50 patients with NETs who underwent both [68Ga]Ga-DOTA-TOC and [18F]FDG PET/TC. The pooled sensitivity of both scans was compared, as well as [68Ga]Ga-DOTA-TOC and [18F]FDG for each tumor grade (grade 1/G1, grade 2/G2 and grade 3/G3). Also, the sensitivity of [68Ga]Ga-DOTA-TOC and [18F]FDG as a function of the continuous variable Ki-67 was investigated. Finally, the number of lesions detected by both PET radiopharmaceuticals for each tumor grade was compared. RESULTS The pooled sensitivity of both PET/CT (96%) was higher than [68Ga]Ga-DOTA-TOC (84%) and [18F]FDG (44%) separately, with statistically significant differences. The sensitivity of [68Ga]Ga-DOTA-TOC was higher than [18F]FDG in both G1 (p = 0.004) and G2 (p < 0.001). In G3 the performance of both scans detected disease in 100% of this subgroup. The sensitivity of [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT correlated significantly with the Ki-67 proliferative index. In G2 patients the number of lesions detected with [68Ga]Ga-DOTA-TOC was higher than [18F]FDG. CONCLUSIONS The performance of both PET/CT, particularly in G2 and G3, demonstrates the molecular heterogeneity of metastatic NETs and contributes to the selection of a more appropriate treatment, particularly in those high-grade patients who may benefit from radionuclide therapy (PRRT).
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Affiliation(s)
- Z Nogareda Seoane
- Servicio de Medicina Nuclear, Hospital Clínico Universitario Santiago de Compostela, Spain.
| | - M C Mallón Araújo
- Servicio de Medicina Nuclear, Hospital Clínico Universitario Santiago de Compostela, Spain
| | - A Calatayud Cubes
- Servicio de Medicina Nuclear, Hospital Clínico Universitario Santiago de Compostela, Spain
| | - C Barberán Corral
- Servicio de Medicina Nuclear, Hospital Clínico Universitario Santiago de Compostela, Spain
| | - Y Domínguez Novoa
- Servicio de Digestivo, Hospital Clínico Universitario Santiago de Compostela, Spain
| | | | - N Martínez Lago
- Servicio de Oncología Médica, Hospital Hospitalario Universitario de Ferrol, Spain
| | - J M de Matías Leralta
- Servicio de Endocrinología y Nutrición, Hospital Universitario Lucus Augusti, Lugo, Spain
| | - V Pubul Nuñez
- Servicio de Medicina Nuclear, Hospital Clínico Universitario Santiago de Compostela, Spain
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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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12
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Yit LFN, Li Y. A Review of the Evolving Role of Radiotherapy in the Treatment of Neuroendocrine Neoplasms. Neuroendocrinology 2024; 114:856-865. [PMID: 38432216 DOI: 10.1159/000538140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 02/20/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND Neuroendocrine neoplasms (NENs) are rare tumours that develop from neuroendocrine cells in various parts of the body. The management of this disease poses a significant challenge because of the heterogeneous clinical presentation and varying degrees of aggressiveness. A multidisciplinary approach is often required in complex clinical situations. Radiotherapy (RT) plays a key role in managing NETs in both curative and palliative settings. SUMMARY In this review, we summarize and discuss recent developments in the field of advanced RT in early-stage, locally advanced, and metastatic NENs. We highlight limitations in current approaches and discuss future potential treatment strategies for patients with NENs.
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Affiliation(s)
- Ling Fung Nelson Yit
- Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Youquan Li
- Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
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13
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Rugge M, Genta RM, Malfertheiner P, Dinis-Ribeiro M, El-Serag H, Graham DY, Kuipers EJ, Leung WK, Park JY, Rokkas T, Schulz C, El-Omar EM. RE.GA.IN.: the Real-world Gastritis Initiative-updating the updates. Gut 2024; 73:407-441. [PMID: 38383142 DOI: 10.1136/gutjnl-2023-331164] [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: 09/18/2023] [Accepted: 12/18/2023] [Indexed: 02/23/2024]
Abstract
At the end of the last century, a far-sighted 'working party' held in Sydney, Australia addressed the clinicopathological issues related to gastric inflammatory diseases. A few years later, an international conference held in Houston, Texas, USA critically updated the seminal Sydney classification. In line with these initiatives, Kyoto Global Consensus Report, flanked by the Maastricht-Florence conferences, added new clinical evidence to the gastritis clinicopathological puzzle.The most relevant topics related to the gastric inflammatory diseases have been addressed by the Real-world Gastritis Initiative (RE.GA.IN.), from disease definitions to the clinical diagnosis and prognosis. This paper reports the conclusions of the RE.GA.IN. consensus process, which culminated in Venice in November 2022 after more than 8 months of intense global scientific deliberations. A forum of gastritis scholars from five continents participated in the multidisciplinary RE.GA.IN. consensus. After lively debates on the most controversial aspects of the gastritis spectrum, the RE.GA.IN. Faculty amalgamated complementary knowledge to distil patient-centred, evidence-based statements to assist health professionals in their real-world clinical practice. The sections of this report focus on: the epidemiology of gastritis; Helicobacter pylori as dominant aetiology of environmental gastritis and as the most important determinant of the gastric oncogenetic field; the evolving knowledge on gastric autoimmunity; the clinicopathological relevance of gastric microbiota; the new diagnostic horizons of endoscopy; and the clinical priority of histologically reporting gastritis in terms of staging. The ultimate goal of RE.GA.IN. was and remains the promotion of further improvement in the clinical management of patients with gastritis.
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Affiliation(s)
- Massimo Rugge
- Department of Medicine-DIMED, University of Padova, Padua, Italy
- Azienda Zero, Veneto Tumour Registry, Padua, Italy
| | - Robert M Genta
- Gastrointestinal Pathology, Inform Diagnostics Research Institute, Dallas, Texas, USA
- Pathology, Baylor College of Medicine, Houston, Texas, USA
| | - Peter Malfertheiner
- Medizinische Klinik und Poliklinik II, Ludwig Maximilian Universität Klinikum München, Munich, Germany
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany
| | - Mario Dinis-Ribeiro
- Porto Comprehensive Cancer Center & RISE@CI-IPO, University of Porto, Porto, Portugal
- Gastroenterology Department, Portuguese Institute of Oncology of Porto, Porto, Portugal
| | - Hashem El-Serag
- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
- Houston VA Health Services Research & Development Center of Excellence, Michael E DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - David Y Graham
- Department of Medicine, Michael E DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Ernst J Kuipers
- Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | - Jin Young Park
- International Agency for Research on Cancer, Lyon, France
| | - Theodore Rokkas
- Gastroenterology, Henry Dunant Hospital Center, Athens, Greece
| | | | - Emad M El-Omar
- Microbiome Research Centre, University of New South Wales, Sydney, New South Wales, Australia
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14
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Zoccarato M, Grisold W. Paraneoplastic neurologic manifestations of neuroendocrine tumors. HANDBOOK OF CLINICAL NEUROLOGY 2024; 200:397-407. [PMID: 38494292 DOI: 10.1016/b978-0-12-823912-4.00023-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from the transformation of neuroendocrine cells in several organs, most notably the gastro-entero-pancreatic system and respiratory tract. The classification was recently revised in the 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. NENs can rarely spread to the central or peripheral nervous systems. Neurologic involvement is determined by the rare development of paraneoplastic syndromes, which are remote effects of cancer. Mechanisms depend on immunologic response to a tumor, leading to the immune attack on the nervous system or the production of biologically active ("functioning") substances, which can determine humoral (endocrine) effects with neurologic manifestations. Paraneoplastic neurologic syndromes (PNS) are immunologically mediated and frequently detected in small cell lung cancer but rarely seen in other forms of NEN. PNS and Merkel cell carcinoma is increasingly reported, especially with Lambert Eaton myasthenic syndrome. Endocrine manifestations are found in a wide spectrum of NENs. They can develop at any stage of the diseases and determine neurologic manifestations. Patient outcomes are influenced by tumor prognosis, neurologic complications, and the severity of endocrine effects.
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Affiliation(s)
- Marco Zoccarato
- Neurology Unit O.S.A., Azienda Ospedale-Università di Padova, Padova, Italy
| | - Wolfgang Grisold
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.
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15
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Davis CH, Laird AM, Libutti SK. Resistant gastroenteropancreatic neuroendocrine tumors: a definition and guideline to medical and surgical management. Proc AMIA Symp 2023; 37:104-110. [PMID: 38174011 PMCID: PMC10761146 DOI: 10.1080/08998280.2023.2284039] [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: 08/22/2023] [Accepted: 11/07/2023] [Indexed: 01/05/2024] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (NETs), also historically known as carcinoids, are tumors derived of hormone-secreting enteroendocrine cells. Carcinoids may be found in the esophagus, stomach, small intestine, appendix, colon, rectum, or pancreas. The biologic behavior of carcinoids differs based on their location, with gastric and appendiceal NETs among the least aggressive and small intestinal and pancreatic NETs among the most aggressive. Ultimately, however, biologic behavior is most heavily influenced by tumor grade. The incidence of NETs has increased by 6.4 times over the past 40 years. Surgery remains the mainstay for management of most carcinoids. Medical management, however, is a useful adjunct and/or definitive therapy in patients with symptomatic functional carcinoids, in patients with unresectable or incompletely resected carcinoids, in some cases of recurrent carcinoid, and in postoperative patients to prevent recurrence. Functional tumors with persistent symptoms or progressive metastatic carcinoids despite therapy are called "resistant" tumors. In patients with unresectable disease and/or carcinoid syndrome, an array of medical therapies is available, mainly including somatostatin analogues, molecular-targeted therapy, and peptide receptor radionuclide therapy. Active research is ongoing to identify additional targeted therapies for patients with resistant carcinoids.
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Affiliation(s)
- Catherine H. Davis
- Division of Surgical Oncology, Baylor University Medical Center, Dallas, Texas, USA
- Texas A&M University School of Medicine, Dallas, Texas, USA
| | - Amanda M. Laird
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
- Rutgers Robert Wood Johnson University Medical School, New Brunswick, New Jersey, USA
| | - Steven K. Libutti
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
- Rutgers Robert Wood Johnson University Medical School, New Brunswick, New Jersey, USA
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16
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Hrncir HR, Hantelys F, Gracz AD. Panic at the Bile Duct: How Intrahepatic Cholangiocytes Respond to Stress and Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1440-1454. [PMID: 36870530 PMCID: PMC10548281 DOI: 10.1016/j.ajpath.2023.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 03/06/2023]
Abstract
In the liver, biliary epithelial cells (BECs) line intrahepatic bile ducts (IHBDs) and are primarily responsible for modifying and transporting hepatocyte-produced bile to the digestive tract. BECs comprise only 3% to 5% of the liver by cell number but are critical for maintaining choleresis through homeostasis and disease. To this end, BECs drive an extensive morphologic remodeling of the IHBD network termed ductular reaction (DR) in response to direct injury or injury to the hepatic parenchyma. BECs are also the target of a broad and heterogenous class of diseases termed cholangiopathies, which can present with phenotypes ranging from defective IHBD development in pediatric patients to progressive periductal fibrosis and cancer. DR is observed in many cholangiopathies, highlighting overlapping similarities between cell- and tissue-level responses by BECs across a spectrum of injury and disease. The following core set of cell biological BEC responses to stress and injury may moderate, initiate, or exacerbate liver pathophysiology in a context-dependent manner: cell death, proliferation, transdifferentiation, senescence, and acquisition of neuroendocrine phenotype. By reviewing how IHBDs respond to stress, this review seeks to highlight fundamental processes with potentially adaptive or maladaptive consequences. A deeper understanding of how these common responses contribute to DR and cholangiopathies may identify novel therapeutic targets in liver disease.
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Affiliation(s)
- Hannah R Hrncir
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia
| | - Fransky Hantelys
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia
| | - Adam D Gracz
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia.
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17
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Liu M, Li N, Tang H, Chen L, Liu X, Wang Y, Lin Y, Luo Y, Wei S, Wen W, Chen M, Wang J, Zhang N, Chen J. The Mutational, Prognostic, and Therapeutic Landscape of Neuroendocrine Neoplasms. Oncologist 2023; 28:e723-e736. [PMID: 37086484 PMCID: PMC10485279 DOI: 10.1093/oncolo/oyad093] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/11/2023] [Indexed: 04/24/2023] Open
Abstract
BACKGROUND Neuroendocrine neoplasms (NENs) represent clinically and genetically heterogeneous malignancies, thus a comprehensive understanding of underlying molecular characteristics, prognostic signatures, and potential therapeutic targets is urgently needed. METHODS Next-generation sequencing (NGS) and immunohistochemistry were applied to acquire genomic and immune profiles of NENs from 47 patients. RESULTS Difference was distinguished based on differentiation grade and primary localization. Poorly differentiated neuroendocrine carcinomas (NECs) and well-differentiated neuroendocrine tumors (NETs) harbored distinct molecular features; we observed that tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were significantly higher in NECs versus NETs. Notably, we identified a 7-gene panel (MLH3, NACA, NOTCH1, NPAP1, RANBP17, TSC2, and ZFHX4) as a novel prognostic signature in NENs; patients who carried mutations in any of the 7 genes exhibited significantly poorer survival. Furthermore, loss of heterozygosity (LOH) and germline homogeneity in human leukocyte antigen (HLA) are common in NENs, accounting for 39% and 36%, respectively. Notably, HLA LOH was an important prognostic biomarker for a subgroup of NEN patients. Finally, we analyzed clinically actionable targets in NENs, revealing that TMB high (TMB-H) or gene mutations in TP53, KRAS, and HRAS were the most frequently observed therapeutic indicators, which granted eligibility to immune checkpoint blockade (ICB) and targeted therapy. CONCLUSION Our study revealed heterogeneity of NENs, and identified novel prognostic signatures and potential therapeutic targets, which directing improvements of clinical management for NEN patients in the foreseeable future.
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Affiliation(s)
- Man Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Na Li
- Department of Translational Medicine, YuceBio Technology Co., Ltd, Shenzhen, People’s Republic of China
| | - Hongzhen Tang
- Department of Medicine, YuceBio Technology Co., Ltd, Shenzhen, People’s Republic of China
| | - Luohai Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, People’s Republic of China
| | - Yu Wang
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Yuan Lin
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Yanji Luo
- Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Shaozhen Wei
- Department of Translational Medicine, YuceBio Technology Co., Ltd, Shenzhen, People’s Republic of China
| | - Wenli Wen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Jiaqian Wang
- Department of Translational Medicine, YuceBio Technology Co., Ltd, Shenzhen, People’s Republic of China
| | - Ning Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Jie Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
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18
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Liu C, Qi Y, Zhang Y, Yang X. Primary neuroendocrine neoplasms of the kidney: a case report and literature review. J Int Med Res 2023; 51:3000605231198384. [PMID: 37773688 PMCID: PMC10541770 DOI: 10.1177/03000605231198384] [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: 03/14/2023] [Accepted: 08/14/2023] [Indexed: 10/01/2023] Open
Abstract
Primary kidney neuroendocrine tumors (NETs) are rare renal malignancies. However, detecting and monitoring neuroendocrine neoplasms remains challenging because of their nonspecific nature. We herein present a case involving a 53-year-old woman who experienced episodes of intermittent abdominal pain, dizziness, and nausea for a period of 5 days. Computed tomography urography revealed a small (approximately 19- × 16-mm) nodular shadow in the left kidney. The nodular shadow exhibited slightly lower density than the surrounding tissue as well as enhancement, with a portion protruding into the renal sinus region. Histological and immunohistochemical analyses of the biopsy specimen from the mass indicated a well-differentiated NET. After analysis of this case, we performed a literature review and herein discuss various techniques for imaging and pathological diagnosis of renal NETs. Additionally, we provide insights into the treatment options and prognosis for affected patients. By combining this case study with the existing published literature, we aim to offer a valuable reference for clinicians treatment patients diagnosed with renal NETs.
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Affiliation(s)
- Changxun Liu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
| | - Yixin Qi
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
| | - Youzhi Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
| | - Xiaokun Yang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
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Beydağı G, Alan Selçuk N, Kabasakal L. Alpha Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors. NUCLEAR MEDICINE SEMINARS 2023; 9:109-115. [DOI: 10.4274/nts.galenos.2023.0015] [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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Banerjee J, Ranjan RP, Alam MT, Deshmukh S, Tripathi PP, Gandhi S, Banerjee S. Virus-associated neuroendocrine cancers: Pathogenesis and current therapeutics. Pathol Res Pract 2023; 248:154720. [PMID: 37542862 DOI: 10.1016/j.prp.2023.154720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/22/2023] [Accepted: 07/26/2023] [Indexed: 08/07/2023]
Abstract
Neuroendocrine neoplasms (NENs) comprise malignancies involving neuroendocrine cells that often lead to fatal pathological conditions. Despite escalating global incidences, NENs still have poor prognoses. Interestingly, research indicates an intricate association of tumor viruses with NENs. However, there is a dearth of comprehension of the complete scenario of NEN pathophysiology and its precise connections with the tumor viruses. Interestingly, several cutting-edge experiments became helpful for further screening of NET for the presence of polyomavirus, Human papillomavirus (HPV), Kaposi sarcoma-associated herpesvirus (KSHV), Epstein Barr virus (EBV), etc. Current research on the neuroendocrine tumor (NET) pathogenesis provides new information concerning their molecular mechanisms and therapeutic interventions. Of note, scientists observed that metastatic neuroendocrine tumors still have a poor prognosis with a palliative situation. Different oncolytic vector has already demonstrated excellent efficacies in clinical studies. Therefore, oncolytic virotherapy or virus-based immunotherapy could be an emerging and novel therapeutic intervention. In-depth understanding of all such various aspects will aid in managing, developing early detection assays, and establishing targeted therapeutic interventions for NENs concerning tumor viruses. Hence, this review takes a novel approach to discuss the dual role of tumor viruses in association with NENs' pathophysiology as well as its potential therapeutic interventions.
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Affiliation(s)
- Juni Banerjee
- Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat 382426, India.
| | - Ramya P Ranjan
- National Institute of Animal Biotechnology (NIAB), Gachibowli, Hyderabad, Telangana 500032, India
| | - Md Tanjim Alam
- CSIR-Indian Institute of Chemical Biology (IICB), 4, Raja S. C. Mullick Road, Kolkata 700032, India; IICB-Translational Research Unit of Excellence(IICB-TRUE), Kolkata 700091, India
| | - Sanika Deshmukh
- Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat 382426, India
| | - Prem Prakash Tripathi
- CSIR-Indian Institute of Chemical Biology (IICB), 4, Raja S. C. Mullick Road, Kolkata 700032, India; IICB-Translational Research Unit of Excellence(IICB-TRUE), Kolkata 700091, India.
| | - Sonu Gandhi
- National Institute of Animal Biotechnology (NIAB), Gachibowli, Hyderabad, Telangana 500032, India.
| | - Shuvomoy Banerjee
- Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat 382426, India.
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21
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Gu Y, Liu D, Gao X, Zhou H, Song P, Qian X. Primary Surgical Management of Laryngeal Neuroendocrine Neoplasms: A Single Institution Case Series. EAR, NOSE & THROAT JOURNAL 2023:1455613231183882. [PMID: 37522341 DOI: 10.1177/01455613231183882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023] Open
Abstract
Objective: Laryngeal neuroendocrine neoplasms (NENs) are rare diseases. A single institution retrospective study was done of the outcome of patients with laryngeal NENs who undergo primary surgery as the first treatment modality. Methods: Retrospective analysis of medical records of patients with laryngeal NENs between 2009 and 2018. Cases were classified by applying the 2022 World Health organization Classification of Head and Neck Tumors (5th edition). Results: Six patients were eligible at our tertiary center: 1 large cell neuroendocrine carcinoma (NEC), 3 small cell NEC, 1 neuroendocrine tumor grade 1, and 1 neuroendocrine tumor grade 2. All admitted patients received upfront surgeries, including 3 transoral CO2 laser surgeries and 3 total laryngectomies with or without elective neck dissection. Four patients underwent subsequent chemoradiotherapy. Although 3 patients had recurrent disease and distal metastasis, the overall survival was generally improved. Conclusion: According to our institutional experience, upfront surgery in the first-line setting of a multi-modality approach with adjuvant chemoradiotherapy plays a very important role in managing laryngeal NECs, and may confer additional survival benefit in some patients of the large cell carcinoma subgroup.
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Affiliation(s)
- Yajun Gu
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Jiangsu Provincial Medical Key Discipline (Laboratory), Nanjing, China
| | - Dingding Liu
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Jiangsu Provincial Medical Key Discipline (Laboratory), Nanjing, China
| | - Xinyu Gao
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Jiangsu Provincial Medical Key Discipline (Laboratory), Nanjing, China
| | - Han Zhou
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Jiangsu Provincial Medical Key Discipline (Laboratory), Nanjing, China
| | - Panpan Song
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Jiangsu Provincial Medical Key Discipline (Laboratory), Nanjing, China
| | - Xiaoyun Qian
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Jiangsu Provincial Medical Key Discipline (Laboratory), Nanjing, China
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22
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Yang K, Li J, Cheng Y, Bai C. Evolving landscape of clinical trials in gastroenteropancreatic neuroendocrine neoplasms in the past two decades. Endocr Connect 2023; 12:EC-22-0441. [PMID: 36724047 PMCID: PMC10083666 DOI: 10.1530/ec-22-0441] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 02/01/2023] [Indexed: 02/02/2023]
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogenous malignancies that require well-designed trials to develop effective management strategies. This cross-sectional study aimed to illustrate the current landscape of clinical trials in GEP-NENs to provide insights for future research. MATERIALS AND METHODS We reviewed all clinical trials registered on ClinicalTrials.gov between 1 January 2000 and 31 December 2021 with GEP-NEN in the 'condition or disease' field. RESULTS We included 206 eligible trials. Most trials enrolled less than 50 patients (59.8%) and were sponsored by institutions other than government or industry (67.0%). Most trials were conducted in high-income countries (86.6%) and countries located in Europe (30.1%) or Northern America (29.6%). The overall result reporting rates of GEP-NEN trials was 41.4%, and the median time from primary completion to result reporting was 101 months. Characteristics that improved the reporting of results included larger sample size, tumor differentiation specification for inclusion, progression-free survival as primary endpoint, industry sponsorship, and multicenter or multinational participation (all P < 0.05). Compared with trials registered between 2000 and 2011 (n = 28), trials registered between 2012 and 2021 (n = 178) were more likely to specify the Ki-67 index for inclusion (68.0% vs 35.7%, P = 0.002) and to be conducted outside Europe or Northern America (16.4% vs 3.7%, P = 0.02), while the sample size and the sponsorship did not change significantly. CONCLUSIONS Novel management options have been explored for GEP-NENs with more specific inclusion criteria during the past two decades. More efforts are needed to promote international collaborations in clinical trials and enhance timely result dissemination.
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Affiliation(s)
- Kaili Yang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiarui Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yuejuan Cheng
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Correspondence should be addressed to C Bai or Y Cheng: or
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Correspondence should be addressed to C Bai or Y Cheng: or
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23
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Smith J, Barnett E, Rodger EJ, Chatterjee A, Subramaniam RM. Neuroendocrine Neoplasms: Genetics and Epigenetics. PET Clin 2023; 18:169-187. [PMID: 36858744 DOI: 10.1016/j.cpet.2022.11.003] [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: 03/02/2023]
Abstract
Neuroendocrine neoplasms (NENs) are a group of rare, heterogeneous tumors of neuroendocrine cell origin, affecting a range of different organs. The clinical management of NENs poses significant challenges, as tumors are often diagnosed at an advanced stage where overall survival remains poor with current treatment regimens. In addition, a host of complex and often unique molecular changes underpin the pathobiology of each NEN subtype. Exploitation of the unique genetic and epigenetic signatures driving each NEN subtype provides an opportunity to enhance the diagnosis, treatment, and monitoring of NEN in an emerging era of individualized medicine.
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Affiliation(s)
- Jim Smith
- Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin 9054, New Zealand; Te Whatu Ora - Southern, Dunedin Public Hospital, 270 Great King Street, PO Box 913, Dunedin, New Zealand.
| | - Edward Barnett
- Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin 9054, New Zealand
| | - Euan J Rodger
- Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin 9054, New Zealand
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin 9054, New Zealand
| | - Rathan M Subramaniam
- Department of Medicine, Otago Medical School, University of Otago, PO Box 56, Dunedin 9054, New Zealand; Department of Radiology, Duke University, 2301 Erwin Rd, BOX 3808, Durham, NC 27705, USA
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24
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Nishioka H. Aggressive pituitary tumors (PitNETs). Endocr J 2023; 70:241-248. [PMID: 36858483 DOI: 10.1507/endocrj.ej23-0007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023] Open
Abstract
The majority of anterior pituitary tumors behave benignly, that is, they grow slowly and do not metastasize, and were therefore called adenomas. However, they would frequently invade adjacent structures, leading to recurrence. One of the misleading assumptions in their previous classification was the simplistic distinction made between adenoma and carcinoma. In the upcoming WHO 2022 classification, a new terminology will be introduced: pituitary neuroendocrine tumor (PitNET) which is consistent with that used for other neuroendocrine neoplasms. In general, aggressive PitNETs are invasive and proliferative tumors with frequent recurrences, resistant to conventional treatments, and yet virtually without metastases. At present, no single morphological or histological marker has been shown as yet to reliably predict their aggressive behavior. In terms of treatment, temozolomide (TMZ) had been considered promising and the sole therapeutic option for aggressive and malignant PitNETs following failure of standard therapies. However, recent reports have disclosed that TMZ does not provide long-term control of many aggressive PitNETs. A further multidisciplinary approach is necessary for both reliable prediction and successful management of aggressive PitNETs.
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Affiliation(s)
- Hiroshi Nishioka
- Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Tokyo 105-8470, Japan
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25
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Batts TL, Sasaki E, Miller M, Sparago J, Bauer RW, Paulsen D, Boudreaux B, Liu CC, Byrum SD, Johnston AN. Neoplastic signatures: Comparative proteomics of canine hepatobiliary neuroendocrine tumors to normal niche tissue. PLoS One 2023; 18:e0280928. [PMID: 36696389 PMCID: PMC9876354 DOI: 10.1371/journal.pone.0280928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 01/11/2023] [Indexed: 01/26/2023] Open
Abstract
Hepatobiliary neuroendocrine neoplasms are rare cancers in humans and dogs. To date, no large-scale primary hepatobiliary neoplasm omics analyses exist in any species. This limits the development of diagnostic biomarkers and targeted therapeutics. Neuroendocrine cancers are a heterogenous group of neoplasms categorized by their tissue-of-origin. Because the anatomic niche of neuroendocrine neoplasms shapes tumor phenotype, we sought to compare the proteomes of 3 canine hepatobiliary neoplasms to normal hepatobiliary tissue and adrenal glands with the objective of identifying unique protein signatures. Protein was extracted from formalin-fixed paraffin-embedded samples and submitted for tandem mass spectroscopy. Thirty-two upregulated and 126 downregulated differentially expressed proteins were identified. Remarkably, 6 (19%) of the upregulated proteins are correlated to non-hepatobiliary neuroendocrine neoplasia and 16 (50%) are functionally annotated within the exosome cellular compartment key to neuroendocrine signaling. Twenty-six (21%) downregulated proteins are enriched in metabolic pathways consistent with alterations in cancer. These results suggests that characteristic neoplastic protein signatures can be gleaned from small data sets using a comparative proteomics approach.
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Affiliation(s)
- Tifini L. Batts
- Veterinary Clinical Sciences Department, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, United States of America
| | - Emi Sasaki
- Department of Pathobiological Sciences and Louisiana Animal Disease Diagnostic Laboratory, Baton Rouge, Louisiana, United States of America
| | - Mayzie Miller
- Veterinary Clinical Sciences Department, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, United States of America
| | - Joshua Sparago
- Veterinary Clinical Sciences Department, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, United States of America
| | - Rudy W. Bauer
- Department of Pathobiological Sciences and Louisiana Animal Disease Diagnostic Laboratory, Baton Rouge, Louisiana, United States of America
| | - Daniel Paulsen
- Department of Pathobiological Sciences and Louisiana Animal Disease Diagnostic Laboratory, Baton Rouge, Louisiana, United States of America
| | - Bonnie Boudreaux
- Veterinary Clinical Sciences Department, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, United States of America
| | - Chin-Chi Liu
- Veterinary Clinical Sciences Department, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, United States of America
| | - Stephanie D. Byrum
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
- Arkansas Children’s Research Institute, Little Rock, AR, United States of America
| | - Andrea N. Johnston
- Veterinary Clinical Sciences Department, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, United States of America
- * E-mail:
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26
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Shi M, Jakobsson V, Greifenstein L, Khong PL, Chen X, Baum RP, Zhang J. Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists. Front Med (Lausanne) 2022; 9:1034315. [PMID: 36569154 PMCID: PMC9767967 DOI: 10.3389/fmed.2022.1034315] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly expanding clinical applications. By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision. Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells' DNA, which induces apoptosis. In addition, to avoid damage to surrounding normal cells, PRRT privileges the use of radionuclides that have little penetrating and more energetic (and thus more ionizing) radiations. To date, the most frequently radioisotopes are β- emitters, particularly Yttrium-90 (90Y) and Lutetium-177 (177Lu), labeled SSTR agonists. Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT. Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment. Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue. Actinium-225 (225Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types. In this article, we give a review of preclinical and clinical applications of 225Ac-PRRT in NETs, discuss the strengths and challenges of 225Ac complexes being used in PRRT; and envision the prospect of 225Ac-PRRT as a future alternative in the treatment of NETs.
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Affiliation(s)
- Mengqi Shi
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Vivianne Jakobsson
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Academy for Precision Oncology, International Centers for Precision Oncology (ICPO), Wiesbaden, Germany
| | - Lukas Greifenstein
- CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, Wiesbaden, Germany
| | - Pek-Lan Khong
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xiaoyuan Chen
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore
- Agency for Science, Technology, and Research (A*STAR), Institute of Molecular and Cell Biology, Singapore, Singapore
| | - Richard P. Baum
- CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, Wiesbaden, Germany
| | - Jingjing Zhang
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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27
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Insights into Epigenetic Changes Related to Genetic Variants and Cells-of-Origin of Pancreatic Neuroendocrine Tumors: An Algorithm for Practical Workup. Cancers (Basel) 2022; 14:cancers14184444. [PMID: 36139607 PMCID: PMC9496769 DOI: 10.3390/cancers14184444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/04/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Pancreatic neuroendocrine tumors are composite entities due to their heterogeneity illustrated in clinical behavior, mutational pattern, and site of origin. Pancreatic neuroendocrine tumors display a low mutation burden with frequently epigenetic alterations, such as histone modifications, chromatin remodeling, or DNA methylation status. Using the epigenomic data of the pancreatic neuroendocrine tumors converged to the identification of molecularly distinct subgroups. Furthermore, epigenetic signatures could be used as biomarkers due to their link to cell lineages and genetic driver mutations. We integrated the current knowledge on genetic and epigenetic alterations involved in endocrine lineage associated with these neoplasms to present a pathway-based overview. In this review, we suggest a simplified algorithm on how to manage pancreatic neuroendocrine tumors from a practical perspective based on pathologist ’analysis. Abstract Current knowledge on the molecular landscape of pancreatic neuroendocrine tumors (PanNETs) has advanced significantly. Still, the cellular origin of PanNETs is uncertain and the associated mechanisms remain largely unknown. DAXX/ATRX and MEN1 are the three most frequently altered genes that drive PanNETs. They are recognized as a link between genetics and epigenetics. Moreover, the acknowledged impact on DNA methylation by somatic mutations in MEN1 is a valid hallmark of epigenetic mechanism. DAXX/ATRX and MEN1 can be studied at the immunohistochemical level as a reliable surrogate for sequencing. DAXX/ATRX mutations promote alternative lengthening of telomeres (ALT) activation, determined by specific fluorescence in situ hybridization (FISH) analysis. ALT phenotype is considered a significant predictor of worse prognosis and a marker of pancreatic origin. Additionally, ARX/PDX1 expression is linked to important epigenomic alterations and can be used as lineage associated immunohistochemical marker. Herein, ARX/PDX1 association with DAXX/ATRX/MEN1 and ALT can be studied through pathological assessment, as these biomarkers may provide important clues to the mechanism underlying disease pathogenesis. In this review, we present an overview of a new approach to tumor stratification based on genetic and epigenetic characteristics as well as cellular origin, with prognostic consequences.
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Escobar KM, Vicente-Villardon JL, Villacís Gonzalez RE, Castillo Cordova PH, Sánchez Rodríguez JM, De la Cruz-Velez M, Siteneski A. Neuroendocrine Tumors: An Analysis of Prevalence, Incidence, and Survival in a Hospital-Based Study in Ecuador. Healthcare (Basel) 2022; 10:1569. [PMID: 36011226 PMCID: PMC9408119 DOI: 10.3390/healthcare10081569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/05/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
Neuroendocrine tumors (NETs) represent a heterogeneous malignancy group of neoplasms, with a limited amount of data from Latin America. Thus, this observational study aimed to provide data about the prevalence, incidence, and survival rates for NET in Ecuadorian hospitals. The study was conducted using data from the Society for the Fight Against Cancer (SOLCA). We evaluated patients with NETs (2000−2020) using the HJ-Biplot method and Cox proportional hazards. Annual age-adjusted incidence and limited-duration prevalence in multivariable analyses as well as hazard ratios (HRs) for mortality and survival were obtained. In the years 2000−2020, the age-adjusted incidence rate increased by 9-fold in the stomach and by 7-fold in the breast. The incidence rates were 1.38 per 100,000 persons in the lung and at 1.79 per 100,000 persons in gastroenteropancreatic sites (rectum, stomach, and pancreas). The prevalence increased from 0.0027% in 2000 to 0.0736% in 2019 and 0.0245% in 2020. Overall survival was worse for metastatic NETs (HR, 4.061; 95% CI, 1.932−8.540; p < 0.001) and advanced local NETs (HR, 2.348; 95% CI, 1.007−5.475 p < 0.048) than for localized NETs. In conclusion, the NET incidence increased in the last 20 years and survival decreased over time, especially for metastatic tumors in the pancreas and the nostril.
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Affiliation(s)
- Karime Montes Escobar
- Department of Mathematics and Statistics, Institute of Basic Sciences, Universidad Técnica de Manabí, Portoviejo 130105, Ecuador
- Statistics Department, University of Salamanca, 37007 Salamanca, Spain
| | | | | | | | - Johanna Mabel Sánchez Rodríguez
- Facultad de Medicina, Universidad Laica Eloi Alfaro de Manabí, Manta 130203, Ecuador
- Facultad de Ciencias de la Salud, Universidad Estatal del Sur de Manabi, Jipijapa 130650, Ecuador
| | - Melina De la Cruz-Velez
- Faculty of Health Sciences, Medicine Career, Universidad Técnica de Manabí, Portoviejo 130105, Ecuador
| | - Aline Siteneski
- Research Institute, Universidad Técnica de Manabí, Portoviejo 130105, Ecuador
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Clinical Data-CT Radiomics-Based Model for Predicting Prognosis of Patients with Gastrointestinal Pancreatic Neuroendocrine Neoplasms (GP-NENs). COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:4186305. [PMID: 36035279 PMCID: PMC9410919 DOI: 10.1155/2022/4186305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/08/2022] [Accepted: 07/23/2022] [Indexed: 12/01/2022]
Abstract
Purpose Based on computerized tomography (CT) radiomics and clinical data, a model was established to predict the prognosis of patients with gastrointestinal pancreatic neuroendocrine neoplasms (GP-NENs). Methods In the data collection, the clinical imaging and survival follow-up data of 225 GP-NENs patients admitted to Xiangyang No.1 People's Hospital and Jiangsu Province Hospital of Chinese Medicine from August 2015 to February 2021 were collected. According to the follow-up results, they were divided into the nonrecurrent group (n = 108) and the recurrent group (n = 117), based on which a training set and a test set were established at a ratio of 7/3. In the training set, a variety of models were established with significant clinical and imaging data (P < 0.05) to predict the prognosis of GP-NENs patients, and then these models were verified in the test set. Results Our newly developed combined prediction model had high predictive efficacy. Univariate analysis showed that Radscore 1/2/3, age, Ki-67 index, tumor pathological type, tumor primary site, and TNM stage were risk factors for the prognosis of GP-NENs patients (all P < 0.05). The area under the receiver operating characteristic (ROC) curves (AUC) of the combined model was significantly higher [AUC:0.824, 95% CI 0.0342 (0.751-0.883)] than that of the clinical data model [AUC:0.786, 95% CI 0.0384(0.709-0.851)] and the radiomics model [AUC:0.712, 95% CI 0.0426(0.631-0.785)]. The decision curve also confirmed that the combined model had a higher clinical net benefit. The same results were achieved in the test set. Conclusion The prognosis of patients with GP-NENs is generally poor. The combined model based on clinical data and CT radiomics can help to early predict the prognosis of patients with GP-NENs, and then necessary interventions could be provided to improve the survival rate and quality of life of patients.
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30
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Fuchs TL, Chou A, Ahadi M, Sheen A, Sioson L, Mittal A, Samra J, Gill AJ. Necrosis is an independent predictor of disease-free and overall survival in pancreatic well-differentiated neuroendocrine tumours (NETs): a proposal to include it in grading systems. Pathology 2022; 54:855-862. [DOI: 10.1016/j.pathol.2022.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/27/2022] [Accepted: 05/08/2022] [Indexed: 11/16/2022]
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Neuroendocrine Neoplasms of the Gynecologic Tract. Cancers (Basel) 2022; 14:cancers14071835. [PMID: 35406607 PMCID: PMC8998008 DOI: 10.3390/cancers14071835] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/01/2022] [Accepted: 04/01/2022] [Indexed: 01/11/2023] Open
Abstract
Simple Summary Neuroendocrine refers to the cells that synthesize and secrete messenger chemicals such as neuropeptides and amines. Neuroendocrine neoplasms (NENs) are aggressive tumors arising from neuroendocrine cells, with an annual incidence of 6.98/100,000 and a prevalence of 170,000 in the United States. Primary gynecologic NENs constitute ≤2% of female reproductive tumors. NENs of the gynecologic tract are associated with high recurrence rates and dismal prognosis, making their treatment challenging. This article focuses on the updated staging classifications, clinicopathological characteristics, imaging, and management of NENs of the gynecological tract. Abstract Gynecological tract neuroendocrine neoplasms (NEN) are rare, aggressive tumors from endocrine cells derived from the neuroectoderm, neural crest, and endoderm. The primary gynecologic NENs constitute 2% of gynecologic malignancies, and the cervix is the most common site of NEN in the gynecologic tract. The updated WHO classification of gynecologic NEN is based on the Ki-67 index, mitotic index, and tumor characteristics such as necrosis, and brings more uniformity in the terminology of NENs like other disease sites. Imaging plays a crucial role in the staging, triaging, restaging, and surveillance of NENs. The expression of the somatostatin receptors on the surface of neuroendocrine cells forms the basis of increasing evaluation with functional imaging modalities using traditional and new tracers, including 68Ga-DOTA-Somatostatin Analog-PET/CT. Management of NENs involves a multidisciplinary approach. New targeted therapies could improve the paradigm of care for these rare malignancies. This article focuses on the updated staging classifications, clinicopathological characteristics, imaging, and management of gynecologic NENs of the cervix, ovary, endometrium, vagina, and vulva, emphasizing the relatively common cervical neuroendocrine carcinomas among these entities.
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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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Ichikawa Y, Kobayashi N, Takano S, Kato I, Endo K, Inoue T. Net theranostics. Cancer Sci 2022; 113:1930-1938. [PMID: 35271754 PMCID: PMC9207370 DOI: 10.1111/cas.15327] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 02/17/2022] [Accepted: 03/03/2022] [Indexed: 11/30/2022] Open
Abstract
Theranostics is a term coined by combining the words “therapeutics” and “diagnostics,” referring to single chemical entities developed to deliver therapy and diagnosis simultaneously. Neuroendocrine tumors are rare cancers that occur in various organs of the body, and they express neuroendocrine factors such as chromogranin A and somatostatin receptor. Somatostatin analogs bind to somatostatin receptor, and when combined with diagnostic radionuclides, such as gamma‐emitters, are utilized for diagnosis of neuroendocrine tumor. Somatostatin receptor scintigraphy when combined with therapeutic radionuclides, such as beta‐emitters, are effective in treating neuroendocrine tumor as peptide receptor radionuclide therapy. Somatostatin receptor scintigraphy and peptide receptor radionuclide therapy are some of the most frequently used and successful theranostics for neuroendocrine tumor. In Japan, radiopharmaceuticals are regulated under a complex law system, creating a significant drug lag, which is a major public concern. It took nearly 10 years to obtain the approval for somatostatin receptor scintigraphy and peptide receptor radionuclide therapy use by the Japanese government. In 2021, 111Lu‐DOTATATE (Lutathera), a drug for peptide receptor radionuclide therapy, was covered by insurance in Japan. In this review, we summarize the history of the development of neuroendocrine tumor theranostics and theranostics in general, as therapeutic treatment for cancer in the future. Furthermore, we briefly address the Japanese point of view regarding the development of new radiopharmaceuticals.
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Affiliation(s)
- Yasushi Ichikawa
- Department of Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | - Shoko Takano
- Department of Radiation Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ikuma Kato
- Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Keigo Endo
- Kyoto College of Medical Science, Kyoto, Japan
| | - Tomio Inoue
- Department of Radiation Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.,Shonan Kamakura General Hospital, Kamakura, Japan
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Neuroendocrine Tumors: a Relevant Clinical Update. Curr Oncol Rep 2022; 24:703-714. [PMID: 35254612 DOI: 10.1007/s11912-022-01217-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2021] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW The field of neuroendocrine oncology has changed much since the time of Oberndorfer first described and coined the term carcinoid. The purpose of this review is to summarize recent findings and highlight clinically relevant updates in the management of NENs, particularly those that are practice changing. RECENT FINDINGS Neuroendocrine tumors (NETs) have replaced carcinoid tumor, for the most part. The classification of neuroendocrine neoplasms (NENs) improved, and the epidemiological understanding of this disease group also expanded with global collaborations and maturation of large tumor registries. Clarity in the utility of some NET biomarkers continues to be evolving. Knowledge of molecular drivers of tumorigenesis increases, and scientific/technological advancements lead the way to multiple drug approvals for the treatment of advanced NETs. The incidence and prevalence of NENs continue to increase, and patients are living longer. Better understanding of molecular drivers and further understanding of the role of immunotherapy in NENs will further elevate the level of care and transform care for all patients with NENs.
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Mejia A, Vivian E, Nwogu C, Shah J, Longoria R, Vo A, Shahin I, Verma J, Bageac A. Peptide receptor radionuclide therapy implementation and results in a predominantly gastrointestinal neuroendocrine tumor population: A two-year experience in a nonuniversity setting. Medicine (Baltimore) 2022; 101:e28970. [PMID: 35244064 PMCID: PMC8896579 DOI: 10.1097/md.0000000000028970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 02/10/2022] [Indexed: 01/04/2023] Open
Abstract
Neuroendocrine tumors (NETs) are rare, but the incidence and prevalence of NETs are increasing in the United States. While surgery is the preferred treatment for NETs, it is not a viable option for metastatic disease. Lutathera (177Lu-DOTATATE) is approved by the United States Food and Drug Administration and the European Medicines Agency for the treatment of gastroenteropancreatic (GEP)-NETs in adults. There is limited information on GEP-NET treatment responses to Lutathera.Our institution launched a peptide receptor radionuclide therapy (PRRT) service line using Lutathera with involvement from a multidisciplinary team and complete collaboration between hospital administration and clinical providers. A prospective registry study was also established in order to collect patient demographics and clinical data regarding the treatment of GEP primary NETs with Lutathera.Between August 2018 and July 2020, 35 GEP-NET patients were treated with Lutathera, of which 65.71% received 4 complete cycles and 25.71% received 3 cycles; 5.71% and 2.86% received 2 and 1 cycles of PRRT, respectively. Most adverse events during the course of our study were low grade using the common terminology criteria for adverse events system. Of the patients who completed all 4 cycles: 22% showed partial response to Lutathera, 44% showed stable disease, and 13% showed disease progression based on a qualitative assessment of positron emission tomography/computed tomography imaging.From our experience, Lutathera was well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with GEP-NET treatment as well as financial considerations for hospitals embarking on a PRRT program.
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Affiliation(s)
- Alejandro Mejia
- The Liver Institute, Methodist Dallas Medical Center, Dallas, TX
| | - Elaina Vivian
- Methodist Digestive Institute, Methodist Dallas Medical Center, Dallas, TX
| | - Christiana Nwogu
- Methodist Digestive Institute, Methodist Dallas Medical Center, Dallas, TX
| | - Jimmy Shah
- Methodist Digestive Institute, Methodist Dallas Medical Center, Dallas, TX
| | - Raquel Longoria
- Cancer Program Administration, Methodist Dallas Medical Center, Dallas, TX
| | - Allison Vo
- Methodist Digestive Institute, Methodist Dallas Medical Center, Dallas, TX
- Cancer Program Administration, Methodist Dallas Medical Center, Dallas, TX
| | - Islam Shahin
- Radiology Associates of North Texas, Fort Worth, TX
| | - Jonathan Verma
- Texas Oncology – Methodist Dallas Medical Center, Dallas, TX
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Mete O, Wenig BM. Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Overview of the 2022 WHO Classification of Head and Neck Neuroendocrine Neoplasms. Head Neck Pathol 2022; 16:123-142. [PMID: 35312985 PMCID: PMC9018952 DOI: 10.1007/s12105-022-01435-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 02/21/2022] [Indexed: 12/17/2022]
Abstract
This review article provides a brief overview of the new WHO classification by adopting a question-answer model to highlight the spectrum of head and neck neuroendocrine neoplasms which includes epithelial neuroendocrine neoplasms (neuroendocrine tumors and neuroendocrine carcinomas) arising from upper aerodigestive tract and salivary glands, and special neuroendocrine neoplasms including middle ear neuroendocrine tumors (MeNET), ectopic or invasive pituitary neuroendocrine tumors (PitNET; formerly known as pituitary adenoma) and Merkel cell carcinoma as well as non-epithelial neuroendocrine neoplasms (paragangliomas). The new WHO classification follows the IARC/WHO nomenclature framework and restricts the diagnostic term of neuroendocrine carcinoma to poorly differentiated epithelial neuroendocrine neoplasms. In this classification, well-differentiated epithelial neuroendocrine neoplasms are termed as neuroendocrine tumors (NET), and are graded as G1 NET (no necrosis and < 2 mitoses per 2 mm2; Ki67 < 20%), G2 NET (necrosis or 2-10 mitoses per 2 mm2, and Ki67 < 20%) and G3 NET (> 10 mitoses per 2 mm2 or Ki67 > 20%, and absence of poorly differentiated cytomorphology). Neuroendocrine carcinomas (> 10 mitoses per 2 mm2, Ki67 > 20%, and often associated with a Ki67 > 55%) are further subtyped based on cytomorphological characteristics as small cell and large cell neuroendocrine carcinomas. Unlike neuroendocrine carcinomas, head and neck NETs typically show no aberrant p53 expression or loss of RB reactivity. Ectopic or invasive PitNETs are subtyped using pituitary transcription factors (PIT1, TPIT, SF1, GATA3, ER-alpha), hormones and keratins (e.g., CAM5.2). The new classification emphasizes a strict correlation of morphology and immunohistochemical findings in the accurate diagnosis of neuroendocrine neoplasms. A particular emphasis on the role of biomarkers in the confirmation of the neuroendocrine nature of a neoplasm and in the distinction of various neuroendocrine neoplasms is provided by reviewing ancillary tools that are available to pathologists in the diagnostic workup of head and neck neuroendocrine neoplasms. Furthermore, the role of molecular immunohistochemistry in the diagnostic workup of head and neck paragangliomas is discussed. The unmet needs in the field of head and neck neuroendocrine neoplasms are also discussed in this article. The new WHO classification is an important step forward to ensure accurate diagnosis that will also form the basis of ongoing research in this field.
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Affiliation(s)
- Ozgur Mete
- Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON, Canada.
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
- Endocrine Oncology Site, The Princess Margaret Cancer Center, Toronto, ON, Canada.
| | - Bruce M Wenig
- Department of Pathology Moffitt Cancer Center, Tampa, FL, USA
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Kohno S. Diagnosis and Surgical Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms: A Literature Review. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:115-125. [PMID: 35399177 PMCID: PMC8962810 DOI: 10.21873/cdp.10085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/31/2022] [Indexed: 06/14/2023]
Abstract
This review aimed to highlight the characteristics and surgical treatments of tumours, and answer questions regarding the assessment of gastrointestinal neuroendocrine neoplasms (NENs) and optimal therapy. NENs comprise tumours that can produce hormones and cause a secretory syndrome. The diagnostic method and accuracy differ depending on the site of occurrence; hence, the relevant scientific society has created NEN treatment guidelines for each organ. Gastroenteric pancreatic (GEP) NENs have been unified and classified together according to the 2019 World Health Organization classification. Treatment is based on complete tumour resection, and when metastatic or primary lesions cannot be completely resected, lesions and symptoms are treated. Except for surgery for NENs, chemotherapy, molecularly targeted drugs, transarterial chemoembolization, etc., have also been confirmed as treatments. GEP NEN treatment methods will continue to advance and change because of surgery and other advances in treatment and diagnostic methods.
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Affiliation(s)
- Shuzo Kohno
- Department of Surgery, The Jikei University Katsushika Medical Center, Tokyo, Japan
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38
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彭 金, 李 笑, 刘 柱, 崔 哲, 金 红. [Clinical analysis of 31 patients with sinonasal neuroendocrine carcinoma]. LIN CHUANG ER BI YAN HOU TOU JING WAI KE ZA ZHI = JOURNAL OF CLINICAL OTORHINOLARYNGOLOGY, HEAD, AND NECK SURGERY 2022; 36:32-35. [PMID: 34979616 PMCID: PMC10128225 DOI: 10.13201/j.issn.2096-7993.2022.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Indexed: 06/14/2023]
Abstract
Objective:To investigate the characteristics and prognostic factors of sinonasal neuroendocrine carcinoma （SNEC）. Methods:The clinical data of 31 patients with SNEC were retrospectively analyzed. Among the 31 patients, 3 cases were simply surgically removed, 4 cases were surgery + radiotherapy, 4 cases were surgery + chemotherapy, 10 cases were surgery + chemoradiotherapy, and 10 cases were simply given chemoradiotherapy without surgery. The study follow-up 8-64 months. Results:By the end of follow-up, 2 patients were lost to follow-up, 17 died, 12 survival, 8 relapsed and 5-year survival rate was 36.4％. High TNM stage, lymph node metastasis, skull base infiltration and Ki-67≥55％ were the negative prognostic factors for survival. Conclusion:SNEC is a rare aggressive tumor, with poor prognosis, high local recurrence rate, metastasis tendency, hidden disease. The comprehensive treatment of surgery combined with chemoradiotherapy is still the best treatment.
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Affiliation(s)
- 金林 彭
- 郑州大学第一附属医院鼻科(郑州，450052)Department of Rhinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - 笑秋 李
- 郑州人民医院耳鼻咽喉头颈外科Department of Otolaryngology Head and Neck Surgery, Zhengzhou People's Hospital
| | - 柱 刘
- 郑州市中心医院耳鼻咽喉头颈外科Department of Otolaryngology Head and Neck Surgery, Zhengzhou Central Hospital
| | - 哲卿 崔
- 郑州大学第一附属医院鼻科(郑州，450052)Department of Rhinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - 红军 金
- 郑州大学第一附属医院鼻科(郑州，450052)Department of Rhinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
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Abstract
Understanding the role played by genetic variations in diseases, exploring genomic variants and discovering disease-associated loci are among the most pressing challenges of genomic medicine. A huge and ever-increasing amount of information is available to researchers to address these challenges. Unfortunately, it is stored in fragmented ontologies and databases, which use heterogeneous formats and poorly integrated schemas. To overcome these limitations, we propose a linked data approach, based on the formalism of multilayer networks, able to integrate and harmonize biomedical information from multiple sources into a single dense network covering different aspects on Neuroendocrine Neoplasms (NENs). The proposed integration schema consists of three interconnected layers representing, respectively, information on the disease, on the affected genes, on the related biological processes and molecular functions. An easy-to-use client-server application was also developed to browse and search for information on the model supporting multilayer network analysis.
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40
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Risk Factors Associated with the Development of Metastases in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Retrospective Analysis. J Clin Med 2021; 11:jcm11010060. [PMID: 35011798 PMCID: PMC8745312 DOI: 10.3390/jcm11010060] [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: 11/29/2021] [Revised: 12/21/2021] [Accepted: 12/21/2021] [Indexed: 11/30/2022] Open
Abstract
Neuroendocrine tumors develop from systemic endocrine and nerve cells, and their occurrence has increased recently. Since these tumors are heterogeneous, pathological classification has been based on the affected organ. In 2019, the World Health Organization introduced a change expected to influence neuroendocrine tumor research, as gastroenteropancreatic neuroendocrine tumors are now included within a unified classification. This retrospective study aimed to investigate the characteristics (e.g., lymph node metastases and all other metastases) of gastroenteropancreatic neuroendocrine tumors using this new classification in 50 cases. Tumor size, depth, MIB-1 index, lymphatic invasion, venous invasion, and neuroendocrine tumor grade were significantly correlated with lymph node metastasis and other metastases. The venous invasion was more strongly correlated with lymph node metastasis and all other types of metastases than with lymphatic invasion. Identification rates for lymphatic invasion were considered lower because of structural problems such as lymphatic vessels being much thinner than veins. However, venous invasion was considered effective in compensating for the low identification rate in cases of lymphatic invasion. In future research, a unified classification and standardized framework for assessment will be important when analyzing the characteristics of neuroendocrine tumors, and large-scale studies are required.
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Emerging Therapeutic Concepts and Latest Diagnostic Advancements Regarding Neuroendocrine Tumors of the Gynecologic Tract. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:medicina57121338. [PMID: 34946283 PMCID: PMC8703600 DOI: 10.3390/medicina57121338] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/29/2021] [Accepted: 12/02/2021] [Indexed: 12/21/2022]
Abstract
Neuroendocrine neoplasms (NENs) are particularly rare in all sites of the gynecological tract and include a variety of neoplasms with variable prognosis, dependent on histologic subtype and site of origin. Following the expert consensus proposal of the International Agency for Research on Cancer (IARC), the approach in the latest World Health Organization (WHO) Classification System of the Female Genital Tumours is to use the same terminology for NENs at all body sites. The main concept of this novel classification framework is to align it to all other body sites and make a clear distinction between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The previous WHO Classification System of the Female Genital Tumours featured more or less the same principle, but used the terms ‘low-grade neuroendocrine tumor’ and ‘high-grade neuroendocrine carcinoma’. Regardless of the terminology used, each of these two main categories include two distinct morphological subtypes: NETs are represented by typical and atypical carcinoid and NEC are represented by small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). High-grade NECs, especially small cell neuroendocrine carcinoma tends to be more frequent in the uterine cervix, followed by the endometrium, while low-grade NETs usually occur in the ovary. NENs of the vulva, vagina and fallopian tube are exceptionally rare, with scattered case reports in the scientific literature.
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42
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Ciobanu OA, Martin S, Fica S. Perspectives on the diagnostic, predictive and prognostic markers of neuroendocrine neoplasms (Review). Exp Ther Med 2021; 22:1479. [PMID: 34765020 PMCID: PMC8576627 DOI: 10.3892/etm.2021.10914] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumors with different types of physiology and prognosis. Therefore, prognostic information, including morphological differentiation, grade, tumor stage and primary location, are invaluable and contribute to the formulation of treatment decisions. Biomarkers that are currently used, including chromogranin A (CgA), serotonin and neuron-specific enolase, are singular parameters that cannot be used to accurately predict variables associated with tumor growth, including proliferation, metabolic rate and metastatic potential. In addition, site-specific biomarkers, such as insulin and gastrin, cannot be applied to all types of NENs. The clinical application of broad-spectrum markers, as it is the case for CgA, remains controversial despite being widely used. Due to limitations of the currently available mono-analyte biomarkers, recent studies were conducted to explore novel parameters for NEN diagnosis, prognosis, therapy stratification and evaluation of treatment response. Identification of prognostic factors for predicting NEN outcome is a critical requirement for the planning of adequate clinical management. Advances in ‘liquid’ biopsies and genomic analysis techniques, including microRNA, circulating tumor DNA or circulating tumor cells and sophisticated biomathematical analysis techniques, such as NETest or molecular image-based biomarkers, are currently under investigation as potentially novel tools for the management of NENs in the future. Despite these recent findings yielding promising observations, further research is necessary. The present review therefore summarizes the existing knowledge and recent advancements in the exploration of biochemical markers for NENs, with focus on gastroenteropancreatic-neuroendocrine tumors.
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Affiliation(s)
- Oana Alexandra Ciobanu
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| | - Sorina Martin
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| | - Simona Fica
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
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Treglia G, Sadeghi R, Giovinazzo F, Galiandro F, Annunziata S, Muoio B, Kroiss AS. PET with Different Radiopharmaceuticals in Neuroendocrine Neoplasms: An Umbrella Review of Published Meta-Analyses. Cancers (Basel) 2021; 13:cancers13205172. [PMID: 34680321 PMCID: PMC8533943 DOI: 10.3390/cancers13205172] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/03/2021] [Accepted: 10/11/2021] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Functional imaging methods and, in particular, positron emission tomography (PET) using several radiopharmaceuticals may play a pivotal role in patients with neuroendocrine neoplasms including neuroendocrine tumors (NETs) located in different sites, paraganglioma (PGL) and neuroblastoma (NB), recurrent medullary thyroid carcinoma (rMTC) and aggressive neuroendocrine neoplasms. Several radiopharmaceuticals can be used in this setting such as Gallium-68 somatostatin analogues (68Ga-SSA), Fluorine-18 fluorodihydroxyphenylalanine (18F-FDOPA), Gallium-68 exendin-4 (68Ga-exendin-4), Fluorine-18 fluorodeoxyglucose (18F-FDG). This umbrella review provides an evidence-based summary about meta-analyses on diagnostic performance, prognostic value, clinical impact and safety of PET with different radiopharmaceuticals in patients with neuroendocrine neoplasms. Overall, evidence-based data support the use of PET with different radiopharmaceuticals in patients with neuroendocrine neoplasms but with specific indications for each radiopharmaceutical. Abstract Background: Several meta-analyses have reported quantitative data about the diagnostic performance, the prognostic value, the impact on management and the safety of positron emission tomography (PET) including related hybrid modalities (PET/CT or PET/MRI) using different radiopharmaceuticals in patients with neuroendocrine neoplasms. We performed an umbrella review of published meta-analyses to provide an evidence-based summary. Methods: A comprehensive literature search of meta-analyses listed in PubMed/MEDLINE and Cochrane Library databases was carried out (last search date: 30 June 2021). Results: Thirty-four published meta-analyses were selected and summarized. About the diagnostic performance: 68Ga-SSA PET yields high diagnostic performance in patients with NETs and PGL; 18F-FDOPA PET yields good diagnostic performance in patients with intestinal NETs, PGL, NB, being the best available PET method in detecting rMTC; 68Ga-exendin-4 PET has good diagnostic accuracy in detecting insulinomas; 18F-FDG PET has good diagnostic performance in detecting aggressive neuroendocrine neoplasms. About the prognostic value: 68Ga-SSA PET has a recognized prognostic value in well-differentiated NETs, whereas 18F-FDG PET has a recognized prognostic value in aggressive neuroendocrine neoplasms. A significant clinical impact of 68Ga-SSA PET and related hybrid modalities in patients with NETs was demonstrated. There are no major toxicities or safety issues related to the use of PET radiopharmaceuticals in patients with neuroendocrine neoplasms. Conclusions: Evidence-based data support the use of PET with different radiopharmaceuticals in patients with neuroendocrine neoplasms with specific indications for each radiopharmaceutical.
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Affiliation(s)
- Giorgio Treglia
- Clinic of Nuclear Medicine, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland
- Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, 1011 Lausanne, Switzerland
- Academic Education, Research and Innovation Area, General Directorate, Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera italiana, 6900 Lugano, Switzerland
- Correspondence: ; Tel.: +41-(91)-8118919
| | - Ramin Sadeghi
- Nuclear Medicine Research Center, Mashhad University of Medical Sciences, Mashhad 9919991766, Iran;
| | - Francesco Giovinazzo
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.G.); (F.G.)
| | - Federica Galiandro
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.G.); (F.G.)
| | - Salvatore Annunziata
- UOC Medicina Nucleare, TracerGLab, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy;
| | - Barbara Muoio
- Department of Medicine and Oncology, Institute of Southern Switzerland, Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland;
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Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplastic proliferations showing different morphological features, immunophenotype, molecular background, clinical presentation, and outcome. They can virtually originate in every organ of the human body and their classification is not uniform among different sites. Indeed, as they have historically been classified according to the organ in which they primarily arise, the different nomenclature that has resulted have created some confusion among pathologists and clinicians. Although a uniform terminology to classify neuroendocrine neoplasms arising in different systems has recently been proposed by WHO/IARC, some issues remain unsolved or need to be clarified. In this review, we discuss the lights and shadows of the current WHO classifications used to define and characterize NENs of the pituitary gland, lung, breast and those of the head and neck region, and digestive and urogenital systems.
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Affiliation(s)
- Stefano La Rosa
- Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland.
- Institut Universitaire de Pathologie, CHUV, 25 rue du Bugnon, CH-1011, Lausanne, Switzerland.
| | - Silvia Uccella
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy
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45
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Pearson JD, Huang K, Pacal M, McCurdy SR, Lu S, Aubry A, Yu T, Wadosky KM, Zhang L, Wang T, Gregorieff A, Ahmad M, Dimaras H, Langille E, Cole SPC, Monnier PP, Lok BH, Tsao MS, Akeno N, Schramek D, Wikenheiser-Brokamp KA, Knudsen ES, Witkiewicz AK, Wrana JL, Goodrich DW, Bremner R. Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity. Cancer Cell 2021; 39:1115-1134.e12. [PMID: 34270926 PMCID: PMC8981970 DOI: 10.1016/j.ccell.2021.06.016] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/17/2020] [Accepted: 06/24/2021] [Indexed: 12/13/2022]
Abstract
Cancer heterogeneity impacts therapeutic response, driving efforts to discover over-arching rules that supersede variability. Here, we define pan-cancer binary classes based on distinct expression of YAP and YAP-responsive adhesion regulators. Combining informatics with in vivo and in vitro gain- and loss-of-function studies across multiple murine and human tumor types, we show that opposite pro- or anti-cancer YAP activity functionally defines binary YAPon or YAPoff cancer classes that express or silence YAP, respectively. YAPoff solid cancers are neural/neuroendocrine and frequently RB1-/-, such as retinoblastoma, small cell lung cancer, and neuroendocrine prostate cancer. YAP silencing is intrinsic to the cell of origin, or acquired with lineage switching and drug resistance. The binary cancer groups exhibit distinct YAP-dependent adhesive behavior and pharmaceutical vulnerabilities, underscoring clinical relevance. Mechanistically, distinct YAP/TEAD enhancers in YAPoff or YAPon cancers deploy anti-cancer integrin or pro-cancer proliferative programs, respectively. YAP is thus pivotal across cancer, but in opposite ways, with therapeutic implications.
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Affiliation(s)
- Joel D Pearson
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON M5T 3A9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Katherine Huang
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
| | - Marek Pacal
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
| | - Sean R McCurdy
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
| | - Suying Lu
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
| | - Arthur Aubry
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON M5T 3A9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Tao Yu
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
| | - Kristine M Wadosky
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Letian Zhang
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Tao Wang
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Alex Gregorieff
- Department of Pathology, McGill University and Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, ON H4A 3J1, Canada
| | - Mohammad Ahmad
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
| | - Helen Dimaras
- Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON M5T 3A9, Canada; The Department of Ophthalmology & Vision Sciences, Child Health Evaluative Sciences Program, and Center for Global Child Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Clinical Public Health, Dalla Lana School of Public Health, The University of Toronto, Toronto, ON M5T 3M7, Canada
| | - Ellen Langille
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Susan P C Cole
- Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, ON K7L 3N6, Canada
| | - Philippe P Monnier
- Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON M5T 3A9, Canada; Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, ON M5T 2S8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Benjamin H Lok
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Ming-Sound Tsao
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Nagako Akeno
- Division of Pathology & Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Daniel Schramek
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Kathryn A Wikenheiser-Brokamp
- Division of Pathology & Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; The Perinatal Institute Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Erik S Knudsen
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Agnieszka K Witkiewicz
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Jeffrey L Wrana
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - David W Goodrich
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Rod Bremner
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON M5T 3A9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
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Becker A, Schalin-Jäntti C, Itkonen O. Comparison of Serum and Urinary 5-Hydroxyindoleacetic Acid as Biomarker for Neuroendocrine Neoplasms. J Endocr Soc 2021; 5:bvab106. [PMID: 34195530 PMCID: PMC8237842 DOI: 10.1210/jendso/bvab106] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Indexed: 11/19/2022] Open
Abstract
CONTEXT Patients with serotonin-secreting neuroendocrine neoplasms (NENs) have increased serum 5-hydroxyindoleacetic acid (5HIAA) concentrations. Serum 5HIAA thus serves as a biomarker in NEN. OBJECTIVE To evaluate an improved tandem mass spectrometric serum 5HIAA assay for diagnosis and follow-up of NEN in a clinical cohort. DESIGN A retrospective study during 2016-2018 at the Diagnostic Center and Department of Endocrinology at Helsinki University Hospital, Finland. METHODS Detailed patient data was obtained from 116 patients. Serum 5HIAA was analyzed by 2 different liquid chromatography with tandem mass spectrometry (LC-MS/MS) assays with samples prepared either by protein precipitation or solid phase extraction. Twenty-four-hour urine 5HIAA samples (n = 33) were analyzed by amperometric LC, and the results were compared. Specificity and sensitivity were calculated by receiver operating characteristic (ROC) analysis. RESULTS We achieved 5 to10 000 nmol/L linearity and ≤2.5% variation with our new serum 5HIAA assay. In ROC analysis, the area under curve was 85% by serum assays [upper reference limit (URL) value 123 nmol/L] and 88% by the 24-h urine 5HIAA assay (URL value of 47.1 µmol), respectively. A difference (P < 0.001) between patients with active NEN and patients in remission was found by all 5HIAA assays. CONCLUSION Serum 5HIAA by LC-MS/MS after protein precipitation performs equally well for the diagnosis of NEN as urinary 5HIAA LC assay. The outcome and sensitivity for serum and 24-h urine assays are convergent. Due to much more reliable and convenient sampling, we recommend serum instead of 24-h urine 5HIAA for diagnosis and follow-up of NEN patients.
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Affiliation(s)
- Anna Becker
- HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Camilla Schalin-Jäntti
- Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Outi Itkonen
- HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Winer I, Kim C, Gehrig P. Neuroendocrine tumors of the gynecologic tract update. Gynecol Oncol 2021; 162:210-219. [PMID: 34023130 DOI: 10.1016/j.ygyno.2021.04.039] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 04/29/2021] [Indexed: 10/21/2022]
Affiliation(s)
- I Winer
- Division of Gynecologic Oncology, Department of Oncology, Wayne State University, Detroit, MI, USA.
| | - C Kim
- New York Cancer Blood Specialists, Patchogue, NY, USA; Division of Hematology/Oncology, Department of Medicine, Stony Brook University Hospital, Stony Brook, NY, USA
| | - P Gehrig
- Department of Obstetrics & Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
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Caruso G, Sassu CM, Tomao F, Di Donato V, Perniola G, Fischetti M, Benedetti Panici P, Palaia I. The puzzle of gynecologic neuroendocrine carcinomas: State of the art and future directions. Crit Rev Oncol Hematol 2021; 162:103344. [PMID: 33933568 DOI: 10.1016/j.critrevonc.2021.103344] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 04/05/2021] [Accepted: 04/25/2021] [Indexed: 10/21/2022] Open
Abstract
Primary gynecologic neuroendocrine carcinomas (gNECs) are a heterogeneous spectrum of rare and highly aggressive neoplasms, accounting for about 2% of all gynecologic malignancies, which mostly resemble the small cell lung carcinoma (SCLC). Due to the lack of standardized treatment guidelines, their management poses a noteworthy clinical challenge. Currently, cumulative data retrieved from the management of SCLC and from retrospective studies supports a multimodality strategy, based on surgery, chemotherapy, and radiotherapy. Nevertheless, the prognosis remains poor and recurrences are extremely frequent. Hence, there is an urgent need for novel treatment options and promising molecular targets. Recently, there has been an increasing interest on the potential role of immune checkpoint inhibitors, especially in the recurrent setting. However, only scant evidence exists and there is still a long road ahead. A solid collaboration between gynecologists and oncologists worldwide is required to improve the treatment of these puzzling tumors.
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Affiliation(s)
- Giuseppe Caruso
- Department of Maternal and Child Health and Urological Sciences, University of Rome "Sapienza", Policlinico "Umberto I", Rome, Italy.
| | - Carolina Maria Sassu
- Department of Maternal and Child Health and Urological Sciences, University of Rome "Sapienza", Policlinico "Umberto I", Rome, Italy
| | - Federica Tomao
- Department of Gynecologic Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Violante Di Donato
- Department of Maternal and Child Health and Urological Sciences, University of Rome "Sapienza", Policlinico "Umberto I", Rome, Italy
| | - Giorgia Perniola
- Department of Maternal and Child Health and Urological Sciences, University of Rome "Sapienza", Policlinico "Umberto I", Rome, Italy
| | - Margherita Fischetti
- Department of Maternal and Child Health and Urological Sciences, University of Rome "Sapienza", Policlinico "Umberto I", Rome, Italy
| | - Pierluigi Benedetti Panici
- Department of Maternal and Child Health and Urological Sciences, University of Rome "Sapienza", Policlinico "Umberto I", Rome, Italy
| | - Innocenza Palaia
- Department of Maternal and Child Health and Urological Sciences, University of Rome "Sapienza", Policlinico "Umberto I", Rome, Italy
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Neuroendocrine tumor (NET) of the vagina in the light of WHO 2020 2-tiered grading system: clinicopathological report of the first described case. Virchows Arch 2021; 480:687-691. [PMID: 33881615 DOI: 10.1007/s00428-021-03078-6] [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] [Received: 01/25/2021] [Revised: 03/04/2021] [Accepted: 03/07/2021] [Indexed: 10/21/2022]
Abstract
Up to now, a vaginal well-differentiated neuroendocrine tumor (NET) has never been well described in the literature. A 2-cm vaginal nodule morphologically revealed a proliferation of mild to moderately atypical eosinophilic epithelioid cells, without tumor cell necrosis. Immunohistochemistry (IHC) showed positivity for CK (AE1/AE3), chromogranin A, and synaptophysin, focal positivity for CDX2, and negativity for PAX8 and TTF1. Metastatic origin was excluded by imaging and the morphological context with benign mucinous glands as present in the surgical resection specimen. Considering mitotic index and Mib1/Ki67 (8 mitoses/2 mm2; >20%), the case was diagnosed as vaginal NET G2 in the light of the WHO 2020 grading system for the gynecologic neuroendocrine neoplasms (NENs). Ranges of Mib1-Ki67 are not yet standardized. Currently, mitotic index and tumor cell necrosis were taken into consideration for the grading system. Gynecologic NENs still represent a diagnostic challenge. A clinico-radiologic workup and an appropriate diagnostic path ruling out the metastatic nature are mandatory to achieve the diagnosis.
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50
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Fernandez CJ, Agarwal M, Pottakkat B, Haroon NN, George AS, Pappachan JM. Gastroenteropancreatic neuroendocrine neoplasms: A clinical snapshot. World J Gastrointest Surg 2021; 13:231-255. [PMID: 33796213 PMCID: PMC7993001 DOI: 10.4240/wjgs.v13.i3.231] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/17/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Our understanding about the epidemiological aspects, pathogenesis, molecular diagnosis, and targeted therapies of neuroendocrine neoplasms (NENs) have drastically advanced in the past decade. Gastroenteropancreatic (GEP) NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors. Most NENs are well-differentiated, and slow growing. Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin, glucagon, vasoactive intestinal polypeptide, gastrin, somatostatin, adrenocorticotropin, growth hormone releasing hormone, parathyroid hormone-related peptide, serotonin, histamine, and 5-hydroxy indole acetic acid (5-HIAA). Biomarkers such as pancreatic polypeptide, human chorionic gonadotrophin subunits, neurotensin, ghrelin, and calcitonin are used in the diagnosis of non-functional NENs. 5-HIAA levels correlate with tumour burden, prognosis and development of carcinoid heart disease and mesenteric fibrosis, however several diseases, medications and edible products can falsely elevate the 5-HIAA levels. Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs. Emerging novel biomarkers include circulating tumour cells, circulating tumour DNA, circulating micro-RNAs, and neuroendocrine neoplasms test (NETest) (simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood). NETest has high sensitivity (85%-98%) and specificity (93%-97%) for the detection of gastrointestinal NENs, and is useful for monitoring treatment response, recurrence, and prognosis. In terms of management, surgery, radiofrequency ablation, symptom control with medications, chemotherapy and molecular targeted therapies are all considered as options. Surgery is the mainstay of treatment, but depends on factors including age of the individual, location, stage, grade, functional status, and the heredity of the tumour (sporadic vs inherited). Medical management is helpful to alleviate the symptoms, manage inoperable lesions, suppress postoperative tumour growth, and manage recurrences. Several molecular-targeted therapies are considered second line to somatostatin analogues. This review is a clinical update on the pathophysiological aspects, diagnostic algorithm, and management of GEP NENs.
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Affiliation(s)
- Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Mayuri Agarwal
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry 605006, India
| | - Nisha Nigil Haroon
- Department of Endocrinology and Internal Medicine, Northern Ontario School of Medicine, Sudbury P3E 2C6, Ontario, Canada
| | - Annu Susan George
- Department of Medical Oncology, VPS Lakeshore Hospital, Cochin 682040, Kerala, India
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, PR2 9HT, Preston, The University of Manchester, Oxford Road M13 9PL, Manchester Metropolitan University, All Saints Building M15 6BH, Manchester, United Kingdom
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